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Sheridan Grant

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Sheridan is a writer from Hamilton, Ontario. She has a passion for writing about what she loves and learning new things along the way. Her topics of expertise include skincare and beauty, home decor, and DIYing.

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About Thesis Nootropics

Hands up if you guzzle five coffees a day to stay awake, have tried all the supplements in the book desperate to improve your headspace, and aren’t interested in prescribed medications. Designed to increase focus , Thesis nootropics might be for you. 

Thesis offers a customized blend of ingredients designed to optimize your cognitive function , with personalized details that tackle your specific needs. Nootropics boost brain performance in the same way a stimulant would, without the common negative effects. 

A study published in the Journal of Alzheimer’s Disease found that nootropics may help improve cognitive function in people with Alzheimer’s disease.

Interested in finding out more about the brand and how it works? Leaf through our Thesis Nootropics review. We’ll be your guide through the company and the process, as well as details on the treatments, highlights from customer reviews, answers to important FAQs, and more, to help you decide if it’s worth the try.

Pros and Cons

• Multiple cognitive benefits: Thesis Nootropics offers a variety of blends that cater to multiple aspects of cognitive function.
• Long-term effects: On top of short term benefits for daily life, Thesis nootropics ingredients are designed to impact the brain in the long-term.
• Personalized recommendations: Thesis Nootropics makes personalized recommendations based on your goals and unique brain chemistry.
• Potential side effects: The most common side effects to watch out for when you start taking Thesis Nootropics include heartburn, headaches, confusion, dizziness, loss of appetite, and digestive issues.
• Need to stop taking if issues arise: If you experience a headache or an upset stomach that won’t go away while taking their nootropics, Thesis recommends that you stop taking them.

What is Thesis Nootropics?

Nootropics are nutrient compounds and substances that are known to improve brain performance , such as caffeine and creatine. They help with issues that affect motivation, creativity, mood, memory, focus, and cognitive processing.

Nootropics are the ideal addition to an already healthy lifestyle that consists of exercise, proper nutrition, and enjoyable activities.  Thesis nootropics are carefully formulated to target specific needs, ranging from energy to creativity. The brand focuses on safety, ensuring that all supplements adhere to FDA guidelines and go through multiple clinical trials. 

How Thesis Nootropics Works

With all that being said, you may be wondering how Thesis provides users with an option that is specific to their needs. Fortunately, the process is simple and hassle free. Here’s how it works:

• Take the Thesis nootropics quiz
• Answer questions about your basic information
• Receive personalized recommendations 
• Get your starter kit for $120 , or $79 monthly when you subscribe 

After that, you’ll select one formula to take each week, taking one day off in between each different option. You’ll also track your results in the daily journal over the month to see how they affect your daily life. 

From there, it operates as a subscription service. Users will be able to optimize their next shipment by telling the brand which formulas worked best.

If you don’t like any of the blends in your box, let the company know and they’ll switch it for something that’s a better fit for your lifestyle, genetics, and goals.

Thesis Nootropics Ingredients

Thesis Nootropics is a brand that offers personalized nootropics designed to enhance cognitive function and overall brain health. Their blends contain a variety of ingredients that are carefully chosen for their cognitive-boosting properties. Here are some of the key ingredients in Thesis Nootropics:

• Cognizin (Citicoline) : Cognizin is a type of choline that is known for its ability to enhance cognitive function, including memory and focus.
• L-Theanine : L-Theanine is an amino acid that is found in green tea, and is known for its ability to promote relaxation and reduce stress and anxiety.
• Lion’s Mane Mushroom : Lion’s Mane Mushroom is a type of medicinal mushroom that is believed to have cognitive-boosting properties, including improved memory and focus.
• Rhodiola Rosea : Rhodiola Rosea is an adaptogenic herb that is known for its ability to reduce stress and fatigue, and improve mental clarity and cognitive function.
• Ashwagandha : Ashwagandha is an adaptogenic herb that is known for its ability to reduce stress and anxiety, and improve memory and cognitive function.
• Phosphatidylserine : Phosphatidylserine is a type of phospholipid that is found in high concentrations in the brain, and is believed to support cognitive function, including memory and focus³
• Alpha-GPC : Alpha-GPC is a type of choline that is known for its ability to enhance cognitive function, including memory and focus.
• TAU (uridine): TAU is a blend of uridine, choline, and DHA, which is believed to support brain health and cognitive function.
• Artichoke extract : Artichoke extract is believed to enhance cognitive function by increasing levels of acetylcholine, a neurotransmitter that is important for memory and learning.
• Dynamine : Dynamine is a type of alkaloid that is believed to enhance cognitive function by increasing levels of dopamine, a neurotransmitter that is important for mood and motivation.

Overall, the ingredients in Thesis Nootropics are carefully chosen for their cognitive-boosting properties, and are designed to work together to enhance overall brain health and cognitive function.

Thesis Nootropics Health Benefits

Thesis Nootropics is a brand that offers personalized nootropics designed to enhance cognitive function and overall brain health. Their blends contain a variety of ingredients that are carefully chosen for their cognitive-boosting properties, and offer numerous health benefits. Here are some of the health benefits of Thesis Nootropics:

• Increased cognitive energy : One of the key benefits of Thesis Nootropics is increased cognitive energy, which can help improve productivity, mental alertness, and motivation, as it contains cognizin .
• Enhanced mental clarity : Another benefit of Thesis Nootropics is enhanced mental clarity,given from Lion’s Mane Mushroom which can help reduce brain fog and improve focus.
• Improved memory and learning abilities : Thesis Nootropics contains ingredients that are believed to improve memory and learning abilities, like Phosphatidylserine , which can help users retain information more effectively.
• Elevated mood : Thesis Nootropics may help elevate mood and reduce symptoms of anxiety and depression, thanks to ingredients like L-Theanine and Ashwagandha .
• Lowered stress levels : The adaptogenic herbs in Thesis Nootropics, such as Rhodiola Rosea and Ashwagandha , are known for their ability to lower stress levels and promote relaxation.
• Boosted focus : Thesis Nootropics contains ingredients like Alpha-GPC and Artichoke extract , which are believed to boost focus and concentration.

While Thesis Nootropics offers numerous health benefits, it’s important to note that the long-term effects of nootropics are not yet fully understood and more research is needed.

3 Thesis Nootropics Bestsellers

Thesis energy review.

If you’re constantly struggling to keep up with the demands of your busy life, it might be time to try a natural energy booster like Thesis Energy. This powerful nootropic blend is specifically designed to increase energy, overcome fatigue, and build mental stamina.

Thesis Energy is caffeine-free, making it a great option for those who are sensitive to caffeine or looking for a natural alternative to traditional energy drinks. The Energy formulation is designed to help improve focus and mental clarity, increase cognitive energy, and reduce fatigue. Whether you’re facing a busy day at work, recovering after a night of poor sleep, or gearing up for an intense workout, Thesis Energy can help you power through.

Each ingredient in Thesis Energy is carefully chosen for its energy-boosting properties. The specific ingredients can vary depending on your needs, but they work together to help increase energy, improve mental clarity, and reduce fatigue.

To get the most out of Thesis Energy, take it every morning on an empty stomach. You can also take it again after lunch if you need an extra boost. It’s designed to help you tackle busy, hectic days, recover from poor sleep, and power through intense workouts.

If you’re tired of relying on coffee and energy drinks to get through the day, it might be time to give Thesis Energy a try. Check availability and start boosting your energy naturally today!

Thesis Creativity

If you’re someone who struggles with creativity or finds yourself feeling stuck in your creative endeavors, Thesis Creativity may be worth considering. This nootropic supplement is designed to help spark inspiration, enhance verbal fluency, and boost confidence in your own great ideas.

So what’s in Thesis Creativity? The ingredients may vary depending on your specific needs, but these ingredients work together to support stress management, memory function, mood regulation, and energy production.

By supporting stress management, memory function, and mood regulation, Thesis Creativity can help free up mental space for more creative thinking. Additionally, the caffeine and L-theanine combo can provide a boost of energy and focus without the jitters and crash that can come with caffeine alone.

To get the most out of Thesis Creativity, it is recommended to take it every morning on an empty stomach and again after lunch if you need an extra boost. This nootropic blend is particularly helpful for brainstorming and creative thinking, writing and creative projects, and public speaking and social situations.

As with any nootropic supplement, it’s important to note that the long-term effects of Thesis Creativity are not yet fully understood and more research is needed. It’s always a good idea to speak with a healthcare professional before adding any new supplements to your routine.

In summary, if you’re looking for a little extra help in the creativity department, Thesis Creativity may be a valuable addition to your nootropic lineup. Its unique blend of ingredients can help support mental clarity, mood regulation, and energy production, making it a valuable tool for any creative individual.

Thesis Logic

If you’ve been having trouble with your memory lately, such as forgetting what you had for lunch yesterday or struggling to recall common words, then Thesis Logic may be just what you need. This formula is designed to help enhance your processing speed, boost your memory, and deepen your thinking.

Thesis Logic is caffeine-free, making it a great option for those who are sensitive to caffeine. The formula is ideal for use during deep, focused work, complex problem-solving, research projects, and completing tedious tasks.

Taking Thesis Logic is easy – simply take it every morning on an empty stomach, and take it again after lunch if you need an extra boost. By incorporating Thesis Logic into your daily routine, you may notice improvements in your cognitive function and overall mental performance.

Who Is Thesis Nootropics For? 

Thesis nootropics are designed for a number of different specific needs, including anyone who wants to focus better, have more energy, and maintain mental clarity. All in all, the products are specifically formulated to improve day to day life and target your specific needs .

Thesis Nootropics Side Effects

While Thesis nootropics are designed to enhance cognitive performance and provide a range of benefits, it’s important to be aware of the potential side effects that can occur. As with any supplement, individual reactions can vary, and some people may experience side effects while others may not.

Some of the potential side effects of Thesis nootropics include:

• Insomnia : Some nootropics contain caffeine or other stimulants that can disrupt sleep patterns and lead to difficulty falling asleep or staying asleep.
• Blurry vision : Certain nootropics, such as those containing alpha GPC, have been linked to temporary blurry vision.
• High blood pressure : Stimulant-based nootropics can increase blood pressure, which can be dangerous for people with hypertension or other heart conditions.
• Fast heart rate : Similarly, stimulants can also increase heart rate, leading to palpitations or a rapid pulse.
• Circulation problem s: Certain nootropics, such as vinpocetine, can affect blood flow and circulation, leading to issues like dizziness, nausea, or headaches.
• Addiction : Some nootropics, such as those containing racetams, have been associated with the potential for addiction or dependence if used long-term.

It’s important to remember that not all nootropics will produce these side effects, and the severity of any reactions will depend on individual factors such as dosage, duration of use, and underlying health conditions. However, it’s always wise to discuss any potential risks with a healthcare professional before starting any new supplement regimen.

Additionally, it’s important to follow dosage instructions carefully and not to exceed recommended amounts, as this can increase the risk of side effects. By being mindful of potential risks and using nootropics responsibly, users can reap the benefits of these supplements without experiencing adverse effects.

Thesis Nootropics Reviews: What Do Customers Think?

At this point in our Thesis nootropics review, it’s time to turn to what customers are saying. So, we sourced testimonials from the brand’s website, Reddit, and ZenMasterWellness. And spoiler alert, the Thesis nootropics reviews we came across have nothing but good things to say.

On takethesis.com , the brand earns 4.4/5 stars out of 7,956 reviews. One patron describes their particular blend as the perfect alternative to prescription meds :

“ I have been off stimulants for months now and these formulas are far superior. My husband and daughter both noticed the change and said I have been more productive, focused, less anxious, and more “thinking outside the box”. I have tried for years to get off stims and nothing would work .”

On Reddit, many reviewers share similar sentiments about how effective the products are. One buyer shares that they tried tons of different nootropics on the market, and Thesis stands out amongst the crowd . 

On ZenMasterWellness, one reviewer states that their blend provided the exact results they were looking for :

“ They offer notable improvements to how well I’m able to focus, stay on task, and grind when it’s time to grind. In practice, this usually looks like a clearer mind and an improved ability to just… chill. With the Clarity and Creativity blends, in particular, I just feel leveled out .”

Backed by clinical trials and real customer experiences, Thesis stands out in the world of nootropics and supplements. The personalized selections prove effective, while the quality ingredients live up to expectations. 

Is Thesis Nootropics Legit?

If you’re wondering if this brand offers products that are too good to be true, this Thesis nootropics review is here to say that it is the real deal .

The brand is backed by numerous clinical trials, which highlight how 86% of customers reported improvements in a wide range of cognitive challenges, while 89% noticed an improvement in their ability to reduce stress and maintain energy.

Is Thesis Nootropics Worth It?

Thesis is an appealing choice in the world of nootropics because it provides a completely customized selection based on your needs and goals. Plus, the ingredients are potent and ensure the best effects—and you only end up paying for the benefits you actually need.

With that in mind, this Thesis nootropics review deems the brand worth the try.

Alternatives

Here are some alternatives to Thesis Nootropics that you might find interesting:

• Mind Lab Pro – This nootropic supplement is designed to improve cognitive function and mental performance. It contains 11 ingredients that work together to enhance memory, focus, and overall brain health.
• Thorne Supplements : If you’re looking for high-quality, science-based supplements, Thorne is a great choice. Their products are designed with the latest research in mind and are rigorously tested for quality and purity. Some of their popular offerings include multivitamins, protein powders, and omega-3 supplements.
• WeAreFeel Supplements : WeAreFeel is a supplement brand that offers a variety of products designed to support different aspects of your health. Their supplements are vegan-friendly and free from artificial colors, flavors, and preservatives. Some of their popular offerings include multivitamins, probiotics, and omega-3 supplements.
• Neuro Gum : If you’re looking for a quick and easy way to boost your focus and energy levels, Neuro Gum is a great option. This gum is infused with caffeine and other natural ingredients that can help improve mental clarity and alertness. Plus, it’s sugar-free and comes in a variety of delicious flavors.
• Neuriva Plus : Neuriva Plus is a brain supplement that’s designed to improve memory, focus, and cognitive performance. It contains a blend of natural ingredients, including coffee fruit extract and phosphatidylserine, that have been shown to support brain health. If you’re looking for a natural way to boost your cognitive function, Neuriva Plus is worth considering.

Thesis Nootropics Promotions & Discounts 

There aren’t currently any Thesis promos or discounts available. That being said, if you subscribe for recurring shipments of your recommended products, you’ll save $40 monthly .

Where to Buy Thesis Nootropics

At the time of this Thesis nootropics review, the products are exclusively available on the brand’s website, takethesis.com .

Is Thesis Nootropics vegan?  

Thesis nootropics are made with only vegan ingredients . That being said, while the brand has taken precautions to protect against cross contamination, the products are not certified vegan.

Is Thesis Nootropics gluten-free? 

On top of being vegan, Thesis products are made without gluten, eggs, or nuts . Again, while the brand strives to protect users against cross contamination, the products are not certified gluten free. 

What is Thesis Nootropics’ Shipping Policy?

If you’re anxiously awaiting your order from this Thesis nootropics review, you’ll be happy to hear that the company offers speedy shipping, sending orders out within 1 business day. After that, packages should arrive within only 1-3 business days . Costs are calculated at checkout.

At this time, Thesis is not able to offer international shipping. This Thesis nootropics review recommends following the brand on social media and signing up for the newsletter to stay up to date with shipping policies. 

What is Thesis Nootropics’ Return Policy?

If you find that your Thesis formula isn’t working out, the company requests that you contact them to make changes and adjustments to ensure you are able to receive the proper help.

If you would still like to make a return, follow these simple steps for a refund:

• Submit your refund request
• Ship the items back within 30 days of the original delivery
• Send an email with your tracking number to the brand
• Return any remaining product in their original packaging to: 

Thesis Returns 902 Broadway

6th Floor New York, NY 

Once your return has been received, a refund will be processed and email confirmation will be sent. It’s also important to note that the brand can only refund one month’s supply per customer and return shipping is the customer’s responsibility. 

How to Contact Thesis Nootropics

We hope you enjoyed this Thesis nootropics review! If you have any further questions about the brand or its products, you can contact them using the following methods:

• Call 1 (646) 647-3599
• Email [email protected]

902 Broadway Floor 6 New York, NY 10010

If you’re looking for other ways to boost your productivity via supplements, check out these other brands we’ve reviewed:

Thorne Supplements Review

WeAreFeel Supplements Review

Neuro Gum Review

Neuriva Plus Review

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Thesis stands out in the wellness industry with its personalized nootropic supplements, designed to cater to the individual’s specific cognitive needs. It has been pushed by health and wellness celebrities, causing a wave of popularity.

Do Thesis nootropics live up to the hype?

• Variety Of Blends: Various nootropic blends based on individual brain chemistry, maximizing effectiveness for each user.
• Strong Advocacy and Support: Gained endorsements from notable wellness advocates and public figures, like Andrew Huberman, enhancing credibility.
• Limited Clinical Research: While the company plans clinical trials, the current scientific backing may be limited.
• Price: The ongoing cost of customized nootropics may be higher than standard off-the-shelf supplements or medications.
• Dependence on Self-Reporting: The effectiveness of blends relies partly on user feedback, which may not always be accurate or consistent.
• Many Underdosed Ingredients: As you’ll read below, many ingredients are dosed below what was used in human clinical trials.

Quick Verdict

Thesis has a range of suitable nootropic blends to cater to many needs.

However, our #1 nootropic of choice is Nooceptin. It’s designed for long-term brain changes, not short-term boosts in mental performance.

What Is Thesis Nootropics?

Thesis Nootropics is a company specializing in customized cognitive performance products. It was founded by Dan Freed in 2017.

Freed’s personal challenges with focusing, which he faced from a young age, led him to discover nootropics.

This personal journey of transformation through nootropics inspired him to create Thesis, aiming to help others find the right combination of nootropic ingredients that work for them.

The company’s unique approach involves allowing customers to experiment with high-quality nootropic ingredients to maximize results systematically.

Thesis has gained popularity primarily through word-of-mouth and a strong focus on personalization.

The company has raised over $13.5 million in funding and is reportedly profitable with a robust growth trajectory.

Thesis has garnered support from health and wellness advocates like Dr. Andrew Huberman, Rich Roll, Kevin Love, and Kate Bock.

Thesis Nootropics

Customized Blends For Cognitive Enhancement

Take the quiz and see which blends are right for you.

Thesis Nootropic Ingredients

Thesis have six unique blends designed to target various aspects of cognitive function. What’s similar between them is the option to include or exclude caffeine and L-theanine. The caffeine and l-theanine combination is the most potent instant nootropic, making each blend effective.

The caffeine L-theanine stack benefits physical and cognitive function. Some advantages include faster reaction time, faster visual processing speed, better working memory, increased awareness, and less tiredness and mental fatigue [1] [2] .

The research employs a 2:1 L-theanine to caffeine ratio, which Thesis has followed. Since this stack is available in every blend, I won’t include it in the ingredients breakdown below.

Thesis Clarity Blend

Alpha gpc (speculative).

Alpha GPC, a choline-containing phospholipid, improves cognitive function in neurological conditions like dementia [3] .

Research indicates it enhances memory and attention and may support brain health. Clinical trials show it can improve cognitive performance, especially when combined with other treatments like donepezil [4] .

It’s generally well-tolerated and safe. Alpha GPC increases acetylcholine levels in the brain, which is essential for memory and learning [5] .

It’s used both as a medicine and a nutritional supplement. Studies suggest Alpha GPC effectively boosts cognitive functions, particularly in adult-onset dementia disorders [6] .

Thesis Clarity Blend contains 500 mg, which is more than any other nootropic available.

Lions Mane Mushroom (Speculative)

The Lion’s Mane mushroom (Hericium erinaceus) includes chemicals that stimulate nerve growth factor (NGF) synthesis, which is necessary for nerve cell proliferation and differentiation [7] .

According to research, Lion’s Mane improves cognitive abilities, particularly memory and brain cell regeneration [8] .

It is renowned for its neuroprotective qualities, which may be effective in treating illnesses such as Alzheimer’s disease and cognitive impairment [9] .

Brain functioning, memory, and mood improvements have been linked to regular ingestion [10] .

While the mushroom does not directly improve cognitive skills, it does increase NGF, which improves brain health [11] . The dosage varies but is generally well-tolerated and has few negative effects.

Thesis Clarity contains 500 mg of Lions Mane, which may give a long-term nootropic effect.

Mycelium is typically avoided since the active chemicals are found in the primary mushroom. Jeff Chilton, a long-time mushroom researcher, discusses this in the podcast below:

Camellia Sinensis Tea Leaf (Speculative)

Camellia Sinensis, commonly known as tea, exhibits varying neuropharmacological effects based on the part of the plant used.

Seed extracts tend to be more stimulating, enhancing motor functions and showing potential as an antidepressant without causing drowsiness.

Leaf extracts, on the other hand, tend to produce a calming effect on the mind and mood. Both seeds and leaves have shown positive results in various tests assessing motor function and behavior in animal models [12] .

The study suggests these parts of the Camellia Sinensis plant have potential as cognitive enhancers, warranting further research, especially on seed extracts for their mode of action and possible new beneficial compounds.

I couldn’t find any human studies for this ingredient, so I can’t give you an efficacious dose range. But Thesis Clarity contains 278 mg of Camellia Sinensis Tea Leaf.

Dihydroxyflavone

Dihydroxyflavone research is all performed in rodents, so extrapolating to humans is rather challenging. 7,8-Dihydroxyflavone (7,8-DHF) is a compound that acts as an agonist for the TrkB receptor, which is associated with brain-derived neurotrophic factor (BDNF).

BDNF is crucial for neuronal survival and brain plasticity. Studies have shown that 7,8-DHF can improve memory and cognitive functions [13] .

It enhanced memory formation in healthy rats, and in Alzheimer’s disease mouse models, it improved spatial memory [14] .

Further, 7,8-DHF has been shown to counteract aging-related cognitive impairments in rats, improving spatial memory and synaptic plasticity in the hippocampus [15] .

This suggests that 7,8-DHF is a potential therapeutic agent for memory impairment and dementia, at least in rodents.

Thesis Energy Blend Ingredients

Citicoline is commonly mentioned in relation to memory enhancement. According to studies, 500 mg daily may improve episodic memory or the ability to recall personal experiences and specific events [16] .

According to other research, taking at least 500 mg of this supplement daily may provide cognitive benefits to healthy persons [17] .

The formulation of Thesis Energy Blend contains 300 mg of Citicoline. This dose may not achieve the full potential seen in studies proposing a higher dose.

Mango leaf extract, rich in the polyphenolic compound mangiferin, shows promise in neuropharmacology due to its anti-inflammatory, antioxidant, and antidiabetic properties.

Studies indicate its potential in treating central complications associated with metabolic disorders like type 2 diabetes, which are risk factors for Alzheimer’s disease and vascular dementia [18] .

In animal models, mango leaf extract has demonstrated effects on reducing brain inflammation and spontaneous bleeding and improving cognitive functions [19] .

These findings suggest its utility in addressing symptoms of neurodegenerative diseases and cognitive impairments [20] .

Thesis Energy contains 300 mg of mango leaf.

Theacrine is a purine alkaloid similar to caffeine, found in the Camellia Kucha plant, and often included in dietary supplements.

Studies show that it can increase energy, focus, and cognitive performance, similar to caffeine, but without habituation [21] .

Theacrine’s impact on cognitive performance and physical endurance has been researched in athletes, indicating possible benefits in reaction time and endurance [22] .

It may work well alone or in combination with caffeine to enhance cognitive function and physical performance [23] .

Theacrine appears to be a promising supplement for improving mental alertness and physical capacity. Bear in mind the manufacturers of Theacrine fund some of these studies.

Thesis Energy contains 100 mg of Theacrine, which tends to be less than the dose used in these studies, suggesting it may have a weaker effect.

N-Acetyl Cysteine

N-acetyl cysteine (NAC) is explored for its potential to improve cognitive functions in psychosis and bipolar disorder due to its antioxidant, neurogenesis, and anti-inflammatory properties.

Studies show N-acetyl cysteine can improve working memory in psychosis [24] . However, results in bipolar disorder didn’t show significant cognitive improvements [25] .

Research indicates potential benefits for Alzheimer’s disease by promoting cognitive health and countering oxidative stress [26] .

The effectiveness of N-acetyl cysteine in various cognitive disorders still requires more targeted, larger studies to confirm its benefits [27] .

N-acetyl cysteine’s role is promising but not yet firmly established in cognitive enhancement.

In human trials, it seems a 600 – 2000 mg dose is needed for cognitive benefits. Thesis Energy contains 500 mg, being potentially underdosed.

Indian Trumpet Tree

Indian Trumpet Tree is known as Oroxylum indicum. In a 12-week study, older adults with memory complaints took 500 mg of Oroxylum indicum extract twice daily [28] .

Compared to a placebo, this supplementation led to improvements in episodic memory and numeric working memory. It also accelerated learning in location tasks.

However, there were no significant changes in other cognitive tests or overall cognitive and memory skills.

The study suggests that Oroxylum indicum, while well-tolerated, may primarily enhance specific memory functions.

Its potential effects could be linked to its antioxidant and anti-inflammatory properties and interactions with neurotransmitters like dopamine and GABA.

This is the only human study on the Indian Trumpet Tree, so more research is needed to fully understand its impact on cognitive health. Thesis Energy only contains 100 mg of this, making it potentially underdosed.

L-tyrosine, an amino acid, has been shown to increase dopamine levels in the brain. L-tyrosine supplementation has improved cognitive regulation, particularly in mentally demanding settings [29] .

It is especially helpful in improving cognitive flexibility, which is impacted by dopamine.

While L-Tyrosine’s promise for treating clinical problems and improving physical activity is limited, it is useful in stressful or cognitively taxing situations.

It has the greatest cognitive benefits when neurotransmitter activity is intact, but dopamine and norepinephrine levels are momentarily decreased [30] .

According to research, optimal doses for cognitive improvement begin at a minimum of 2 grams. That is more than six times the dose in Thesis Energy.

Thesis Creativity Blend Ingredients

Thesis Creativity contains 150 mg of Alpha GPC, yet their Clarity Blend contains 500 mg. I’m not sure why there is a large discrepancy, especially when 500 mg is likely a more efficacious dose.

Agmatine Sulfate

Currently, agmatine sulfate has only been tested in rodents. It is a central nervous system (CNS) neurotransmitter/neuromodulator that has been studied for its potential effects on stress-related conditions like depression, anxiety, and cognitive performance.

Research suggests that agmatine can have antidepressant and anxiolytic (anxiety-reducing) effects, possibly related to its influence on the nitric oxide pathway [31] .

It may reduce oxidative stress and corticosterone levels while increasing brain-derived neurotrophic factor (BDNF), which is beneficial for brain health.

Agmatine sulfate has been shown to be safe and well-tolerated in animal studies, with oral administration effectively increasing its levels in the brain [32] .

This indicates potential for therapeutic use in neurological disorders, though more research is needed to fully understand its effects and mechanisms.

Thesis Creativity contains 250 mg. In these studies, patients were administered 15-600 mg per kg, which is a much higher dose.

Panax Ginseng

Panax ginseng is available in two varieties: white ginseng and red ginseng. It has vasorelaxant and moderately hypotensive effects on nitric oxide generation in the body [33] .

It increases antioxidant enzyme activity and may prevent oxidative damage associated with aging in rats [34] .

Ginseng has shown promise in boosting memory, particularly in age-related cognitive decline, as well as in improving mental and physical resilience, reducing fatigue, and assisting the body in adapting to stress [35] .

Daily doses of 200 mg extract or 0.5 to 2 g dry root are recommended. It is not suggested for persons with acute asthma or hypertension because it may cause overstimulation and elevate blood pressure in excessive dosages.

Thesis Creativity has an effective dose of 200 mg, which may provide you with these mental performance benefits.

Ashwagandha Root

Ashwagandha is a traditional herbal remedy used to improve various health conditions. Animal studies have shown that it can increase blood cell counts, which might enhance aerobic capacity [36] .

It also demonstrates the potential to reduce oxidative stress and lipid peroxidation, which could be beneficial in treating disorders like tardive dyskinesia [37] .

Additionally, Ashwagandha has shown nootropic effects and might be useful in treating Alzheimer’s disease [38] . Recommended dosages range from 6 to 10 grams of ground roots or 100 to 1250 mg of extract daily [39] [40] .

It’s generally safe but should be used cautiously, especially in cases of hyperthyroidism or pregnancy. High doses can have sedative effects and may cause gastrointestinal issues.

Thesis Creativity contains 300 mg of Ashwagandha, which is within the recommended range for cognitive benefits.

Sceletium Tortuosum

Sceletium tortuosum, also known as Kanna, is traditionally used for its mood-enhancing properties. It’s been studied for its potential in treating cognitive and neurodegenerative disorders like Alzheimer’s and Parkinson’s [41] .

Research suggests its constituents could target enzymes and receptors relevant to these diseases, offering neuroprotective benefits like antioxidant activity [42] .

Additionally, Sceletium Tortuosum is known for its antidepressant and anxiolytic effects, promoting relaxation and well-being, which could be beneficial in managing stress, anxiety, and depression [43] .

The plant’s bioactive alkaloids are also being explored for commercial medicinal use.

The 25 mg dose in Thesis Creativity is the same as used within the human trials.

Thesis Motivation Blend Ingredients

L-phenylalanine.

L-phenylalanine is a vital amino acid and has been explored for its potential benefits in managing conditions like attention deficit disorder and depression.

In studies, doses of up to 1200 mg showed initial improvements in mood and attention in individuals with attention deficit disorder, but tolerance developed over 2-4 months [44] .

In another study involving depressed patients, a dosage range of 75–200 mg/day for 20 days led to significant improvements in 12 out of 20 patients [45] .

However, the effectiveness and safety of L-phenylalanine can vary, and it is used in the treatment of various conditions, including depression and arthritis, and even as part of addiction recovery [46] .

Thesis Motivation has a 500 mg dose, which may provide some of these benefits. Will it improve motivation? I’m not sure.

Methylliberine

Methylliberine is a purine alkaloid explored for its cognitive and mood-enhancing effects. Studies have shown it can improve concentration, motivation, and mood, especially when combined with caffeine.

Methylliberine also appears to positively affect energy levels and well-being without significantly impacting vital signs like heart rate and blood pressure [47] .

These findings suggest its potential as a nootropic supplement, particularly for enhancing cognitive function and mood in various contexts, such as gaming or in tactical scenarios [48] [49] .

However, it’s essential to consider the dosage and combination with other compounds like caffeine for optimal effects.

The 100 mg dose in Thesis Motivation aligns with the current research.

Vitamin B12 (Speculative)

Vitamin B12 is essential for cognitive health and may be linked to neurodegenerative diseases like Alzheimer’s and Parkinson’s.

Low levels of B12 are associated with cognitive impairment, but supplementation is only shown to be effective in improving cognition in cases of existing B12 deficiency [50] .

There is limited evidence that increasing B12 levels benefits people without B12 deficiency [51] .

B12’s impact on cognitive health may involve multiple mechanisms, including brain volume and function [52] . However, more extensive research is needed to fully understand its effects and potential as a cognitive enhancer.

Thesis Motivation contains 1000mcg. The research states that it may have no effect if you’re not Vitamin B12 deficient.

Forskolin (Speculative)

Forskolin has only been studied in rodents regarding cognitive function. Forskolin is an herbal extract that shows the potential to improve memory and reduce Alzheimer’s disease symptoms.

In studies, it restored nest-building and social behaviors in mice with Alzheimer-like symptoms, reduced amyloid plaque deposition, and regulated brain inflammation [53] .

Forskolin also influences memory and tau protein phosphorylation in the brain, which is relevant in Alzheimer’s [54] .

Additionally, forskolin has shown protective effects against Huntington’s disease-like neurodegeneration in rats by improving learning and memory and reducing oxidative stress [55] .

These findings indicate forskolin’s potential as a neuroprotective agent for certain neurological conditions, at least in rodents.

I’m skeptical whether 250 mg of Forskolin in Thesis Motivation will help you “feel” more motivated.

Artichoke (Speculative)

Artichoke extract is known for its prebiotic properties and promotes probiotic bacteria growth in the gut, potentially benefiting cognitive functions in mice [56] .

In elderly individuals with mild cognitive impairment, combining artichoke extract and aerobic training improved cognitive status and reduced blood glucose and insulin resistance [57] .

Artichoke varieties Spinoso Sardo and Romanesco Siciliano demonstrated antioxidant properties and potential protective effects against cardiovascular and neurodegenerative disorders, with Romanesco Siciliano showing higher antioxidant power [58] .

The 450 mg dose is well under the dose used in these studies.

Thesis Confidence Blend Ingredients

Saffron (speculative).

Saffron is traditionally used in herbal medicine and shows promise in improving cognitive function in individuals with Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI) [59] .

Research indicates that saffron’s effectiveness is comparable to common drugs used for these conditions without increasing side effects. It’s also well-tolerated in cognitively normal individuals [60] .

However, most current studies have a high risk of bias. More comprehensive, low-bias clinical trials are needed to confirm saffron’s potential as a treatment for cognitive impairments like AD and MCI.

All of the research used 30 mg of saffron daily. Thesis Confidence has 28 mg, and I’m unsure why they formulated it without the extra 2 mg.

Magnesium Bisglycinate

Magnesium is essential for brain functions and has been researched for its potential cognitive benefits. Magnesium is particularly effective in increasing brain magnesium levels and has shown promise in improving memory and cognition in healthy adults [61] .

However, its role in anxiety and mood disorders is less clear [62] .

Studies indicate magnesium may help reduce symptoms of depression, but results are not consistent across all mental health conditions [63] .

Further research is needed to conclusively establish magnesium’s effectiveness and appropriate use as a therapeutic supplement in various psychiatric and cognitive disorders [64] .

500 mg of magnesium may help if you’re deficient, but there’s no clear benefit to making you more confident.

Sage (Speculative)

Sage is known as Salvia and has been traditionally known to enhance memory. A recent study supports this, showing that acute ingestion of sage oil can significantly improve immediate word recall in healthy young adults [65] .

This suggests that sage may positively influence cognitive functions like memory, potentially due to its acetylcholinesterase inhibition activity in the brain.

However, this has not been replicated.

While historically used for various mental disorders, such as depression and age-related memory loss, contemporary research is needed to fully understand its benefits and potential as a cognitive enhancer.

Regardless of the 333 mg dose, this is one of the more speculative ingredients in all Thesis blends.

Sceletium Tortuosum (Speculative)

As mentioned in the Creativity Blend, Sceletium Tortuosum is known for its mood-enhancing properties. It is the same dose of 25 mg, which is used in human trials.

Magnolia Bark (Speculative)

Magnolia officinalis is commonly used in traditional medicine for mental disorders like anxiety and depression and shows potential as a nootropic supplement.

Studies have demonstrated that its ethanol extract can improve cognitive function and memory in stress-induced situations. It also exhibits anxiolytic properties, reducing anxiety-related behaviors in rats [66] .

The extract’s effectiveness is also evident in lowering stress-induced increases in corticosterone and tyrosine hydroxylase levels.

Moreover, Magnolia officinalis, especially its component honokiol, has neuroprotective effects and can regulate mood disorders by modulating GABA and CB1 receptors in rats [67] .

These are rodent studies, so it’s impossible to extrapolate to humans. Regardless, it’s included based on the mechanistic data with the theory of doing the same thing in humans with the 10 mg dose.

Ashwagandha Leaf & Root

The 120 mg of root and leaf ashwagandha may be enough to have a nootropic effect as the extract dose is between 100-1200 mg, as stated in the Creativity Blend section. However, this is root and leaf, and the main benefits are derived from the root.

Thesis Logic Blend Ingredients

Ginko biloba.

Ginkgo biloba is extracted from the leaves and fruit to improve cognitive function. Its compounds include antioxidants, enhance blood flow, and have anti-inflammatory properties.

Ginkgo biloba extract has been shown in animal studies to help with chronic brain difficulties by modifying inflammatory mediators and the cholinergic system [68] .

It has been shown in clinical trials to improve working memory and processing speed [69] . However, its usefulness in healthy people under the age of 60 is debatable [70] .

Typical daily doses vary from 120 to 300 mg. Although side effects are uncommon, they can include stomach irritation and headaches, which may cause blood to thin, affecting people on certain drugs.

Thesis Logic contains 160 mg of Ginkgo Biloba, which is within the recommended dosage range.

Theobromine

Theobromine is a compound found in chocolate and has been studied for its potential cognitive effects.

Research indicates that theobromine might have a lesser immediate nootropic effect compared to caffeine but could have neuroprotective benefits with long-term consumption, possibly reducing Alzheimer’s disease-related pathology [71] .

Further studies are needed to fully understand its impact on cognition.

Additionally, theobromine’s effects on mood and vigilance appear to be different from caffeine, with some studies suggesting it might not significantly influence these aspects in nutritionally relevant doses [72] .

However, combining theobromine with caffeine could modify its effects, potentially offering cognitive and mood benefits without significant blood pressure increases [73] .

More research is required to confirm theobromine’s cognitive and mood-related effects.

Thesis Logic contains 100 mg of theobromine, but it seems doses greater than 400 mg are needed to enhance cognition.

Phosphatidylserine

Phosphatidylserine is essential for proper brain function. Phosphatidylserine has been proven to be critical for maintaining nerve cell membranes and myelin, which is required for successful neurotransmission [74] .

Phosphatidylserine can help reverse cognitive loss as the brain ages by boosting cognitive activities such as memory formation, learning, concentration, and problem-solving [75] .

It is well absorbed in humans and crosses the blood-brain barrier.

Supplements containing phosphatidylserine have been shown to increase cognitive functions and are generally well-tolerated, with dosages ranging from 100 to 800 mg per day advised for cognitive support [76] [77] .

Thesis Logic contains 400 mg of phosphatidylserine, which may provide you with these cognitive-enhancing effects.

High DHA Algae

DHA is a vital component of neuronal membranes and plays an important role in brain health and cognitive function.

Adult cognitive abilities are improved by DHA consumption, especially when paired with eicosapentaenoic acid (EPA) [78] .

This impact is most noticeable in older people who have mild memory problems. Higher DHA and EPA doses (above 1 g per day) have been associated with better episodic memory.

Observational studies also show a link between DHA/EPA intake and memory performance in the elderly. DHA, both alone and in combination with EPA, improves memory in the elderly.

Thesis Logic contains 200 mg of DHA, suggesting insufficient DHA to provide a benefit.

Triacetyluridine (Speculative)

Triacetyluridine is being explored as a potential treatment for bipolar depression. In a study involving eleven patients with bipolar depression, high doses of triacetyluridine (up to 18 g per day) were administered over 6 weeks [79] .

The study measured the effects on depression symptoms using the Montgomery-Asberg Depression Rating Scale (MADRS) and evaluated cellular bioenergetics using phosphorus magnetic resonance spectroscopic imaging (P-MRSI).

Results indicated significant early improvement in depression symptoms.

Additionally, triacetyluridine responders showed notable differences in pH changes from baseline, suggesting triacetyluridine may improve mitochondrial function and reduce symptoms of depression.

Thesis Logic has 30 mg of triacetyluridine, which is well below the dose used in this study.

Bacopa Monnieri

Bacopa monnieri is a traditional plant that has been shown to improve cognitive performance, particularly memory.

Bacopa extract, namely bacosides A and B, has been demonstrated in studies to increase memory formation, recall, and cognitive function [80] .

It has neuroprotective properties and is used to treat cognitive dysfunctions such as Alzheimer’s disease.

Adults should take between 200 and 400 mg each day. Bacopa is generally well accepted, with only rare reports of mild drowsiness or stomach difficulties.

Clinical trials show that older people have better memory, attention, mood, and overall cognitive ability [81] [82] [83] . More research is needed, however, to thoroughly grasp its usefulness across many cognitive domains.

Thesis Logic contains 320 mg of Bacopa, giving you the efficacious dose to feel these benefits.

Thesis Nootropics Price

Thesis has two options: one time purchase or a subscription. Here’s how the prices break down:

• Subscription = $79
• One Time Purchase = $119

This is regardless of whether you purchase a personalized starter kit or build your own box.

You can’t buy them individually either. You must purchase 4 boxes. When building your own, you can choose if you want 4 of the same blend or mix and match.

They want you to try each blend for a week as part of the starter kit (there’s only a week’s worth of each blend in each container) to see which you like best.

Thesis has positioned itself as the most expensive nootropic available by adding the personalized element.

Is Thesis Nootropics Really Personalized?

I went through the initial quiz to see how they “personalize” their nootropic stack.

Here is what they recommended me:

Look, I get the marketing angle. In no way is this a truly personalized nootropic product. It’d be nearly impossible to create custom formulations for every unique individual.

However, the fact they have multiple blends means people can experiment to find which works best for them.

I will say, though, if you choose the caffeine options, every blend will work. Many of the ingredients used in these blends are speculative and only based on animal research, with many being underdosed.

Benefits Of Thesis Nootropics

Multiple blends for different purposes.

To be honest, this benefit is more of a marketing tactic. However, some people may find certain blends jive well with them over others, giving you options within the same brand.

Further, Thesis claims the ingredients in each formulation work synergistically. There’s no research to back that claim, but at least know there are no negative side effects from their interaction.

Options For Stimulants Or Not

You can choose whether or not you want stimulants within your Thesis Blends. Every blend will provide similar benefits if you add the caffeine and L-theanine nootropic stack, which is the most potent synergistic brain booster.

However, if you’re already a coffee addict or plan to take Thesis in the evening, having no stimulants is the better option.

My Experience With Thesis

Based on my quiz, I was recommended Thesis Clarity, Logic, Motivation, and Confidence Blends. I tried each for a week to see if one stood out. I took them without caffeine as they all work if you have the caffeine L-theanine stack.

I have to say the Confidence and Motivation Blends did absolutely nothing for me. I didn’t “feel” any brain-boosting effects or feel more confident or motivated.

I felt the Logic and Clarity Blends had small positive effects when concentrating on mentally demanding tasks like writing, coaching, or podcasting.

If I were to continue taking Thesis, I’d opt for either of these two blends.

Who Is Thesis For?

Busy working professionals.

Thesis Nootropics are ideal for busy professionals facing demanding schedules and high-stress environments. These blends can help enhance focus, improve decision-making, and increase productivity.

They are designed to support sustained mental energy throughout the day, enabling professionals to manage their workload more effectively without the usual mental fatigue.

Creative Artists

For creative artists, Thesis offers blends that stimulate creativity and enhance divergent thinking. These nootropics can aid in breaking through creative blocks, fostering innovative thinking, and maintaining a heightened state of inspiration.

They are particularly beneficial for artists seeking longer periods of creative flow and those seeking fresh perspectives.

Students can significantly benefit from Thesis Nootropics, especially during intense studying or when facing challenging academic projects.

The blends are formulated to enhance memory retention, improve concentration, and boost learning capabilities. This makes them a valuable tool for students who need to absorb and retain large amounts of information and perform well in academic assessments.

Gamers find Thesis Nootropics beneficial for improving their gaming performance. The blends can enhance reaction times, increase focus, and improve strategic thinking skills.

They are particularly useful during long gaming sessions, helping gamers stay alert and responsive, which is crucial in competitive gaming scenarios.

Coffee Haters

Thesis Nootropics provides an excellent alternative for those who dislike coffee or want to avoid caffeine jitters.

These blends offer a way to boost mental energy and alertness without relying on caffeine. This makes them ideal for individuals sensitive to caffeine or those seeking to reduce caffeine intake while maintaining high cognitive function.

User Testimonials And Reviews

You can’t access the review database on the Thesis website, so I did some digging to find user reviews. Here’s a couple of positive reviews:

“I must admit that during the weeks that I consistently take them, I perform better & I generally feel better just knowing I’ve ingested something intended to positively alter my natural brain state. Minor tasks/chores no longer seem as daunting and I get this underlying kick to complete my work well.” – ParsnipExtreme2502 (Reddit)

“I didn’t find Weeks 1 and 4 to do anything for me, but Weeks 2 and 3 really helped avoid the post-lunch, post-work slumps I tend to get now that I’ve been working from home; Energy is especially useful for days when I haven’t gotten enough sleep the night before.” – leftylucy88 (Reddit)

I can’t find many negative reviews other than potential side effects like migraines, which can be caused by many different factors.

Thesis Side Effects

Side effects are rare from the ingredients in these blends. I personally didn’t have any adverse reactions to the four blends I tried. However, like any supplement, they may have potential side effects.

Consult with a healthcare provider before starting any nootropic regimen, especially if they have pre-existing health conditions, are pregnant or breastfeeding, or are taking other medications.

Thesis Alternatives

If Thesis Nootropics isn’t quite the right match for you or you’re just curious about other products, here are some alternatives I’ve tried and can provide an insider’s look into.

SAP Nutra nootropic Nooceptin improves memory, concentration, and cognitive performance without stimulants. It offers gradual brain health gains.

It improves memory and focus and provides a prolonged boost without a caffeine crash. Students, gamers, professionals, and seniors should use Nooceptin to boost cognition.

This brain supplement contains Lion’s Mane Extract, Citicoline, Rhodiola Rosea Extract, L-Theanine, Bacopa Monnieri, Ginkgo Biloba, and Panax Ginseng.

Some of these compounds have been shown to be useful, but others are experimental. Nooceptin, a non-stimulant method for long-term cognitive enhancement, usually works after 7-14 days.

Despite the risk of underdosed components and increased cost, Nooceptin may provide a stimulant-free cognitive boost.

Read more in our Nooceptin review .

Mind Lab Pro

Mind Lab Pro is a popular nootropic that has gained appeal as a result of its alleged cognitive benefits.

Pure substances are used in its formulation, which is intended to improve mental clarity and attention. It is stimulant-free, making it an excellent choice for anyone seeking a well-rounded routine.

Its unique combination of 11 research-backed components distinguishes it from competitors in the brain health supplement sector.

These compounds were carefully chosen to help cognitive processes like memory, focus, mental clarity, mood, and cognitive processing speed.

Despite some criticism about the quantity of specific substances and the need for more scientific data, Mind Lab Pro has earned worldwide recognition for its ability to improve cognitive performance in professionals, students, the elderly, and athletes.

Our Mind Lab Pro review goes into great detail.

Braini distinguishes itself by being stimulant-free, providing long-term results, and having a short ingredient list focusing on long-term cognitive gains. It does not, however, deliver the immediate euphoric boost that some users may expect from a brain supplement.

Peptylin, a silk protein peptide with neuroprotective effects and potential benefits for executive function; NeurXcel, which is rich in omega fatty acids; and Wild Canadian Blueberry extract, which is known for its antioxidant characteristics and cognitive support, are all key ingredients in Braini.

Braini is backed by clinical trials, a 60-day money-back guarantee, and a 30-day challenge to scientifically quantify changes in brain function.

Our Braini review contains an in-depth breakdown.

Vyvamind is a nootropic supplement containing caffeine and L-theanine to help focus and improve cognitive performance. Users claim increased focus, vitality, and cognitive abilities without big crashes.

Vyvamind’s formulation, which contains less L-tyrosine and citicoline than some studies suggest, is intended to supplement the major nootropic duo of caffeine and L-theanine.

This combination is well-known for boosting concentration and cognitive function. The supplement is touted as a non-stimulant alternative, appealing to clients seeking a more natural and less intensive approach to cognitive growth.

Vyvamind is suitable for coffee-averse people, busy professionals who require a focus boost, and students during study sessions.

Our Vyvamind review goes into great detail.

Because of its purported fast cognitive effects, NooCube is a popular brain-boosting product. NooCube contains ingredients such as Bacopa Monnieri, L-Tyrosine, and L-Theanine.

These are well-known for their mental health advantages. Several compounds, such as Huperzine-A and Alpha GPC, remain speculative without additional investigation.

NooCube is intended to improve cognition and alertness without using stimulants, and the amounts of each ingredient are clearly labeled.

Because it gives different cognitive benefits without the jittery side effects associated with caffeine, NooCube is especially good for working professionals, students, elders, gamers, and combat athletes.

Our detailed analysis can be found in our NooCube review .

Frequently Asked Questions

What is thesis nootropic and what does it do.

Thesis Nootropic is a personalized supplement formulated to enhance cognitive functions. Users can expect improvements in focus, reduction in procrastination, stress management, and memory recall, depending on which blend you choose.

Does Thesis Work Like Adderall?

Thesis Nootropics and Adderall are used to enhance cognitive functions, but they are fundamentally different. Adderall is primarily prescribed for treating Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy.

Adderall is an amphetamine, classified as a controlled substance due to its strong stimulating effects and potential for abuse and dependency.

Thesis Nootropics are dietary supplements designed to enhance healthy individuals’ cognitive functions, such as memory, focus, and mental clarity. They are not intended to treat medical conditions like ADHD.

How Long Does It Take Thesis Nootropics To Work?

If you have the caffeine version, within 30 minutes. You may feel the non-stimulant blends kicking in just as quickly, but they won’t be as pronounced. Sometimes, they can take multiple weeks to feel them working.

I’ve taken a deep dive into the world of nootropics and shared my firsthand experience with Thesis Nootropic’s various blends. While the personalization is nothing more than a marketing tactic, the different blends are a nice touch for those who want to experiment with different ingredients.

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• Published: 25 February 2021

The impact of daily caffeine intake on nighttime sleep in young adult men

• Janine Weibel 1 , 2 ,
• Yu-Shiuan Lin 1 , 2 , 3 ,
• Hans-Peter Landolt 4 , 5 ,
• Joshua Kistler 1 , 2 ,
• Sophia Rehm 6 ,
• Katharina M. Rentsch 6 ,
• Helen Slawik 7 ,
• Stefan Borgwardt 3 ,
• Christian Cajochen 1 , 2   na1 &
• Carolin F. Reichert 1 , 2   na1  

Scientific Reports volume  11 , Article number:  4668 ( 2021 ) Cite this article

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• Slow-wave sleep

Acute caffeine intake can delay sleep initiation and reduce sleep intensity, particularly when consumed in the evening. However, it is not clear whether these sleep disturbances disappear when caffeine is continuously consumed during daytime, which is common for most coffee drinkers. To address this question, we investigated the sleep of twenty male young habitual caffeine consumers during a double-blind, randomized, crossover study including three 10-day conditions: caffeine (3 × 150 mg caffeine daily), withdrawal (3 × 150 mg caffeine for 8 days, then switch to placebo), and placebo (3 × placebo daily). After 9 days of continuous treatment, electroencephalographically (EEG)-derived sleep structure and intensity were recorded during a scheduled 8-h nighttime sleep episode starting 8 (caffeine condition) and 15 h (withdrawal condition) after the last caffeine intake. Upon scheduled wake-up time, subjective sleep quality and caffeine withdrawal symptoms were assessed. Unexpectedly, neither polysomnography-derived total sleep time, sleep latency, sleep architecture nor subjective sleep quality differed among placebo, caffeine, and withdrawal conditions. Nevertheless, EEG power density in the sigma frequencies (12–16 Hz) during non-rapid eye movement sleep was reduced in both caffeine and withdrawal conditions when compared to placebo. These results indicate that daily caffeine intake in the morning and afternoon hours does not strongly impair nighttime sleep structure nor subjective sleep quality in healthy good sleepers who regularly consume caffeine. The reduced EEG power density in the sigma range might represent early signs of overnight withdrawal from the continuous presence of the stimulant during the day.

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Introduction.

Caffeine is the most popular psychoactive substance in the world 1 , consumed daily by around 80% of the population 2 . While caffeine is frequently used to counteract sleepiness and boost performance 3 , its consumption is commonly avoided in the evening 4 , 5 to prevent adverse consequences on nocturnal sleep 3 . The sleep disrupting effects of caffeine are mainly attributed to its influence on the homeostatic component of sleep-wake regulation. Sleep homeostasis describes the increase in sleep pressure during time awake and its dissipation during the following sleep episode 6 , which has been suggested to be related to rising and decreasing concentrations of adenosine 7 . Caffeine is an adenosine receptor antagonist, which blocks the A 1 and A 2A adenosine receptors in the central nervous system 1 . It may, thus, attenuate the increase in sleep pressure during wakefulness 8 and lead to delayed sleep initiation and more superficial sleep 9 .

The effects of caffeine intake on the quality and quantity of sleep depend on the timing of its consumption. More specifically, caffeine consumed in the evening hours prolongs sleep latency 10 , 11 , 12 , 13 , 14 , reduces total sleep time (TST) 10 , 11 , 12 , 14 , 15 , shortens deep sleep 10 , 12 , 13 , 14 , 15 , and decreases electroencephalographically (EEG)-derived slow-wave activity (SWA) 10 , while activity in the sigma range is increased 10 . However, evening caffeine intake only accounts for approximately 10–20% of the total daily caffeine intake in regular consumers 4 , 5 . It needs to be elucidated whether habitual caffeine intake restricted to the morning and afternoon hours similarly affects nighttime sleep.

Furthermore, not only the timing but also the frequency of preceding caffeine intake prior to sleep may be an important factor for the repercussions on sleep. The majority of the worldwide population consumes caffeine on a daily basis 2 , which can lead to tolerance development due to the recurrent supply of the psychostimulant 1 . In line with these results, the sleep-disrupting effects of continuous high-dose caffeine in the morning, afternoon, and evening (3 × 400 mg) intake vanished and only stage 4 sleep remained reduced after 1 week of caffeine intake 12 . However, whether more sensitive markers for sleep intensity such as spectral sleep EEG measures, adapt to the long-term exposure to the stimulant has to our best knowledge not yet been investigated.

Importantly, not only caffeine per se, but also the state of acute abstinence to which regular consumers expose themselves every night, might affect sleep. This so-called overnight abstinence represents the start of a caffeine withdrawal phase 16 . Withdrawal symptoms such as increased tiredness 17 , longer sleep duration, and better sleep quality 18 can be observed at a subjective level starting roughly 12 h after last caffeine intake 17 . However, the influence of caffeine withdrawal on objective EEG-derived sleep variables were not systematically reported up to date and remain to be compared against a placebo-baseline.

Here we aimed at determining whether daily caffeine intake during morning and afternoon hours impairs nighttime sleep structure and sleep intensity after continuous daytime caffeine intake over 9 days. We hypothesized a reduced depth of sleep after caffeine intake, indexed in shortened slow-wave sleep (SWS) duration and a decrease in SWA compared to placebo. Moreover, we hypothesized that the abrupt cessation from the daily intake generates acute subjective withdrawal symptoms, and changes sleep structure and intensity compared to both the daily caffeine intake and the placebo-baseline.

Salivary caffeine levels

Caffeine levels significantly differed between each of the three conditions (main effect of condition: F 2,90.7  = 46.12, p  < 0.001) with the highest levels in the caffeine condition and the lowest in the placebo condition (post-hoc comparisons: p all  < 0.01). In addition, a significant interaction of the factors condition and time ( F 2,89.6  = 10.65, p  < 0.001) confirmed that caffeine levels were modulated by time with levels decreasing during nighttime sleep in the caffeine condition only (post-hoc comparison: p  < 0.001), see Fig.  1 .

Average caffeine levels collected prior to and after nighttime sleep (grey bar) in the placebo (black open circles), caffeine (blue filled circles), and withdrawal (red semi-filled circles) condition (mean values ± standard errors). The x-axis indicates the mean time of day of sample collection and color-coded asterisks represent significant ( p  < 0.05) post-hoc comparisons of the interaction effect condition × time.

Table 1 summarizes the statistical analyses of subjective sleep quality and objective sleep structure assessed during nighttime sleep. Analyses of subjective sleep quality assessed with the Leeds Sleep Evaluation Questionnaire (LSEQ) did not reveal significant differences among the three conditions in any of the four domains of sleep quality ( p all  > 0.05).

In line with these results, the analyses of the polysomnography (PSG) did not reveal significant differences in total sleep time (TST), sleep efficiency (SE), sleep latencies, or the relative amount of sleep stages among the three conditions ( p all  > 0.05).

In a next step, we analyzed all-night EEG power density in the range of 0.75–32 Hz over the central derivations recorded during non-rapid eye movement (NREM) sleep. In contrast to our assumptions, we did not find any significant differences among the three conditions in the lower frequency bins (0.75–13.25 Hz; p all  > 0.05). However, power density was significantly reduced compared to placebo in the sigma range during both withdrawal (frequency bins 13.5–17.25 Hz and 18–18.5 Hz; p all  < 0.05) and caffeine (frequency bins 13.5–16 Hz; p all  < 0.05).

In a second step, we were interested in the temporal dynamics of both SWA and sigma activity across the night assessed during NREM sleep. As depicted in Fig.  2 (top panel), SWA showed a typical temporal pattern with increased activity during the first NREM cycle followed by a steady decline across the night (main effect of time: F 39,613  = 26.28, p  < 0.001). However, differences among the three conditions did not reach significance (main effect of condition: F 2,178  = 1.33, p  = 0.27). Also, the interaction of condition and time was not significant ( F 78,1060  = 0.89, p  = 0.74).

Temporal dynamics of SWA (top) and sigma activity (bottom) during the first four sleep cycles in the placebo (black open circles), caffeine (blue filled circles), and the withdrawal (red semi-filled circles) condition (mean values). The x-axis indicates the mean time of day. While SWA (0.75–4.5 Hz) was not significantly affected by the treatment, sigma activity (12–16 Hz) showed reduced activity during both caffeine and withdrawal compared to the placebo condition ( p all  < 0.05). The inset in each right upper corner represents the mean values ± standard errors of the all-night SWA and sigma activity respectively during NREM sleep in the placebo, caffeine, and withdrawal condition. While all-night SWA (0.75–4.5 Hz) did not differ among the conditions, sigma activity (12–16 Hz) was lower in the caffeine and withdrawal condition compared to placebo ( p  < 0.05). All analyses are based on log-transformed data.

As illustrated in Fig.  2 (bottom panel), sigma activity was significantly reduced in both the caffeine and withdrawal conditions compared to placebo intake (main effect of condition: F 2,209  = 19.96, p  < 0.001; post-hoc comparisons: p  < 0.001) and the interaction of condition and time tended to be significant ( F 78,1049  = 1.25, p  = 0.08).

Taken together, we could not confirm our assumption of a caffeine-induced reduction of sleep depth, neither in terms of shorter SWS nor in terms of reduced SWA in the caffeine compared to the placebo condition. Based on the discrepancies between the present results and a previous study about the effects of chronic caffeine intake on sleep 12 , we thus explored whether differences in the individual levels of caffeine before sleep could explain the variance within SWS and SWA. However, no significant effects were observed when controlling for dependent observations within subjects ( p  > 0.05).

Subjective caffeine withdrawal symptoms

Analyses of the relative withdrawal symptoms yielded a significant main effect of condition ( F 2,20.2  = 11.30, p  < 0.01) indicating more withdrawal symptoms during the withdrawal compared to the caffeine condition (post-hoc comparison: p  < 0.01), depicted in Fig.  3 . This effect was modulated by time (interaction of condition × time: F 2,37.2  = 3.43, p  = 0.04), such that the increase in symptoms during the withdrawal compared to caffeine condition was particularly present during the last measurement ( p  < 0.01), i.e. 31 h after the last caffeine intake in the withdrawal condition.

Relative withdrawal symptoms in the caffeine and withdrawal condition (i.e. withdrawal score of the caffeine and withdrawal condition respectively minus the score of the placebo condition) assessed 35 min, 4 h, and 8 h after wake-up on day ten of treatment. Depicted are mean values and standard errors of the relative values (i.e. difference to placebo). Overall, volunteers reported more withdrawal symptoms in the withdrawal condition compared to the caffeine condition ( p  < 0.05). This difference was particularly present 8 h after wake-up during withdrawal compared to caffeine ( p  < 0.001).

The aim of the present study was to investigate the influence of daily daytime caffeine intake and its cessation on nighttime sleep in habitual caffeine consumers under strictly controlled laboratory conditions. Strikingly, caffeine consumption did not lead to clear-cut changes in nighttime sleep structure nor in subjective sleep quality when assessed 8 and 15 h after the last intake in the caffeine and withdrawal condition, respectively. The evolution of subjective withdrawal symptoms indicates that withdrawal becomes perceivable at earliest between 27–31 h after intake. However, compared to placebo, EEG power density was reduced in the sigma range during both caffeine and withdrawal conditions. We conclude that daily daytime intake of caffeine does not strongly influence nighttime sleep structure nor subjective sleep quality in healthy men when consumed in the morning, midday, and in the afternoon. In contrast to the reported increases in sigma activity after acute caffeine intake 10 , the observed changes in the sigma frequencies might point to early signs of caffeine withdrawal which occur due to overnight abstinence and presumably derive from preceding caffeine-induced changes in adenosine signaling.

To quantify the influence of caffeine on sleep, the stimulant is commonly administered close to the onset of a sleep episode 10 , 11 , 12 , 13 , 14 , for instance within 1 h prior to bedtime 10 , 11 , 13 , 14 . Taking into account that caffeine plasma levels peak within 30–75 min following caffeine ingestion 19 , consumption within 1 h prior to sleep allows the stimulant to exert its maximum effects at sleep commencement. Indeed, the sleep disrupting effects of caffeine are frequently reported to affect sleep initiation or the first half of the sleep episode 10 , 11 , 12 , 13 , 14 . Moreover, sleep intensity, which is usually strongest at the beginning of the night 20 , was particularly disrupted during the first sleep cycle, as indexed in reduced SWS and SWA 10 . However, caffeine intake in the evening, particularly after 9 pm is rare 5 , presumably to avoid impairment of subsequent sleep 3 . Up to date it remained fairly unclear whether caffeine intake in the morning and afternoon still bears the potential to disrupt nighttime sleep. While we observed a delay of 25 min in sleep episodes during caffeine intake prior to the laboratory part, PSG-derived data after 9 days of regular caffeine intake did not yield a significant change in sleep architecture. Thus, our data provide first evidence that daily daytime caffeine intake does not necessarily alter subsequent sleep structure and SWA when consumed > 8 h prior to sleep. Importantly, our findings do not preclude potential impairments of nighttime sleep after morning caffeine intake, if preceded by several days of abstinence from the stimulant 21 . It rather appears likely that the duration of preceding caffeine consumption drives the discrepancies between acute and chronic effects of caffeine on sleep.

Chronic caffeine intake induces some tolerance development in both physiological measures such as cortisol 22 , blood pressure 23 , heart rate 24 , and also subjective measures such as alertness 18 . Over time, the stimulatory effects of the substance vanish potentially due to changes in adenosine levels 25 and/or adenosine receptors 26 , 27 , 28 . Accordingly, a 1-week treatment of caffeine reduced the sleep disrupting effects, even under conditions of high evening dosages 12 . Thus, the available evidence and the absence of clear-cut changes in the present study point to adaptive processes in sleep initiation, sleep structure, and subjective sleep quality due to the long-term exposure to the stimulant.

However, chronic caffeine consumption bears the risk of withdrawal symptoms when abruptly ceased. These symptoms have been reported to occur as early as 6 h but with peak intensity being reached within 20–51 h after last caffeine intake 17 . While 25 h of caffeine abstinence might not affect nighttime sleep structure 12 , 32 h of abstinence improved subjective sleep quality 18 . Thus, scheduling the start of the sleep episode to 15 h after the last caffeine intake, as in our withdrawal condition, was probably too early to detect changes in sleep structure or subjective sleep quality. In line with this assumption, volunteers subjectively indicated withdrawal symptoms 31 h after caffeine abstinence in the withdrawal condition compared to caffeine. Thus, our findings support the notion that the alterations in sleep structure and subjective sleep quality induced by caffeine abstinence potentially develop at a later stage (> 27 h) of caffeine withdrawal.

Most strikingly and unexpectedly, a reduction in NREM sigma activity during both the withdrawal and caffeine conditions was observed, a phenomenon which is commonly reported under conditions of enhanced sleep pressure 29 , 30 , 31 , 32 . Thus, it seems at first glance in contrast to the reported increases in this frequency range 10 , 21 and the well-known alerting effects after acute caffeine intake 18 . However, during conditions of chronic caffeine intake, mice showed a deeper sleep compared to placebo 33 . Moreover, repeated caffeine intake enhances the sensitivity of adenosine binding 34 presumably due to upregulated adenosine receptors 26 , 27 , 28 or changes in the functions of adenosine receptor heteromers 35 . These neuronal alterations in the adenosinergic system might drive the commonly observed changes in the homeostatic sleep-wake regulation such as increased sleepiness when caffeine intake is suddenly ceased 17 . As reported previously, we also observed in the present study higher subjective sleepiness following caffeine withdrawal when compared to the placebo and caffeine conditions 36 . Thus, the reduction in sigma activity might reflect adenosinergic changes which already emerge 8 and 15 h after the last caffeine intake in the caffeine and withdrawal condition, respectively. This reduction might reflect withdrawal symptoms which chronic consumers reverse daily by the first caffeine dose. Given the high prevalence of daily caffeine consumers in the society, these findings stress the importance to carefully control for prior caffeine intake when assessing sleep in order to exclude potential confounding by induced withdrawal symptoms which are only detectable in the microstructure of sleep.

Our study has some limitations which must be taken into careful consideration when interpreting the present findings. First, age moderates the effects of caffeine on sleep 11 , 14 . Thus, the present results cannot be generalized to other age groups such as to middle-aged consumers which are more vulnerable to the caffeine-induced effects on sleep 11 , 14 . Second, only a limited number of participants were studied. However, a well-controlled study design was employed and power calculation on the basis of an earlier study 12 indicated a sufficient sample size. Third, we do not have any information about the participants’ genetic polymorphisms which have been shown to modulate the metabolism of caffeine 37 . In addition, a genetic variation of the ADORA2A genotype has been linked with caffeine sensitivity to the effects on sleep 38 . Thus, carriers of this genetic variance are more likely to curtail caffeine consumption and are consequently excluded from the present study leading to a selection bias. However, the focus of the present study was to investigate habitual caffeine consumers as they represent the majority of the worldwide population 2 . Fourth, to reduce variance in the data incurred by the influence of the menstrual cycle on sleep 39 and the interaction between caffeine metabolism and the use of oral contraceptives 40 , 41 , only male volunteers were included which clearly reduces the generalizability of the findings.

In conclusion, we report evidence that daily daytime intake of caffeine and its cessation has no strong effect on sleep structure or subjective sleep quality. However, the quantitative EEG analyses revealed reduced activity in the sigma range during both caffeine and withdrawal. These subtle alterations point to early signs of caffeine withdrawal in the homeostatic aspect of sleep-wake regulation which are already present as early as 8 h after the last caffeine intake. Thus, habitual caffeine consumers constantly expose themselves to a continuous change between presence and absence of the stimulant. Around the clock, their organisms dynamically adapt and react to daily presence and nightly abstinence.

Participants

Twenty male volunteers were recruited into the present study through online advertisements and flyers distributed in public areas. Interested individuals aged between 18 and 35 years old (mean age ± SD: 26.4 ± 4 years) and reporting a daily caffeine consumption between 300 and 600 mg (mean intake ± SD: 478.1 ± 102.8 mg) were included. The self-rating assessment for the daily amount of caffeine intake was structured based on Bühler et al. 42 , and the amount of caffeine content was defined according to Snel and Lorist 3 . To ensure good health, volunteers were screened by self-report questionnaires and a medical examination conducted by a physician. Additionally, all volunteers reported good sleep quality assessed with the Pittsburgh Sleep Quality Index (PSQI; score ≤ 5) 43 and showed no signs of sleep disturbances (SE > 70%, periodic leg movements < 15/h, apnea index < 10) in a PSG recorded during an adaptation night in the laboratory scheduled prior to the start of the study. To control for circadian misalignment, volunteers who reported shiftwork within 3 months and transmeridian travels (crossing > 2 time zones) within 1 month prior to study admission were excluded. Further exclusion criteria comprised body mass index (BMI) < 18 or > 26, smoking, drug use, and extreme chronotype assessed by the Morningness-Eveningness Questionnaire (MEQ; score ≤ 30 and ≥ 70) 44 . To reduce variance in the data incurred by the effect of menstrual cycle on sleep 39 and the interaction between caffeine metabolism and the use of oral contraceptives 40 , 41 , only male volunteers were studied. A detailed description of the study sample can be found in Weibel et al. 36 .

All volunteers signed a written informed consent and received financial compensation for study participation. The study was approved by the local Ethics Committee (EKNZ) and conducted according to the Declaration of Helsinki.

Design and protocol

We employed a double-blind, randomized, crossover study including a caffeine, a withdrawal, and a placebo condition. Volunteers were allocated to the order of the three conditions based on pseudo-randomization, for more details see Weibel et al. 36 . As illustrated in Fig.  4 , each condition started with an ambulatory part of 9 days, followed by a laboratory part of 43 h. In each condition, participants took either caffeine (150 mg) or placebo (mannitol) in identical appearing gelatin capsules (Hänseler AG, Herisau, Switzerland) three times daily, scheduled at 45 min, 255 min, and 475 min after awakening, for a duration of 10 days. This regimen was applied based on a previous study investigating tolerance to the effects of caffeine and caffeine cessation 18 . To enhance caffeine withdrawal in the withdrawal condition, treatment was abruptly switched from caffeine to placebo on day nine of the protocol (255 min after wake-up, 15 h before sleep recording).

Illustration of the study design. Twenty volunteers participated in a placebo, a caffeine, and a withdrawal condition during which they ingested either caffeine or placebo capsules three times daily (wake-up + 45 min, + 255 min, and + 475 min). Each condition started with an ambulatory part of 9 days and was followed by a laboratory part of 43 h. After 9 days of continuous treatment, we recorded 8 h of polysomnography (PSG), indicated as arrows, during nighttime sleep under controlled laboratory conditions. The sleep episode was scheduled to volunteers’ habitual bedtime.

During the 9 days of the ambulatory part, volunteers were asked to maintain a regular sleep-wake rhythm (± 30 min of self-selected bedtime/wake-up time, 8 h in bed, no daytime napping), verified by wrist actimetry (Actiwatch, Cambridge Neurotechnology Ltd., Cambridge, United Kingdom), and to keep subjective sleep logs. While the participants were compliant, they scheduled sleep episodes differently within the accepted range of ± 30 min. During intake of caffeine (i.e. caffeine and withdrawal condition), the ambulatory sleep episodes were on average around 25 min later as compared to placebo (results see supplements). The duration of the ambulatory part was set for 9 days based on the maximum duration of withdrawal symptoms 17 and thus, to avoid carry-over effects from the previous condition. Furthermore, volunteers were requested to refrain from caffeinated beverages and food (e.g. coffee, tea, soda drinks, and chocolate), alcohol, nicotine, and medications. Caffeine abstinence and compliance to the treatment requirements were checked by caffeine levels from the daily collection of fingertip sweat of which results are reported in the supplemental material of Weibel et al. 36 and which indicate very good adherence to the treatments.

On day nine, volunteers admitted to the laboratory at 5.5 h prior to habitual sleep time. Upon arrival, a urinary drug screen (AccuBioTech Co., Ltd., Beijing, China) was performed to ensure drug abstinence. Electrodes for the PSG were fitted and salivary caffeine levels collected. An 8-h nighttime sleep episode was scheduled at volunteers’ habitual bedtime starting 8 and 15 h after the last caffeine intake in the caffeine and withdrawal condition, respectively. The next day, volunteers rated their subjective sleep quality by the LSEQ 45 and potential withdrawal symptoms by the Caffeine Withdrawal Symptom Questionnaire (CWSQ) 46 .

To reduce potential masking effects on our outcome variables, we standardized food intake, light exposure, and posture changes throughout the laboratory part. Accordingly, volunteers were housed in single apartments under dim-light (< 8 lx) during scheduled wakefulness and 0 lx during sleep. Volunteers were asked to maintain a semi-recumbent position during wakefulness, except for restroom breaks. In addition, volunteers received standardized meals in regular intervals. Social interactions were restricted to team members and no time-of-day cues were provided throughout the in-lab protocol.

Salivary caffeine

To characterize individual caffeine levels during nighttime sleep, we report salivary caffeine levels assessed 3 h prior to the scheduled sleep episode and 5 min after wake-up. Samples were stored at 5 °C following collection, later centrifuged (3000 rpm for 10 min) and subsequently kept at − 28 °C until analyses. Liquid chromatography coupled to tandem mass spectrometry was used to analyze the levels of caffeine. One dataset in the withdrawal condition was lost.

Subjective sleep quality

Subjective sleep quality was assessed 10 min upon scheduled wake-up time with a paper and pencil version of the LSEQ 45 . Volunteers were asked to rate 10 items on visual analogue scales which are grouped into four domains (getting to sleep (GTS), quality of sleep (QOS), awake following sleep (AFS), and behavior following wakening (BFW)).

Polysomnographic recordings

PSG was continuously recorded during 8 h of nighttime sleep using the portable V-Amp device (Brain Products GmbH, Gilching, Germany). Grass gold cup electrodes were applied according to the international 10–20 system including two electrooculographic, two electromyographic, two electrocardiographic, and six electroencephalographic derivations (F3, F4, C3, C4, O1, O2). Channels were referenced online against the linked mastoids (A1, A2). Signals were recorded with a sampling rate of 500 Hz and a notch filter was online applied at 50 Hz.

Each epoch of 30 s of the recorded PSG data was visually scored according to standard criteria 47 by three trained team members blind to the condition. SWS was additionally classified into stage 3 and 4 based on Rechtschaffen and Kales 48 . The scoring agreement between the three scorers was regularly confirmed to reach > 85%.

TST was defined as the sum of the time spent in sleep stages 1–4 and rapid eye movement (REM) sleep. Sleep latency to stage 1 and 2 was calculated as minutes to the first occurrence of the corresponding sleep stage following lights off. REM sleep latency was calculated as minutes to the first occurrence of REM sleep following sleep onset. NREM sleep was calculated as sum of sleep stages 2, 3 and 4. All sleep stages are expressed as relative values (%) of TST.

Spectral analysis was performed by applying fast Fourier transformation (FFT; hamming, 0% overlapped, 0.25 Hz bins) on 4-s time windows. Artifacts were manually removed based on visual inspection, and data were log-transformed prior to spectral analyses. All-night EEG power density during NREM sleep was analyzed for each 0.25 Hz frequency bin in the range of 0.75–32 Hz recorded over the central derivations (C3, C4). SWA was defined as EEG power density between 0.75–4.5 Hz and sigma activity between 12–16 Hz. Sleep cycles were defined based on adapted rules developed by Feinberg and Floyd 49 and divided into 10 NREM and four REM sleep intervals within each cycle. Ten nights were excluded from sleep analyses due to technical problems (placebo: n  = 3; caffeine: n  = 4; withdrawal: n  = 3).

Caffeine withdrawal symptoms

Withdrawal symptoms were first assessed 35 min after wake-up and subsequently prior to each treatment administration with the self-rating CWSQ 46 . Twenty-three items are grouped into seven factors (fatigue/drowsiness, low alertness/difficulty concentrating, mood disturbances, low sociability/motivation to work, nausea/upset stomach, flu-like feelings, headache) and were rated on a 5 point scale by choosing between 1 (not at all) and 5 (extremely). Prior to analyses, eight items have been reversed scored as they were positively worded (e.g. alert or talkative) in the questionnaire. To assess caffeine withdrawal, we first calculated a sum score comprising all 23 items of the caffeine withdrawal questionnaire. Missing responses to single items were replaced by the median response of each condition over all volunteers in the respective time of assessment. In a next step, we calculated relative withdrawal symptoms in the caffeine and withdrawal condition (i.e. the difference of the withdrawal score in the caffeine and withdrawal condition respectively minus the score of the placebo condition). The data of one volunteer was lost due to technical difficulties.

Statistical analyses

Analyses were performed with the statistical package SAS (version 9.4, SAS Institute, Cary, NC, USA) by applying mixed model analyses of variance for repeated measures (PROC MIXED) with the repeated factors ‘condition’ (placebo, caffeine, withdrawal) and/or ‘time’ (levels differ per variable) and the random factor ‘subject’. The LSMEANS statement was used to calculate contrasts and degrees of freedom were based on the approximation by Kenward and Roger 50 . Post-hoc comparisons were adjusted for multiple comparisons by applying the Tukey-Kramer method. A statistical significance was defined as p  < 0.05. One dataset has been excluded from all the analyses due to non-compliance with the treatment requirements (caffeine: n  = 1).

Data availability

The present data are available upon request from the corresponding author.

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Acknowledgements

The present work was performed within the framework of a project granted by the Swiss National Science Foundation (320030_163058) and was additionally funded by the Nikolaus und Bertha Burckhardt-Bürgin-Stiftung and the Janggen-Pöhn-Stiftung. Further, we thank our interns Andrea Schumacher, Laura Tincknell, Sven Leach, and all our study helpers for their help in data acquisition and all our volunteers for participating in the study. Moreover, we gratefully acknowledge the help in study organization provided by Dr. Ruta Lasauskaite and the medical screenings conducted by Dr. med. Martin Meyer and Dr. med. Corrado Garbazza.

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These authors contributed equally: Christian Cajochen and Carolin F. Reichert.

Authors and Affiliations

Centre for Chronobiology, Psychiatric Hospital of the University of Basel, Basel, Switzerland

Janine Weibel, Yu-Shiuan Lin, Joshua Kistler, Christian Cajochen & Carolin F. Reichert

Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Basel, Switzerland

Neuropsychiatry and Brain Imaging, Psychiatric Hospital of the University of Basel, Basel, Switzerland

Yu-Shiuan Lin & Stefan Borgwardt

Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland

Hans-Peter Landolt

Sleep & Health Zürich, University Center of Competence, University of Zürich, Zürich, Switzerland

Laboratory Medicine, University Hospital Basel, Basel, Switzerland

Sophia Rehm & Katharina M. Rentsch

Clinical Sleep Laboratory, Psychiatric Hospital of the University of Basel, Basel, Switzerland

Helen Slawik

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C.R., C.C. and S.B. designed the study; J.W., Y.S.L. and HS collected the data; J.W., C.R. and C.C. analyzed and interpreted the data; J.W. and C.R. drafted the manuscript; C.C., Y.S.L. and H.P.L. critically revised the manuscript regarding its intellectual content; J.K., S.R. and K.R. provided the resources for the caffeine measurements and performed its analyses; all authors reviewed the present article.

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Correspondence to Christian Cajochen .

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Weibel, J., Lin, YS., Landolt, HP. et al. The impact of daily caffeine intake on nighttime sleep in young adult men. Sci Rep 11 , 4668 (2021). https://doi.org/10.1038/s41598-021-84088-x

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7 Benefits of Quitting Caffeine That Make It Worth the Struggle

By Ayana Underwood

Medically reviewed by Mathew Devine, DO

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If you slam a double espresso before work, order a latte as soon as you get to the office, have a soda with lunch, and sip an energy drink as your preworkout—you likely feel wired. You’re not alone in your love of a cup of joe. According to a 2023 study published in European Review for Medical and Pharmacological Sciences , between 80% and 90% of US adults and children have caffeine on a regular basis. 1

Still, you’re probably well aware of how bad too much caffeine can make you feel. As SELF previously reported , caffeine can make you jittery and screw with your stomach (the coffee poops are real!). Your sleep schedule might be kind of shitty too. 2

You might have reached a point where you’re ready to quit caffeine or, at the very least, cut back on the amount of caffeine you drink. The degree to which you feel better if you quit caffeine depends on how much you’re drinking to begin with, Rachel O’Connor, RD, CDN , an oncology dietician at NewYork-Presbyterian, tells SELF. If you’re consuming over 400 mg of caffeine (about four cups of coffee or two energy shots drinks) per day, that’s considered heavy caffeine use, says O’Connor.

Here are some of the health benefits that you could see if you quit caffeine—some of which you might not have even thought about.

FYI: Before you reap the perks of drinking less coffee, you might feel some gnarly caffeine withdrawal symptoms.

Because caffeine use is pretty common, people might forget that it’s still a drug (a stimulant), and it’s possible to become dependent on it. 3 (That often looks like multiple attempts to ditch caffeine without success. 4 )

“When regular caffeine consumers stop [ingesting it], they often experience withdrawal symptoms for three to seven days,” Jennifer Temple, PhD , a director and researcher at the University at Buffalo specializing in caffeine studies, tells SELF. 3

Common withdrawal symptoms include fatigue, headaches, and low energy, says Dr. Temple. 3 According to O’Connor, withdrawal symptoms will likely start between 12 and 24 hours after you quit 3 Whether you quit cold turkey or wean yourself off caffeine, grab some OTC headache relief medication. 3 Staying hydrated and getting enough rest can make withdrawal symptoms easier to handle too. 3

Seven benefits of quitting caffeine

As you know, caffeine likes to steal your sleep—it can shave about 45 minutes off of your time in dreamland. 5,6 If you don’t sleep enough, you might compensate the next day by downing some espresso—which creates a vicious cycle of crappy sleep followed by caffeine use, per a 2023 review published in Sleep Medicine Reviews . 6 As SELF previously reported , caffeine can stay in your system for hours, so it’s possible to feel the stimulating effects well into the night.

Some signs caffeine is wrecking your sleep include trouble falling asleep (of course), headaches, nausea, and feelings of nervousness. So if you give up caffeine, you could end up getting much better rest, says Dr. Temple. (People with insomnia might find this to be especially helpful, per the Sleep Foundation .)

It’s worth noting that quitting might not feel so great at first. “Someone’s energy levels will drop when they quit caffeine, at least initially,” says O’Connor, so you might feel daytime drowsiness or sluggishness. It’s hard to say if your energy levels will go back to where they were before you started consuming coffee, but if you tend to drink coffee later in the day and decide to quit, you might simply have more energy because you’re getting more sleep at night, as O’Connor explains.

If your sleep schedule seems to be off after quitting (which it might be for a few days or, sometimes, a few weeks), try to wake up at the same time each day to get yourself on a more consistent track. Trouble falling asleep? Try a guided meditation or some simple pre-bedtime tricks for a more restful night.

Caffeine can majorly contribute to daily or chronic headaches. It might also trigger migraine in people who are prone to them, according to the American Migraine Foundation . If you struggle with those, you might think going cold turkey will ease your discomfort—but that’s not always true, thanks to caffeine withdrawal, according to O’Connor. This could look like low energy, difficulty concentrating, irritability, and worsening headaches. Because caffeine narrows blood vessels around the brain, “a sudden lack of caffeine, especially when you’re drinking it daily or drinking a lot of it, can trigger a cascade of events that leads to dilated blood vessels which contribute to the headache,” says O’Connor.

In other words, your headaches will likely get worse before they get better. Gradually decreasing your caffeine intake over a week or two, rather than quitting cold turkey, “could help limit some of that severity,” O’Connor says—you could try slowly swapping your regular coffee for decaf.

Caffeine might not be the best thing for your mental health: It stimulates the nervous system and can cause anxiety, and people diagnosed with panic disorders are especially vulnerable to feeling on edge following caffeine use. 7,8,9

“Some people might have anxiety at baseline that’s exacerbated by caffeine, especially when it’s had in excess,” says O’Connor. For those people, she says that caffeine use might cause muscle tremors, a fast heart rate, and nervousness, which can work to make you feel even more anxious.

If you feel jittery after a Dr. Pepper (or three), you might find some relief if you kick the habit, says O’Connor—who also clarifies that how anxious caffeine makes you is different for everyone, so even if your habit is lighter or heavier, individual results here will vary.

Coffee poops are a real pain (literally) in the butt. Caffeine stimulates muscle contractions and gut motility in the body, which makes you go number two, says O’Connor: “If someone is really relying on their cup of coffee for a bowel movement, they might notice that they don’t use the bathroom as quickly in the morning [after quitting].”

By Nikki Campo

By Anna Borges

By Julia Sullivan

You might be dealing with a bit of constipation when you first quit. To get things flowing, O’Connor suggests switching to hot water because hot drinks can help smooth muscle relaxation and help out with your bowel movements. You can also try upping your fiber at breakfast. Oatmeal and bananas are good fiber-rich options !

If you have gastroesophageal reflux disease ( GERD ), which coffee can exacerbate, then you know it’s absolutely no fun. “Certain things may trigger reflux in one person and not in someone else. If caffeine is a known [GERD] trigger for someone, cutting back on it will, of course, be helpful,” says O’Connor.

Keep in mind that your acid reflux might not be caused by caffeine. To figure out if caffeine is really the issue, O’Connor suggests eliminating coffee (or however you get your fix) for a week to see if you feel different. If caffeine is, in fact, causing GERD symptoms, remember that the extent of the relief you’ll experience from GERD symptoms after quitting caffeine is individualized, according to O’Connor.

Caffeine is a diuretic. Not only does that mean caffeine makes you pee more, but it also dries out your mouth, Chrystle Cu, DDS , a dentist at Young Dental Group in California and founder of Cocofloss , tells SELF. Dry mouth (meaning you don’t have enough saliva to keep your mouth moist) isn’t great for your oral health . Saliva not only contains minerals that prevent tooth decay, but it also helps to wash away leftover food from the teeth and gum line—and makes swallowing easier. Too little saliva can cause “an imbalance of the oral microbiome,” says Dr. Cu. 10 “Reducing one’s caffeine intake would help in reducing one’s dry mouth, which will translate into a healthier mouth overall.”

If you’re worried about coffee stains, scheduling a routine dental cleaning can help lift some of them from your tooth enamel. 11 You can also give whitening toothpaste a shot.

Without your daily dose of caffeine, your mornings might look a little different. That’s not a bad thing: There are a ton of non-caffeinated beverages that you can give a whirl, many of which can feel like a special treat.

See what sparks the most joy: You can try caffeine-free herbal teas, which come in a number of delicious flavors, like Glazed Lemon Loaf , Calm Chamomile , and Organic Baked Cinnamon Apple . Now is your moment to up your smoothie game, too! Fruit “will provide an easily digestible source of carbohydrates to give you a boost of energy,” O’Connor says. Yogurt can help stabilize your blood sugar to help make sure that energy lasts throughout your whole morning. If you’re a soda lover, consider swapping your Sprite for seltzer.

You might be ready to retire your Mr. Coffee or 86 yourself from your favorite coffee shop ASAP, but let’s be very real: Quitting caffeine is hard! Cut yourself some slack if you’re struggling. You can always give it another shot—just maybe not one of espresso.

• So, Is Coffee Bad for You in Any Way?
• Why Starbucks’s New Olive Oil Coffee Is Allegedly Making People Poop a Whole Lot
• So, What’s the Latest I Can Pound Coffee and Still Sleep Like a Baby?
• European Review for Medical and Pharmacological Sciences, Caffeine Addiction and Determinants of Caffeine Consumption Among Health Care Providers: A Descriptive National Study
• Journal of Biological Rhythms , Regular Caffeine Intake Delays REM Sleep Promotion and Attenuates Sleep Quality in Healthy Men
• StatPearls , Caffeine Withdrawal
• Journal of Caffeine and Adenosine Research, Prevalence and Correlates of Caffeine Use Disorder Symptoms Among a United States Sample
• Risk Management and Healthcare Policy, Effects of Caffeine on Sleep Quality and Daytime Functioning
• Sleep Medicine Reviews , The Effect of Caffeine on Subsequent Sleep: A Systematic Review and Meta-Analysis
• Psychiatry Research , The Association Between Coffee Consumption and Risk of Incident Depression and Anxiety: Exploring the Benefits of Moderate Intake
• Cureus, The Neurophysiology of Caffeine as a Central Nervous System Stimulant and the Resultant Effects on Cognitive Function
• General Hospital Psychiatry, Effects of Caffeine on Anxiety and Panic Attacks in Patients With Panic Disorder: A Systematic Review and Meta-Analysis
• The Public Library of Science One , Dysbiotic Salivary Microbiota in Dry Mouth and Primary Sjögren’s Syndrome Patients
• Dentistry Journal , A Critical Review of Modern Concepts for Teeth Whitening

SELF does not provide medical advice, diagnosis, or treatment. Any information published on this website or by this brand is not intended as a substitute for medical advice, and you should not take any action before consulting with a healthcare professional.

• Undergraduate Honors Thesis

The Effects of Caffeine on Sleep Following Sleep Deprivation Public Deposited

• Introduction: In modern day society, pressures from the business and academic worlds cause people to consistently self-impose sleep restriction in order to meet deadlines. To maintain a level of alertness during these periods, many individuals rely upon caffeinated beverages in order to heighten their awareness and repress their drive for sleep. However, caffeine’s wakefulness promoting properties can negatively affect sleep quality during the following night’s sleep, resulting in an individual feeling less rested upon awakening. This thesis looked at the combined effects of sleep deprivation and caffeine on daytime recovery sleep. The study design mimics staying up all night in order to meet societal demands (e.g. tests, deadlines) and thus is directly translatable to common society. Methods: Thirty drug free males and females ages 18 to 35 participated in this study. Subjects completed an in-laboratory study. Subjects were given an 8 h baseline polysomnographically recorded sleep opportunity on the first night. Following the baseline night, subjects were sleep deprived for 28 h. Ten subjects were assigned to a caffeine group and administered a caffeine pill at 23 h awake. A 5 h recovery sleep opportunity followed the sleep deprivation episode. Sleep records were visually scored and compared within subjects and between conditions. Results: Sleep deprivation significantly decreased amounts of stage 2, REM and REM latency during recovery sleep in both the caffeine and placebo groups. Caffeine, in combination with sleep deprivation, significantly increased the amount of wakefulness and decreased the amount of stage 3/4 sleep when compared to placebo. These effects were seen when comparing the entire sleep episodes as well as when comparing the first 300 minutes of each sleep episode. Conclusion: The effect of caffeine attenuates the ability to dissipate the homeostatic build-up of sleep pressure that results from extended wakefulness. This is seen as a significant interaction between caffeine and sleep deprivation in the amount of deep sleep present in the recovery sleep episode. We also see a significant increase in the percent wakefulness in the caffeine group when compared to placebo indicate that caffeine 5 hours prior to daytime recovery sleep disturbs sleep even when sleep pressure is high. The disturbed sleep findings have important implications for individuals who use caffeine to promote wakefulness at night. Support: NIH R01 HL081761
• Smith, Benjamin
• Integrative Physiology
• Jr., Kenneth P. Wright
• University of Colorado Boulder
• In Copyright
• English [eng]

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Get better sleep with these 5 tips from experts

FILE - This Nov. 11, 2013 file photo shows a bedroom built by Mike Spangler using some reclaimed materials, in Belle, W.Va. Nearly one-third of American adults don’t get the recommended seven to nine hours of sleep per night. Some of the major causes: Stress, anxiety and a culture that experts say is about productivity, not rest. (Craig Cunningham/Charleston Daily Mail via AP, file)

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Spending too many nights trying to fall asleep — or worrying there aren’t enough ZZZs in your day ? You’re not alone.

Nearly one-third of American adults say they don’t get the recommended seven to nine hours a night. Some of the major causes: Stress, anxiety and a culture that experts say is about productivity, not rest.

“You need to understand what your body needs and try your hardest to prioritize that and not just see sleep as kind of what’s left over of the day,” said Molly Atwood, an assistant professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine.

Don’t fall for online fads or unproven methods to fall asleep and stay asleep. Instead, try these simple tricks recommended by sleep experts.

CREATE A BUFFER ZONE

Work-related stress is inevitable, and it can be hard to disconnect. Try creating a “buffer zone” between the end of your work day and your bedtime.

Experts suggest leaving career work and daily responsibilities alone about an hour before bed. Don’t check email, pay bills, do chores or scroll endlessly through social media. Instead, create a routine where you relax with a book, indulge in a hobby or spend time with loved ones.

“It goes back to the core value of mindfulness,” said Dr. Annise Wilson, an assistant professor of neurology and medicine at Baylor University. “Anything that helps to center you and just helps you focus and release a lot of that tension from the day will then help promote sleep.”

WATCH WHAT YOU EAT

Eating a large meal right before bedtime can disrupt your sleep, so try to grub in the early evening hours.

“I would say that eating a large meal is impactful simply because it’s like giving your body a really large job to do right before sleep at a time when things are supposed to be shutting down,” Atwood said.

But don’t go to bed super-hungry, either. Try snacks with protein or healthy fats, like cheese, almonds or peanut butter on whole grain bread.

AVOID CAFFEINE AND ALCOHOL

Having a nightcap or post-dinner espresso might feel relaxing, but it could lead to a long night.

While alcohol can help you fall asleep initially, it can disrupt your sleep cycle, reducing the quality of sleep and increasing the chances you’ll wake up more often in the middle of the night.

Caffeine is a stimulant that blocks adenosine , a chemical that contributes to the feeling of sleepiness — and it can take your body up to 10 hours to clear caffeine.

For these reasons, experts suggest finishing up your caffeinated or boozy beverages several hours before bed.

LIMIT TECHNOLOGY

Light from phones and computer screens can disrupt the circadian rhythm – or the internal clock that naturally wakes us up – by suppressing melatonin, which assists with sleep.

But you’ll need self-discipline to stop streaming or scrolling, said Dr. Dianne Augelli, an assistant professor of clinical medicine at Weill Cornell Medicine.

“TikTok doesn’t want you to stop,” Augelli said. “Only you can stop you, so you have to learn to put that stuff away.”

TALK TO YOUR DOCTOR

If nothing’s working and you’ve struggled to get a good night’s sleep for more than a month, experts say it’s time to go to a doctor. This is especially true if your sleepless nights are interfering with your work performance or your mood.

“It doesn’t matter how much relaxation you do. At a certain point, it’s not going to be effective if there’s a significant amount of stress,” Atwood said. “... It might involve some problem-solving to figure that out.”

In a story published April 23, 2024, about sleep tips, The Associated Press erroneously reported the name of an academic medical institution. It is Weill Cornell Medicine, not Weill Cornell Medical College.

The Associated Press Health and Science Department receives support from the Robert Wood Johnson Foundation. The AP is solely responsible for all content.

Prime energy, sports drinks contain PFAS and excessive caffeine, class action suits say

YouTubers Logan Paul and KSI founded Prime Hydration in 2022, and while their products have become increasingly popular and profitable, the company continues to face class action suits over the ingredients in their energy and sports drinks.

Prime Hyrdation LLC was sued April 8 in the Southern District of New York over "misleading and deceptive practices" regarding the company's 12-ounce energy drinks containing between 215-225 milligrams of caffeine as opposed to the advertised 200 milligrams, according to the class action suit.

Lara Vera, a Poughkeepsie, New York resident, filed the suit in federal court on behalf of herself and others who bought Prime products across the U.S., the complaint says. Vera purchased Prime's Blue Raspberry products several times in August 2022 for about $3 to $4 each, but she would have never bought the drinks if she had known the actual caffeine content, according to the suit.

Vera's suit is seeking $5 million from the company owned by Paul and KSI, real name Olajide Olayinka Williams "JJ" Olatunji, court records show.

Court records do not say whether Prime Hydration retained legal counsel for Vera's suit.

How much caffeine is in Prime energy drinks?

Prime's advertised 200 milligrams of caffeine is equivalent to "half a dozen Coke cans or nearly two (12-ounce) Red Bulls," Vera's class action suit says.

A 12-ounce can of Red Bull energy drink contains 114 milligrams of caffeine, and a cup of coffee contains around 100 milligrams of caffeine, according to the suit.

The suit continues to say that "there is no proven safe dose of caffeine for children." Side effects of kids consuming caffeine could include rapid or irregular heartbeats, headaches, seizures, shaking, upset stomach and adverse emotional effects on mental health, according to the complaint.

Sen. Charles Schumer , D-N.Y., called on the Food and Drug Administration (FDA) to investigate Prime energy drinks in 2023 because of dangerously high caffeine levels. Schumer alleged in a letter to the FDA that vague marketing targeting young people influenced parents to buy a “cauldron of caffeine" for their kids.

Schumer's call to action to the FDA is referenced in Vera's suit.

USA TODAY contacted Prime Hydration's attorneys Tuesday afternoon but did not receive an immediate response.

What are the Prime Hydration lawsuits?

Vera's legal battle is beginning, but Prime is still dealing with another class action suit from 2023 alleging a flavor of the company's sports drinks contains PFAS, or "forever chemicals."

Independent third-party testing determined the presence of PFAS chemicals in Prime Hydration grape flavor, according to a class action suit filed Aug. 2, 2023, in the Northern District of California by the Milberg law firm on behalf of Elizabeth Castillo and others similarly affected.

"Lead plaintiff Elizabeth Castillo, a resident of California, purchased Prime Hydration on multiple occasions but says she would not have bought it at all if the product had been accurately marketed and labeled as containing PFAS," the Milberg law firm said in an August 2023 news release . "These chemicals were not reasonably detectible to consumers like herself."

Castillo's suit is seeking a $5 million judgment, court records show.

As of April 18, the judge in the case has heard Prime's argument to dismiss the suit due to Castillo not alleging "a cognizable injury" and her not alleging "facts showing a concrete (and) imminent threat of future harm," according to the drink company's motion.

Paul addressed Castillo's claims Wednesday in a 3-minute TikTok video.

"First off, anyone can sue anyone at any time that does not make the lawsuit true," Paul said in the TikTok video. "And in this case, it is not… one person conducted a random study and has provided zero evidence to substantiate any of their claims."

What are forever chemicals?

PFAS are called forever chemicals because they "bioaccumulate, or accrue in the body over time," the Milberg law said in its news release.

"These man-made chemicals are well-studied and have been found to have adverse effects on the human body and environment," the New York City-headquartered law firm said.

Many PFAS are found in people's and animal's blood and can be detected at low levels in a variety of food products and in the environment, the U.S. Environmental Protection Agency (EPA) said. Forever chemicals can be found in water, air, fish and soil at locations across the nation and the globe, according to the EPA.

"There are thousands of PFAS chemicals, and they are found in many different consumer, commercial, and industrial products," the EPA said. "This makes it challenging to study and assess the potential human health and environmental risks."

Who made Prime energy drinks?

Before founding Prime Hydration LLC, Logan Paul, 29, and KSI, 30, were YouTubers who turned their millions of subscribers into supporters of their boxing, wrestling, music, social media content and other endeavors.

Going into the drinks business proved to be profitable for both YouTubers as "Prime Hydration generated more than $250 million in retail sales in its first year, including $45 million in a single month," according to the Milberg law firm.

Paul and KSI continue to keep Prime products in the spotlight whether it is paying for an ad during Super Bowl 57 , having livestreamer IShowSpeed dress up in a Prime sports drink bottle during Wrestlemania 40 or signing athletes including Patrick Mahomes, Aaron Judge, Israel Adesanya, Tyreek Hill, Kyle Larson, Alisha Lehmann and others to sponsorship deals.

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Prime Hydration sued over caffeine content in energy drinks

Prime hydration was co-founded by influencer logan paul.

Prime’s controversial energy drink is ‘comparable’ to every competitor: Logan Paul

Prime co-founder and boxer Logan Paul joins ‘Varney & Co.’ to discuss recent reports that kids are buying the company’s energy drink by mistake due to confusion with the non-caffeinated option.

Logan Paul's sports drink company, Prime, is being sued for allegedly deceiving consumers about the ingredients in its energy drink. 

A New York woman is claiming that Prime Hydration LLC, distributed by Congo Brands, is using "deceptive, and misleading advertising" regarding the caffeine content of its 12-ounce energy drinks.

The bottles advertise that there are 200 milligrams of caffeine per container. But "based upon testing commissioned by plaintiff’s attorneys, the products actually contain between 215-225 milligrams of caffeine," according to the class action suit, filed in the Southern District of New York in early April.

FOX Business reached out to Congo Brands for comment.

PRIME FOUNDER LOGAN PAUL CORRECTS 'FALSE NARRATIVE' OVER HEALTH CONCERNS FOR CAFFEINE DRINK: 'NOTHING TO HIDE'

The suit noted that the company's marketing campaign had already come under fire "for targeting children and adolescents despite their high concentration of caffeine."

Federal health officials have said that caffeine can be part of a healthy diet for most adults, but too much can pose a danger to a person's health.

Various flavors of the energy drink Prime are seen in a shop window in London on March 9, 2023. (Mike Kemp/In Pictures via Getty Images / Getty Images)

Healthy adults can drink about 400 milligrams of caffeine a day — or four to five cups of coffee — without "dangerous, negative effects," according to the Federal Drug Administration (FDA). 

The FDA does not have a set level for children, "but the American Academy of Pediatrics discourages the consumption of caffeine and other stimulants by children and adolescents," it said.

The lawsuit was filed less than a year after a woman in California accused the company of putting harmful chemicals — otherwise known as per- and polyfluoroalkyl substances ("PFAS") — in its drink products.

JAKE PAUL SAYS BROTHER LOGAN, A WWE SUPERSTAR, IS 'PERFECTLY CURATED' FOR WRESTLING: 'HE'S LIKE A NINJA'

According to the Centers for Disease Control and Prevention (CDC), PFAS are a group of chemicals used to make fluoropolymer coatings and products that resist heat, oil, stains, grease and water.

Side-by-side comparison of Prime Hydration and Prime Energy. (Getty Images)

Paul, who co-founded the company in 2022 with social media influencer KSI, addressed claims that the drinks contain forever chemicals.

"First off, anyone can sue anyone at any time, that does not make the lawsuit true," Paul said in a TikTok video on Wednesday. "And in this case, it is not… one person conducted a random study and has provided zero evidence to substantiate any of their claims."

Paul also issued a "correction" during an appearance on "Varney & Co." in August regarding the "false narrative" that Prime is under investigation by federal health officials.

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"Every ingredient in our products is FDA approved. And if they want to reach out and ask any questions, we're more than happy to answer them because we've retained samples from every single batch of prime that's ever come off the line," he said. "But the fact is, we're a legitimate business. We have nothing to hide, and we take quality and safety very seriously. But I came on here to correct some misconstrued information."

Paul also addressed the criticism that it was hard for kids to distinguish the difference between the caffeinated and non-caffeinated versions. 

"One is in a can and says ‘energy drink’ on it. The other is in a bottle. It says ‘hydration drink’ on it. One is 18+, the other is suitable for all ages. And we believe we've done as good of a job as we possibly can, differentiating our products," Paul explained.  

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Breaking news, my strength training ‘drastically’ improved with a pre-workout supplement — then the side effects kicked in.

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It was the lift she needed — or so she thought.

Julia Pugachevsky, a senior health reporter for Insider , revealed that she started taking Cellucor C4 pre-workout powder after reaching a plateau in strength training.

At first, she wrote in a Friday essay for Insider , she “felt ‘Popeye’-level strength, opting for 5lb-heavier dumbbells without hesitation. Even my instructors gave me more compliments on my form.”

But within a few months, she lost sleep, noticed an itchiness “akin to bees buzzing under my skin,” and grew “entirely dependent” on the scoop of the fruit-punch-flavored supplement.

Now, Pugachevsky is warning others about this “quick fix,” which she has tried to replace by consuming more protein , getting more sleep , and logging additional rest days.

The pre-workout supplements market, which includes powders, capsules/tablets, and ready-to-drink mixtures, is expected to reach $23.7 billion by 2027 , up from $13.9 billion in 2020.

Ingredients typically include beta-alanine, caffeine , citrulline, tyrosine, taurine , and/or creatine.

Pugachevsky’s pre-workout powder, which sparked “cartoonishly drastic” results, contains beta-alanine, creatine, caffeine, and citrulline, among other ingredients, according to its label.

Healthline reports that beta-alanine helps prevent lactic acid buildup in muscle tissue that can cause fatigue, pain, and soreness; creatine may enhance energy and muscle strength; caffeine can boost alertness and concentration; and citrulline may increase endurance and lower blood pressure.

The outlet notes that dietary supplements are regulated by the Food and Drug Administration as food, not drugs, which may lead to false marketing.

Pugachevsky said she was aware that beta-alanine can temporarily cause tingling or itching of the skin known as paresthesia, which is why she initially started with half a scoop before her strength training class before eventually doubling the amount.

She said she felt the itchiness when she increased the dosage. The Post reached out to the makers of Cellucor for comment.

“Taking pre-workout every time you exercise can get you in the habit of not listening to your body,” she wrote for Insider.

“It can mask natural tiredness, leading you to potentially injure yourself,” she continued. “Too much caffeine can also cause heart issues, such as changes in your heart rate or shakiness.”

Pugachevsky is not alone in questioning the value of workout supplements .

Rob Hobson, a UK registered sports dietitian and co-author of “The Detox Kitchen Bible,” recently told The Daily Mail that few supplements have been shown to offer real benefits .

“Relying on supplements to help manage your body weight or percentage of body fat will teach you nothing about the importance of diet, exercise and lifestyle and how you can manipulate these factors to help you achieve more sustainable performance goals,” Hobson said.

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Caffeine as a Factor Influencing the Functioning of the Human Body—Friend or Foe?

Kamil rodak.

1 Student Research Club, “Biomarkers in Medical Diagnostics”, Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, Borowska Street 211A, 50-556 Wroclaw, Poland

Izabela Kokot

2 Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, Borowska Street 211A, 50-556 Wroclaw, Poland; [email protected]

Ewa Maria Kratz

Associated data.

Not applicable.

Nowadays, caffeine is one of the most commonly consumed substances, which presents in many plants and products. It has both positive and negative effects on the human body, and its activity concerns a variety of systems including the central nervous system, immune system, digestive system, respiratory system, urinary tract, etc. These effects are dependent on quantity, the type of product in which caffeine is contained, and also on the individual differences among people (sex, age, diet etc.). The main aim of this review was to collect, present, and analyze the available information including the latest discoveries on the impact of caffeine on human health and the functioning of human body systems, taking into account the role of caffeine in individual disease entities. We present both the positive and negative sides of caffeine consumption and the healing properties of this purine alkaloid in diseases such as asthma, Parkinson’s disease, and others, not forgetting about the negative effects of excess caffeine (e.g., in people with hypertension, children, adolescents, and the elderly). In summary, we can conclude, however, that caffeine has a multi-directional influence on various organs of the human body, and because of its anti-oxidative properties, it was, and still is, an interesting topic for research studies including those aimed at developing new therapeutic strategies.

1. Introduction

Caffeine is one of the most popular and widely consumed beverages in the world. Its main source is coffee, however, it may also be present in other plants such as tea leaves, guarana berries, and cacao beans. It is worth pointing out that caffeine may also be found in energy drinks, soft drinks, gums, and medications [ 1 , 2 ]. Chawla et al. [ 3 ] stated that average caffeine consumption from all sources reaches 76 mg/person/day; in the United States and Canada, it is approximately 210–238 mg/person/day and exceeds 400 mg/person/day in Sweden and Finland. On the other hand, Conway [ 4 ] reported that in 2020–2021, coffee consumption was around 166.63 million 60 kg bags worldwide. This huge interest in coffee is due to its taste attributes and stimulating effects, and it additionally stems from the culture and habits of people in many countries. Due to the times and culture we live in, the presence of coffee rituals in our daily lives does not seem particularly surprising. However, it is amazing that a humble Yemeni bush has wrapped its branches around all continents. Interestingly, despite such a large consumption of caffeine, research shows that it is more a habit than a compulsive addiction [ 5 ]. Recently, caffeine has been of scientific interest because, as a bioactive molecule, it has been shown to have beneficial health effects (e.g., it is able to protect against oxidative stress in Alzheimer’s disease (AD)) [ 6 ]. However, people with hypertension, children, adolescents, and the elderly may be more susceptible to the negative effects of caffeine consumption [ 7 ]. Due to the widespread presence of caffeine, we present its impact (both positive and negative) on the human body, taking into account individual systems.

1.1. Caffeine—General Information

Caffeine (1,3,7-trimethylcanthine or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione), a well-known purine alkaloid, was described by Gennaro [ 8 ] as a white, odorless powder with a slightly bitter taste. Its chemical formula is C 8 H 10 N 4 O 2 . Caffeine occurs in more than 60 plant species globally [ 9 ]. This substance is produced by extraction from green coffee beans, tea leaves, and cola nuts, and also by synthetic procedures (e.g., methylation of various xanthines and theophylline) [ 8 ]. The most popular plants and products containing caffeine are shown in Figure 1 .

The most popular plants and products containing caffeine. Based on de Mejia et al. [ 10 ].

1.2. Metabolism of Caffeine

In the human body, caffeine is rapidly absorbed by the small intestine after oral administration into the body within 45 min and its average peak value occurs at 30 min [ 11 ], which directly depends on pH [ 8 ] and may be prolonged by food intake [ 12 ]. Its metabolic half-life is 3–5 h [ 13 ] and it readily penetrates the blood–brain barrier [ 12 ]. The first step in caffeine’s biotransformation is mediated by hepatic microsomal enzymes—selective catalysis by cytochrome P450PA in human liver microsomes [ 8 ]. Caffeine is primarily metabolized in the liver via the isoenzyme CYP1A2 (in about 80%), which causes its 3-demethylation to major metabolite, which is 1,7-dimethylxanthine (paraxanthine). Moreover, caffeine itself may increase CYP1A2 activity [ 14 ], and this isoenzyme is also responsible for the 1- and 7-demethylation of caffeine to 3,7-dimethylxanthine (theobromine) and 1,3-dimethylxanthine (theophylline), as shown in Figure 2 . These metabolites may be further primarily demethylated via CYP1A2, then acetylated via N-acetyltransferase 2, and oxidized via xanthine oxidase or CYP3A4 to yield major metabolites that are excreted primarily in the urine including 1-methyluric acid, 5-acetylamino-6-formylamino-3-methyluracil, 1-methylxanthine (e.g., after further demethylation of paraxanthine via CYP1A2), 1,7-dimethyluric acid, and 1,7-dimethylxanthine (paraxanthine) [ 14 ]. A low percentage (0.5–4.0%) of an ingested dose of caffeine is excreted unchanged in urine and in bile and is also found in saliva, semen, and breast milk [ 8 ].

The main pathways of caffeine metabolism in the liver.

1.3. Genetics and Caffeine

Individual variation in response to caffeine consumption is connected with genetic aspects. There are two genes especially linked with caffeine metabolism— CYP1A2 and ADORA2A [ 15 ]. The CYP1A2 gene, which codes CYP1A2, is mainly responsible for caffeine metabolism, as above-mentioned. A single nucleotide polymorphism (SNP) (–163 C > A, rs762551) in intron 1 is considered responsible for individual differences in caffeine biotransformation [ 16 ]. Sachse et al. [ 16 ] determined that there is a homozygous variant A (AA)—“fast metabolizers”, a heterozygous variant (CA), and a homozygous variant C (CC)—“slow metabolizers”. Womack et al. [ 17 ] examined 35 male cyclists (16 AA homozygotes and 19 C allele carriers) and showed that there was a significantly greater performance improvement among men with AA genotypes. On the other hand, Pataky et al. [ 18 ] reported that athletes with the C allele had a better response to caffeine. Overall, most studies found that response to caffeine was not associated with CYP1A2—163 C > A polymorphism [ 19 , 20 , 21 ].

Gene ADORA2A encodes adenosine receptor A 2A R, which plays a role in caffeine metabolism [ 22 ]. A 1976 T > C (rs5751876) SNP in the ADORA2A categorized people in TT—“high responders to caffeine” and CC/CT—“low responders to caffeine” [ 23 ]. Loy et al. [ 24 ] reported that TT athletes had higher improvements in cycling performance than C allele carriers. On the other hand, Carswell et al. [ 23 ] found that there were no differences in performance between TT and CT/CC genotypes. The results of the above investigations lead to the conclusion that further research into the influence of genetics on caffeine metabolism is needed. Future research should also be focused on detailed determination of which genes may affect the caffeine metabolism.

1.4. Effects on Receptors

Caffeine causes most of its biological effects via antagonizing all types of adenosine receptors (ARs): A 1 R, A 2A R, A 2B R, and A 3 R [ 25 ]. The blockade of adenosine receptors is observed in low concentrations of caffeine (<250 µM) [ 26 ]. Caffeine is also an agonist of ryanodine receptors (RyRs), stimulation of which increases the release of Ca 2+ from the endoplasmic reticulum (ER) and a non-selective competitive inhibitor of phosphodiesterases (PDEs), the enzymes degrading cyclic adenosine monophosphate (cAMP), which leads to increases in cAMP concentration in the cell, but the effect of caffeine action with the stimulation of RyRs and the blockade of PDEs is possible only at higher doses (blood plasma concentration of 100 μM for RyRs and 2000 mg of caffeine intake for PDEs) [ 6 , 27 ]. Caffeine also interferes with γ-aminobutyric acid type A (GABAA) receptors [ 28 ], and may also exert anti-inflammatory activity by decreasing pro-inflammatory (CRP: C-reactive protein, interleukins (ILs): IL-1β, IL-6, IL-18, TNF-α: tumor necrosis factor α) and increasing anti-inflammatory (IL-10, adiponectin) marker levels [ 29 , 30 ].

1.5. Toxicity of Caffeine

A single dose consumption of 200 mg of caffeine, or less, by healthy people without comorbidities and pharmacokinetic disturbances, is usually not associated with toxic effects [ 31 ]. However, a dose above 300 mg at once can cause caffeine intoxication, the symptoms of which are mainly related to its stimulating effect. The most common ones are: restlessness, nervousness, excitement, insomnia, facial flushing, increased urination, gastrointestinal disorders, muscle tremors, chaotic flow of thoughts and speech, irritability, arrhythmia, tachycardia, and psychomotor agitation. The severity of the undesirable effects of caffeine consumption is dose dependent [ 32 , 33 ]. The threshold of caffeine toxicity appears to be about 400 mg/day in healthy adults (19 years or older), 100 mg/day in healthy adolescents (12–18 years old), and 2.5 mg/kg/day in healthy children (less than 12 years old) [ 34 , 35 ].

1.6. Adenosine

Caffeine is so close in structure to adenosine that it is able to bind to the receptors that are specific to adenosine, which plays an important role in understanding how caffeine acts in the human body. Adenosine is an endogenous purine nucleoside, which is able to modulate the release of excitotoxic mediators, limit calcium influx, hyperpolarize neurons, and exert modulatory effects on glial cells when high concentrations of this nucleoside are observed [ 36 ]. Enhanced nerve activity, hypoxia, ischemia, or central nervous system damage may increase its level from 30–300 nM (physiological conditions) to 10 μM or even higher [ 37 ]. Adenosine binds to specific receptors expressed on the cell surface—A 1 R, A 2A R, A 2B R, A 3 R, which are members of G protein-coupled family receptors [ 38 ]. The A 1 subtype is mainly localized in the brain, spinal cord, eye, adrenal gland, heart, and to a lesser extent in tissues such as skeletal muscle and adipose, while the A 2A subtype is mainly localized in the spleen, thymus, striatopallidal GABAergic neurons and to a lesser extent in the heart, lung, and blood vessels [ 39 ]. Caffeine causes most of its biological effects via antagonizing all types of ARs: A 1 , A 2A , A 3 , and A 2B and, similar to adenosine, exerts effects on neurons and glial cells of all brain areas. As a consequence, caffeine, when acting as a nonselective AR antagonist, is doing the opposite of the activation of adenosine receptors due to the removal of endogenous adenosinergic tone [ 25 , 40 , 41 ]. The similarities between the caffeine and adenosine chemical structures are shown in Figure 3 .

The comparison of caffeine and adenosine chemical structures.

2. The Role of Caffeine in Various Systems in the Human Body

2.1. central nervous system.

Caffeine has multiple targets in the brain such as adenosine, ryanodine, γ-aminobutyric acid receptors, and cyclic nucleotide phosphodiesterase isoenzymes. Its action on A 2A Rs may explain the psychomotor stimulant effect, mediated by dopaminergic mechanisms. Caffeine, through antagonism of ARs, affects brain functions such as sleep, cognition, learning, and memory, and modifies brain dysfunctions and diseases: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, epilepsy, pain/migraine, depression, and schizophrenia [ 25 ]. Another possible mechanism of caffeine’s action on the nervous system is inhibition of the neurotransmitter acetylcholinesterase (AChE) [ 7 ]. This may be an important discovery for many studies on the effects of caffeine, clinically proven, but with unknown mechanisms of action. At low doses (<2 μg/mL in blood), caffeine stimulates the central nervous system but high blood concentration of caffeine (10–30 μg/mL) may produce restlessness, excitement, tremor, tinnitus, headache, and insomnia [ 8 ]. This conclusion was reported by Kaplan et al. [ 42 ], who observed that a lower dose (250 mg) of caffeine produced more positive effects (elation, peacefulness, pleasantness) than the higher dose (500 mg), which produced more negative effects (tension, nervousness, anxiety, excitement, irritability, nausea, palpitations, restlessness). Additionally, Watson et al. [ 43 ] documented the association between caffeine consumption and sleep quality in a group of 80 Australian adults (aged 38.9 ± 19.3 years). The study was based on a caffeine food frequency questionnaire and proved that higher doses of caffeine (192.1 ± 122.5 mg) were associated with worse sleep quality compared to lower doses of caffeine (25.2 ± 62.6 mg).

2.1.1. Caffeine Impact on Children and Adolescent

Caffeine intake has an impact not only on adults but also on children. In a subsequent study, Watson et al. [ 44 ] examined 309 Australian children (aged 8–12 years) on the basis of an interview conducted from the parents containing information about the consumption of caffeine (mostly in coffee, tea, and sodas) from 0 to 151 mg per day. This study showed that increased age, higher puberty scores, and higher morning tiredness values were associated with increased caffeine consumption. Otherwise, decreased total caffeine consumption was correlated with better internalization and decreased total behavior problems. Moreover, higher caffeine consumption was associated with a worse sleep routine, morning tiredness, and restless sleep. In another study, Richards and Smith [ 45 ] aimed to examine the connection between caffeine consumption and stress, anxiety, and depression in 3071 children from three academies in the southwest of England (aged 11–17 years). Participants were asked to complete a questionnaire about common dietary and caffeinated drink intake (total and separately) and well-being. Data analysis (made after adjusting additional dietary, demographic, lifestyle covariates, and sex) showed that caffeine consumption may be associated with stress, anxiety, and depression in secondary school children. Observed effects differed between men and women—effects relating to depression were strongest in females. Authors also reported that high caffeine intake (>1000 mg/week) was a risk factor associated with anxiety and depression in both sexes [ 45 ].

2.1.2. Caffeine and Taste Perception

Caffeine can also affect taste perception. Circulating adenosine intensifies the sweet-tasting signals in the taste buds [ 46 ]. Caffeine blocks adenosine receptors [ 47 ] and negatively affects the perception of sweet tastes [ 48 ]. The bitter taste of caffeine may have an influence on how the human body reacts. The results of some studies suggest that bitter products can enhance performance and also give the signal to our brain that the organism is ready for action [ 49 ]. These aspects are still to be examined, and seem to be potentially important for research in the field of sports medicine.

Gramling et al. [ 50 ] examined 12 males and 16 females (both caffeine consumers and non-consumers) using functional magnetic resonance imaging (fMRI), and showed differences in blood-oxygenation-level-dependent activation. The study was based on hedonic evaluation of caffeine, sucrose, or saccharin. During the hedonic evaluation of caffeine or sucrose, caffeine non-consumers had greater activation in neuronal areas associated with memory and reward, while during the hedonic evaluation of saccharin, greater activation in neuronal areas associated with memory, reward, and information processing occurred in the group of caffeine consumers. The results of the above studies support the observations on differential memory, reward, and information processing of taste between those who habitually consume caffeine and those who do not [ 50 ].

2.1.3. Caffeine and Alzheimer’s Disease

Alzheimer’s disease is the reason for 50–70% of neurodegenerative dementia cases and is characterized by a progressive decline in cognitive function, and pathologically by loss of synaptic integrity and neurons, amyloid plaques composed of amyloid beta (Aβ), and neuronal tangles composed of hyperphosphorylated tau protein [ 47 , 51 ]. Li et al. [ 52 ] described a mechanism whereby caffeine protects against Aβ generation. This mechanism includes suppression of LDL cholesterol-enhanced amyloidogenic processing of amyloid beta protein precursor (AβPP) by blocking AβPP internalization via its actions on adenosine receptors—A 3 Rs. Additionally, neuronal cell cultures with Aβ in the presence of an A 2A R antagonist completely prevented Aβ-induced neurotoxicity [ 53 ].

The neuromodulatory effects mediated by caffeine rely on a balanced activation of the inhibitory A 1 R and excitatory A 2A R receptors [ 54 ]. There are also premises that caffeine may have a neuromodulatory effect via receptors RyRs and inhibition of PDEs, and this applies to all doses of caffeine within the range of normal, habitual consumption, so the only molecular targets for caffeine at nontoxic doses are the adenosine receptors in the brain, especially the inhibitory A 1 R and the faciliatory A 2A R [ 55 ]. Upregulation of adenosine receptors A 1 R and A 2A R is observed in AD. Activation of ARs affects synaptic neurotransmission and the release of various neurotransmitters (acetylcholine, glutamate) [ 53 ].

The consumption of some caffeinated drinks, and caffeine itself, is correlated with lower risk of AD and dementia. The neuroprotective effect of caffeine has been demonstrated by Maia et al. [ 56 ] in a study among 54 patients with AD who consumed 73.9 ± 97.9 mg/day of caffeine during the 20 years before diagnosis of AD in relation to individuals without AD who consumed 198.7 ± 135.7 mg/day during the corresponding 20 years of their lifetimes. Authors showed that caffeine consumption was associated with lower risk for AD. Kolahdouzan and Hamadeh [ 6 ] also stated that caffeine is protective in AD and the dosages of caffeine at which this effect is noticeable is 3–5 mg/kg body weight. According to Ritchie et al. [ 57 ], consumption of at least three cups of coffee per day is associated with less decline in verbal memory. Eskelinen et al. [ 58 ] also studied the association between caffeine intake and AD and dementia. A study among 1409 subjects, aged 50 years, showed that midlife coffee drinking reduced risk of dementia and AD by 62–70% in people who drank 3–5 cups of coffee per day, compared to low coffee consumers (0–2 cups). However, it was also shown that tea drinking is not associated with risk of dementia/AD. Other studies by Lindsay et al. [ 59 ] in the Canadian community of 10,236 participants over the age of 65 years stated that coffee consumption was correlated with reduced risk (31%) of AD in the Canadian population. Overall, it should be emphasized that active constituents of coffee or tea, other than caffeine, may contribute to their effects on cognition/AD risk [ 59 ]. Recently, Dong et al. [ 60 ] investigated the association of intake of coffee (caffeinated and decaffeinated) and caffeine derived from caffeinated coffee with cognitive performance in older adults. They analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2011–2014 that included a total of 2513 participants aged 60 years or older. The information on coffee and caffeine consumption were received from two 24-h dietary recalls, whereas cognitive performance was evaluated by the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) test, Animal Fluency test and Digit Symbol Substitution Test (DSST). The authors observed no significant association between decaffeinated coffee intake and various dimensions of cognitive performance. It was suggested that caffeinated coffee and caffeine from coffee were associated with cognitive performance, while decaffeinated coffee was not associated with them [ 60 ]. Confirmation of the above findings was a placebo-controlled study involving sixty elderly people that showed that there was no significant association between decaffeinated coffee and cognitive functions [ 61 ]. In contrast, in a randomized, placebo-controlled study provided by Haskell-Ramsay et al. [ 62 ], it was shown that decaffeinated coffee may have a protective effect on cognitive performance. It should be noted, however, that the final analysis was carried out on a relatively small number of male and female participants: older (61–80 years, N = 30) and young (20–34 years, N = 29).

The results of studies on the effect of caffeine on the nervous system and cognitive functions are very promising, thus it would be justified to include this substance in the algorithm of management in people exposed to neurodegenerative diseases. However, taking into account the above data, a detailed study on the effects of caffeine and caffeine-containing products must first be carried out, as these products can contain many various bioactive ingredients that can alter the primary effect of caffeine.

2.1.4. Caffeine and Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disease with motor and non-motor symptoms [ 63 ]. Some studies reported that caffeine intake is beneficial for PD patients, similarly to Alzheimer’s disease. First of all, caffeine intake is associated with lower risk of Parkinson’s disease. Ross et al. [ 64 ] analyzed data on 8004 Japanese-American men (aged 45–68 years) drinking at least 28 ounces (421 mg of caffeine) of coffee, who were 5-times less exposed to PD, and this risk decreased as coffee consumption increased. Another study by Liu et al. [ 65 ] examining 187,499 men and 130,761 women showed that higher caffeinated coffee consumption was associated with lower PD risk in a dose-dependent manner, but consumption of other caffeine-containing beverages (soft drinks, hot tea, and iced tea) was not associated with the risk of PD. Moreover, Palacios et al. [ 66 ], after adjustment for age, smoking, and alcohol intake showed that the association of caffeine consumption with lower risk of PD was stronger for men compared to woman. These findings may be explained by the combined effects of caffeine and other coffee substances and should be further investigated. Although caffeine may reduce the risk of Parkinson’s disease, its intake does not improve the motor symptoms of the disease, as postulated by Postuma et al. [ 67 ], who treated 60 PD patients with caffeine and 61 with placebo. Patients with PD ongoing for 1–8 years consumed 200 mg of caffeine twice a day through 6–18 months. The authors found that caffeine does not influence sustained motor improvement in PD [ 67 ]. Caffeine not only reduces risk of PD, but may also be a promising diagnostic biomarker for early PD. Fujimaki et al. [ 63 ] examined 108 patients with PD and 31 age-matched healthy controls by using liquid chromatography-mass spectrometry to measure levels of caffeine and its 11 metabolites in serum. The authors showed that the absolute serum concentrations of caffeine and nine of its downstream metabolites were significantly lower in patients with PD than in healthy controls [ 63 ]. The above observations show new possibilities for laboratory diagnostics, but more research is needed for confirmation of those observations and complete evaluation of these findings.

There are also indications that caffeine may be an adjuvant in the treatment of PD. It was hypothesized that caffeine may increase excitatory activity in local areas by inhibiting astrocytic inflammatory processes, but evidence remains inconclusive. Roshan et al. [ 68 ] suggested that the co-administration of caffeine with currently available PD drugs helps to reduce drug tolerance and increases the effectiveness of the drug action. Despite the positive aspects, caffeine in combination with other substances can sometimes have a negative effect. Simon et al. [ 69 ] examined 1549 patients with early PD who completed a caffeine intake questionnaire. Half of the examined subjects were treated with creatine (10 g per day). Studies showed that higher caffeine intake was associated with significantly faster PD progression among subjects taking creatine [ 69 ], most probably caused by the caffeine action, which completely negates the effect of creatine on muscle contractions [ 70 , 71 ], potentially by counteracting the creatine-associated facilitation of calcium uptake by the sarcoplasmic reticulum [ 71 ].

2.1.5. Caffeine and Huntington’s Disease

Huntington’s disease (HD), an inherited neurodegenerative disorder caused by expanded CAG (cytosine, adenine, guanine) repeats, is characterized by motor, cognitive, and psychiatric disturbances [ 72 ]. HD is caused by a mutation in the IT15 gene that encodes for the protein huntingtin (Htt), which is widely distributed in the central nervous system, but to date, the exact cellular function of Htt is still not completely understood [ 73 , 74 ]. Htt is involved in many physiological functions including brain-derived neurotrophic factor expression/transport. When the Htt protein becomes mutated (mHtt), not only is normal Htt function impaired, but several mechanisms important for neuronal activity and survival become impaired, leading to a gain of function that can be toxic to the cells [ 75 ]. It is not clear whether HD is a prion-like disorder comparable to Alzheimer’s or Parkinson’s diseases, but experimental data suggests that mHtt triggers mis-conformation of wild-type Htt, and neuropathological observations in patients who received intracerebral allografts support the transfer of HD pathology from cell to cell [ 76 ].

In their review, Blum et al. [ 74 ] showed that many genetic, epidemiological, and experimental studies suggest that adenosine receptors, both A 1 R and A 2A R, are linked to HD pathophysiology, although their exact involvement remains unclear. Additional investigations are needed to dissect the pre- and postsynaptic aspects of A 2A R, and the relationship between A 2A R and mHtt induced glial dysfunction, which has been largely underestimated. Since HD is a chronically progressive disease, there are multiple mechanisms along the degenerative process that may be affected by their interactions with A 2A R. The role of A 1 R in HD pathogenesis also needs to be reconsidered.

Simonin et al. [ 72 ] assessed caffeine consumption in 80 patients with HD and it turned out that among people who consumed a caffeine dose greater than 190 mg per day, the risk of earlier HD was higher. As ARs, especially A 1 R and A 2A R, are known targets for caffeine, the possible mechanism of caffeine action in HD pathophysiology may be associated with its activity as a nonselective AR antagonist. Chronic caffeine intake may reduce adenosine A 2A R activity [ 77 ]. In the 3-NP model of Huntington’s disease, A 2A R antagonism has been associated with worsening signs [ 78 ]. However, Tanner et al. [ 79 ], based on their study results, concluded that only caffeinated soda, but not other caffeinated beverages, was associated with Huntington’s disease risk, nor was a combined caffeine dose associated, but this finding may be spurious, or not related to caffeine.

2.1.6. Caffeine and Perception of Pain

Caffeine is a constituent of many over-the-counter pain relievers and prescription drugs because the vasoconstricting and anti-inflammatory effects of caffeine act as a compliment to analgesics, in some cases, increasing the effectiveness of pain relievers by up to 40% [ 80 ]. Studies conducted on 62 people (aged 19–77 years) by Overstreet et al. [ 81 ] showed that habitual dietary caffeine consumption was associated with a higher pain threshold, higher heat pain tolerance, and higher pressure pain threshold. The mechanism by which caffeine can reduce pain sensation appears to be closely related to its direct effects on adenosine receptors, especially through the central blocking of those receptors that influence pain signaling or block peripheral adenosine receptors on sensory afferents. The antagonism of adenosine receptors as well as the inhibition of cyclooxygenase activity in some places may explain the anti-nociceptive effect of caffeine and its supportive effect [ 82 , 83 , 84 , 85 , 86 , 87 ]. This is the reason why low-dose caffeine is present as an adjuvant in conjunction with antidepressants, acetaminophen, and non-steroidal anti-inflammatory drugs in many over-the-counter (OTC) pain medications [ 88 , 89 ].

2.1.7. Caffeine and Mental Health

Depression, anxiety, and suicide are becoming an increasingly common problem among children and adults. This prompts not only the search for new therapies, but also for the causes of these ailments more closely. Over the years, caffeine has been investigated as a potential protective or risk factor for psychiatric disorders [ 90 ]. It has already been documented that caffeine intake is associated with depressive symptoms. Lucas et al. [ 91 ] indicated that the risk of depression is associated with the dose of consumed caffeine. They showed that people who drank more than two cups of caffeinated coffee per day were 24% less exposed to depression than those who did not drink coffee. In addition, Richards and Smith [ 45 ] found that the incidence of depression decreased as the dose of caffeine intake increased, but they did not verify the differences between men and women. Botella et al. [ 92 ] investigated the effect of caffeine on depression in 2307 students aged 11–17 and showed that consuming less than 1000 mg of caffeine per week increased the risk of depression in girls, but not in boys. This conclusion has been confirmed by Iranpour and Sabour [ 93 ], who analyzed data derived from 4737 adults and found that women who consumed more caffeine had a lower risk of depression.

Kendler et al. [ 94 ] analyzed data from the Virginia Twin Registry of about 3600 adult twins and reported that the risk of developing anxiety increased after consumption of >6 cups of caffeinated coffee per day. Additionally, Bertasi et al. [ 95 ], in their study among 114 college students, showed that high caffeine intake is associated with higher levels of anxiety. Botella et al. [ 4 ] examined 3323 students (11–17 years old) and showed that the effect of caffeine on anxiety is significant mainly in boys—the anxiety increased with increased dose of caffeine intake. According to this, Hedstrom et al. [ 96 ] obtained similar results among 39 men and 60 women aged 18–31 years, and reported that at the same doses of caffeine consumption, men had a higher anxiety state than women.

Some studies have examined the effect of a single instance of caffeine intake on neurocognitive performance. Konishi et al. [ 97 ] investigated the effect on driving performance in 100 healthy Japanese volunteers (50 males, 50 females, aged 22–59 years) with a valid driver’s license. In this double-blinded, randomized, placebo-controlled study, half of the participants formed a caffeine intake group and the other a placebo group. Individuals did not consume caffeine for three days before the examination, then the “caffeine group” was given 200 mg of caffeine. Thirty minutes after administration, cognitive functions were evaluated via the Symbol Digit Coding Test (SDC), the Stroop Test (ST), the Shifting Attention Test (SAT), and the Four Part Continuous Performance Test (FPCPT). After these tests, the authors checked driving performance (brake reaction time and standard deviation of the lateral position) using a driving simulator. Research showed that the “caffeine group” had more appropriate responses than the placebo group on the SAT, made less mistakes, and had shorter times in the brake reaction time test. Studies conducted by Yu et al. [ 98 ] using long-term self-renewing neuroepithelial stem cells showed that consumption of caffeine (3 μM and 10 μM) activates immediate early genes after 1 h, while neuronal projection development processes were upregulated and negative regulation of axon extension processes were downregulated at 3 h.

It is known that caffeinated coffee consumption may be associated with a lower risk of suicide, depending on the amount of coffee consumed daily [ 99 , 100 ]. Lucas et al. [ 91 ] analyzed three prospective cohorts of American adults consisting of 43,599 men and 164,825 women, among which caffeine consumption was tested every four years. The authors documented 277 deaths from suicide and showed correlations between caffeine intake and deaths as an inverse relationship [ 91 ]. However, in a Finnish population study [ 101 ] of over 43,000 people who were followed for an average of 14.6 years, a J-shaped relation was found between daily coffee drinking and the risk of suicide. Compared to those who drank one cup of coffee per day, the risk of suicide was lower with moderate coffee consumption (2–3 cups per day to 6–7 cups per day), but increased with higher consumption (8–9 and 10 cups per day). The main effects and probable mechanisms of caffeine action on the nervous system are shown in Table 1 .

The main effects of caffeine action on the nervous system and the most likely mechanisms of its action.

Aβ—amyloid beta, Ars—adenosine receptors, AChE—acetylcholinesterase, RyRs—ryanodine receptors. ↓—decrease, ↑—increase.

In conclusion, caffeine action in a variety of central nervous system diseases and disturbances is multi-directive, as caffeine has multiple targets in the brain and affects many brain functions such as sleep, cognition, learning, and memory, while on the other hand modifying brain dysfunctions and diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, epilepsy, pain, and depression. The effect of caffeine depends mainly on the amount of the substance. At low concentrations, it has a positive effect on the human brain, but higher doses may be responsible for negative effects in mood and behavior. In some diseases, caffeine consumption in high doses may be a risk factor (AD, PD, Huntington’s disease), however, on the other hand, thanks to its therapeutic properties and ability to antagonize ARs, caffeine may be useful in the treatment of PD and pain symptoms or, in connection with some other medications, may delay the progression of the disease. The utility of caffeine and its metabolites in laboratory diagnostics as markers of certain diseases (e.g., PD) also seems promising.

2.2. The Immune System

The immune system is complex and is made up of various cells and proteins that are responsible for the body’s resistance, particularly through the immune response, which is a weapon against foreign antigens [ 103 ]. More and more attention is paid to the two-way relationship between the immune system and diet [ 104 ]. The role of caffeine in the functioning of the immune system reaches the cells themselves. Gibbs et al. [ 105 ] reported that caffeine in high concentrations (5 mM) inhibits the mammalian target of rapamycin (mTOR) in human myeloid leukemia cells, primary human acute myeloid leukemia cells, and primary human basophils, and affects glycolysis and the release of pro-inflammatory cytokines. Additionally, in monocytes, the effect of caffeine was potentiated by its ability to inhibit xanthine oxidase (purine catabolism), and in basophiles, caffeine increased intercellular cAMP levels [ 105 ].

Adenosine receptors are expressed on monocytes and macrophages and through these receptors, ligands (e.g., adenosine, caffeine) can modulate monocyte and macrophage function [ 38 ]. Chavez-Valdez et al. [ 106 ] used cord blood monocytes (CBM) from 28 full-term infants (>37 weeks’ gestation at birth) to investigate changes in the ARs mRNA profile (by qRT-PCR) and protein expression (by western blot) after in vitro culture, caffeine, or lipopolysaccharide (LPS) exposure, and the modulation of cytokine release and cAMP production (by ELISA) induced by caffeine and ARs antagonists. After 48 h in culture, it turned out that caffeine (50 μM) decreased tumor necrosis factor-alpha (TNF-α) from LPS activated-CBM by 20% and TNF- α gene expression by 30%, in conjunction with a minimum 2-fold increase in cAMP. This suggests that caffeine increases cAMP production and inhibits pre-transcriptional TNF-α production by CBM via A 1 R blockade. These observations were later confirmed by Chavez-Valdez et al. [ 107 ], where the authors used LPS-activated CBM from 19 infants and exposed them to caffeine in various concentrations (0–200 μM) with or without previous exposure to ARs antagonists, and showed that caffeine at ≤100 μM reduced TNF-α levels by 25% and IL-10 levels by 17–25%. The results of the same study confirmed that caffeine concentration is directly positively correlated to toll-like receptor 4 (TLR4) gene expression, and therefore it promotes inflammation [ 107 ]. Steck et al. [ 108 ] demonstrated that caffeine may act as a phosphodiesterase inhibitor, suppressing phagocytosis in mononuclear phagocytes by promoting an anti-inflammatory response. Although the obtained results were promising, in the human body, it is a complex and dynamic process that involves many pathways that may contradict each other, resulting in inconsistent results dependent on dosage of caffeine and state of the exposed cell. In their study, Shushtari et al. [ 109 ] used mesenchymal stem cells (MSCs) isolated from bone marrow and treated them with different concentrations of caffeine (0, 0.1, 0.5, and 1 mM) for 72 h, out of which 24 h consisted of incubation with macrophages. The authors observed that MSCs treated with caffeine enhanced phagocytosis and the expression of reactive oxygen species, nitric oxide, and IL-12 by macrophages. These results proved that caffeine augments the instruction of anti-inflammatory macrophages and showed the potential mechanism of the immunomodulatory and anti-inflammatory effects of caffeine [ 109 ]. However, the presented results indicate the therapeutic properties of caffeine, high doses of caffeine necessary to obtain certain effects, may be toxic to the human body.

In summary, caffeine reaches cells by interaction with ARs, which are expressed on them. Its anti-inflammatory effect is important in the functioning of the immune system, however, more attention is required to the potential use of caffeine as a therapeutic agent in hematological diseases related to the malfunction of the immune system.

2.3. Digestive System

Caffeinated coffee consumption is one of the causes of gastrointestinal discomfort reported by patients as well as digestive system problems noted by doctors. The main pharmacologically active substance in coffee is caffeine, which may increase gastric acid secretion [ 8 ], relax smooth muscles by increasing gastrin concentration [ 110 ], and stimulate the secretion of hydrochloric acid [ 111 ], causing higher risk of inflammation of the intestinal mucosa and stomach. On the other hand, caffeine is said to be antioxidant and to have anti-inflammatory activity [ 112 ], thanks to which caffeine can reduce alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin level in serum [ 112 ]. There is also a connection between coffee consumption and γ-glutamyltransferase (GGT) activity—together with higher coffee consumption, lower GGT activity was observed [ 113 ]. It should be noted, however, that coffee ingredients may disturb iron absorption [ 114 ], and zinc’s bioavailability [ 115 ]. It is suggested that coffee and its compounds may also affect intestinal microbiota, especially Bacteroides , and increase its level [ 116 ]. The effects of caffeine action on the digestive system are schematically shown in Figure 4 .

The scheme of the main effects of caffeine action on the digestive system. ALT—alanine aminotransferase, AST—aspartate aminotransferase, GGT—γ-glutamyltransferase. ↓↓↓—decrease, ↑↑↑—increase.

2.3.1. Caffeine Action on the Small and Large Intestine

Caffeine has an impact on net fluid movement and transit times, although the data in this respect are not conclusive. It has been reported that caffeine ingestions (75–300 mg) caused increased net secretion in jejunum for a minimum of 15 min, and 35 min later in ileum in the same doses of caffeine [ 117 ]. The results of another study showed that caffeine affects esophageal function by decreasing the pressure on the lower esophageal sphincter, leading to its relaxation [ 118 ]. Relaxed lower esophageal sphincter may be a reason for gastric reflux [ 119 ]. Moreover, it was also documented that caffeinated coffee stimulates gallbladder contraction and colonic motor activity, but there were no connections between coffee consumption and dyspepsia [ 119 ].

It is still unclear whether and to what extent the consumption of caffeinated coffee and caffeinated products affects gastrointestinal transit time and whether this is an effect of caffeine content. Boekema et al. [ 119 ] investigated the effect of caffeinated coffee consumption on gastrointestinal motility, on gastric emptying, and oro-cecal transit time. In a randomized, controlled, cross-over study gastric emptying and oro-cecal transit time, the authors studied 12 healthy volunteers using applied potential tomography and the lactulose hydrogen breath test. The lag-phase duration after coffee intake was not significantly different from that after water (median 19.8 min vs. 19.3 min, respectively), nor was the gastric half-emptying time (median 75.7 min vs. 83.4 min, respectively). Furthermore, coffee had no significant effect on oro-cecal transit time (median 135 min vs. 140 min, respectively). No significant correlation between any of the examined parameters and mean daily caffeinated coffee intake was found, which confirms that coffee consumption does not affect gastric emptying of a liquid meal or small bowel transit. On the other hand, Rao et al. [ 120 ], who investigated the effects of caffeinated coffee on colonic motor activity in healthy humans, revealed that coffee stimulates colonic motor activity. Its magnitude was similar to a meal, 60% stronger than water, and 23% stronger than decaffeinated coffee.

2.3.2. Caffeine and the Liver

Animal models (mice and rats) have shown that caffeine may play a potential role in the stimulation of β-oxidation in hepatic cells, intrahepatic lipid content reduction, and hepatic autophagy [ 5 , 6 ], which suggests that caffeine ingestion suppresses inflammation and lipogenesis [ 121 ], reduces lipid peroxidation [ 112 ], and is linked with lower risk for nonalcoholic fatty liver disease [ 122 ]. Caffeine is inversely associated with the risk of cirrhosis [ 123 ] and the risk of hepatocellular carcinoma, especially among people with the hepatitis C virus and other liver diseases [ 124 ]. Modi et al. [ 125 ] examined 177 patients (among which 99 were male, 104 Caucasian, 121 with hepatitis C) who underwent liver biopsy and completed the caffeine questionnaire. The authors analyzed caffeine consumption by coffee-cup equivalents, and revealed an association between caffeine consumption and lower risk of liver fibrosis, especially in patients with HCV infection when two coffee-cup equivalents were consumed per day [ 125 ]. Li et al. [ 126 ] examined the molecular aspects of the protective role of caffeine in fibrogenesis by using a LX-2 cell line (immortalized human hepatic stellate cells) and exposing it to various concentrations of caffeine. The results of the study showed that caffeine inhibits the viability and increases the apoptosis of the LX-2 cells in a dose- and time-dependent manner by autophagy of endoplasmic reticulum, via the inositol-requiring enzyme 1α signaling pathway. In another study, Salomone et al. [ 117 ] suggested that through stimulation of the nuclear factor erythroid 2-related factor 2 (Nrf2) (which reduces oxidative stress and inflammation), peroxisome proliferator-activated receptors alfa (PPARα) (which increase β-oxidation and reduce lipid accumulation), 5’ adenosine monophosphate-activated protein kinase (AMPK) (which increases autophagy and reduces lipid accumulation), and inhibition of sterol regulatory element-binding transcription factor (SREBP1c) (which reduces de novo lipogenesis and reduces lipid accumulation) and receptor A 2A R, coffee and its components suppress liver fibrogenesis and carcinogenesis [ 117 ]. Moreover, caffeine, depending on the dose, is said to increase apolipoprotein A1 and paraoxonase-1 protein levels in liver cells [ 127 ].

2.3.3. Caffeine and Glycaemia

High doses of caffeine increase glucose tolerance [ 128 ] and decrease insulin sensitivity [ 129 ]. It has been shown that decaffeinated coffee, in contrast to caffeinated, reduces HbA 1c levels [ 130 ] used in glycaemia monitoring, which suggests that coffee contains other substances that may improve glucose metabolism, and this needs to be examined. The studies on caffeine consumption among people with type 2 diabetes do not show any correlation between decaffeinated coffee and improvement in glycemic control [ 130 ], and should be confirmed by additional research, since the results of another study have shown that frequent (at least seven cups per day) coffee consumption may reduce the risk of type 2 diabetes by 50% [ 131 ], as confirmed in many studies [ 132 , 133 , 134 ]. It has also been documented that caffeine may affect the phosphatase activity of glycogen synthase [ 110 ]. When linked with glucose, there was only slight stimulation over a wide concentration range, thus it seems that there is no synergy between these two compounds in the activation of glycogen synthase phosphatase [ 135 ].

2.3.4. Caffeine and Digestive Tract Cancer

Some studies indicate that coffee with caffeine may reduce the probability of digestive tract cancer occurrence, especially liver cancer [ 117 , 136 ] and colon cancer [ 137 ]. Liu et al. [ 114 ] used human gastric cancer cells in in vitro studies to show that caffeine treatment suppressed gastric cancer cell growth and viability, and activated the caspade-9/-3 pathway, which induced apoptosis. Taking the above into consideration, it seems that caffeine may be useful as a sustained anticancer agent in the therapy of gastric cancer, however, these observations should be confirmed by additional studies. The meta-analysis conducted by Li et al. [ 138 ] consisting of 25 case-control and 16 cohort studies showed that the risk of colorectal cancer was reduced by 15% for the highest coffee drinkers compared to low or non-drinkers, and the authors concluded that the risk of colon cancer was reduced by 21%. In this meta-analysis, information on the classification of subjects to the group of high, low, or non-coffee drinkers was taken by the authors from the classifications described previously in other, original articles, and thus there was no possibility of assigning unambiguous values for these groups. Tian et al. [ 139 ] reported a significant decrease in the risk of colorectal and colon cancer among subjects consuming at least four cups of coffee a day. The results of meta-analysis conducted by Sang et al. [ 140 ] showed that the risk of liver cancer for high coffee drinkers was 50% lower than for non/almost never drinkers. Additionally, Bravi et al. [ 141 ] analyzed some studies and in their meta-analysis showed that the risk of hepatocellular carcinoma was reduced by 40% for any coffee consumption versus no consumption. The authors suggested that the effect on liver enzymes and development of cirrhosis may be responsible for the protective effect of caffeine against liver carcinogenesis [ 141 ].

As documented by the many studies above-mentioned, caffeine action covers a variety of points in the food pathway, starting from the mouth, through the stomach, small intestine, and liver to the large intestine. It increases the secretion of gastric acid, decreases the activity of liver enzymes, and improves the motor functions of the intestines. Caffeine’s antioxidant and anti-inflammatory properties reduce the risk of liver disease (cirrhosis, fibrogenesis, nonalcoholic fatty liver disease, etc.) and some cancers. Additionally, caffeine is considered to be a promising anticancer agent because of its antioxidant potential, which is especially important in cancer treatment because cancer progression and metastasis are accompanied by oxidative–antioxidant imbalance.

2.4. Respiratory System

The effect of caffeine on the respiratory system is mainly described as beneficial, regardless of whether it is administered individually, as a component of drugs, or synergistically with applied therapy [ 142 ]. Caffeine acute ingestion (3 mg/kg body weight) may improve peak aerobic performance and increase peak pulmonary ventilation. The role of caffeine in this effect may be explained by its ability to affect respiratory muscle [ 143 ]. Supinski et al. [ 144 ] examined the effect in six healthy people of single, orally administered doses of caffeine (600 mg) on diaphragmatic muscle, and showed that caffeine increased trans-diaphragmatic pressure, probably by increases in muscle contractility. This suggests that caffeine may be used in the treatment of patients with respiratory muscle weakness. Another possible mechanism of caffeine action is without a doubt its influence on receptors. For example, Bruce et al. [ 145 ] showed that caffeine (200 mg) caused a decrease in exhaled nitric oxide via AR antagonism, or by altering levels of cGMP. The main effects of caffeine action in respiratory system diseases are summarized in Table 2 .

The effects of caffeine action in respiratory system diseases.

COPD—Chronic Obstructive Pulmonary Disease. ↓—decrease, ↑—increase.

2.4.1. Caffeine and Asthma and Chronic Obstructive Pulmonary Disease

An important action of caffeine is the stimulation of the respiratory system, hence caffeine is a common ingredient in bronchodilators [ 146 ]. Welsh et al. [ 146 ] examined 75 people with mild to moderate asthma and showed that caffeine (even at less than 5 mg/kg body weight) improved lung function for up to two hours after consumption (differences in forced expiratory volume in one second about 5%). The authors concluded that caffeine improves airway function modestly, for up to four hours, in people with asthma [ 146 ].

There is little information about the association of caffeine with chronic obstructive pulmonary disease (COPD). Hirayama et al. [ 147 ] examined 277 Japanese COPD patients (aged 50–75 years) who drank more caffeinated coffee and had a significantly higher mean caffeine intake (311.3 ± 176.2 mg/day) than the control group (278.4 ± 188.1 mg/day). Relative to the control group of non-drinkers (340 individuals), the risk of COPD apparently increased for those drinking at least two cups of coffee daily. Similarly, total caffeine intake was associated with the prevalence of COPD—for consuming over 312 mg/day, the risk of COPD was higher when compared to a low intake of less than 184 mg/day. In their retrospective study, Lopes et al. [ 148 ] evaluated the effect of chronic caffeine consumption on the risk for COPD exacerbations among 90 patients with COPD and showed that mean caffeine consumption (149.7 ± 140.9 mg/day) was not associated with an effect on the frequency of COPD exacerbations. Due to the small amount of research on the effects of caffeine on COPD, the results of the above studies should be confirmed in further investigations.

2.4.2. Caffeine and Breathing Problems

Aranda et al. [ 149 ] in their study examined 12 infants with infantile apnea and observed significant increases in ventilation, tidal volume, and mean inspiratory flow with plasma concentrations of caffeine ranging from 8 to 20 mg/L. The above results show that caffeine may be valuable medicine, but more studies are required for confirmation of these findings. Another study was conducted by Kassim et al. [ 150 ] among 18 prematurely born infants being weaned from mechanical ventilation. The infants were given caffeine (5 mg/kg body weight/24 h), and after 6 h, measurements were made. The maximum pressures generated by occlusions at end inspirations and end expirations, and lung volume, had significantly improved. This suggests that caffeine administration increases respiratory muscle function, and is associated with lung function improvement. Davis et al. [ 151 ] measured the effect of caffeine upon pulmonary mechanics in 16 infants with bronchopulmonary dysplasia. A dose of 10 mg/kg body weight of caffeine caused a 37% increase in minute ventilation, 42% increase in tidal volume, and 47% improvement in total pulmonary compliance. Total lung resistance decreased by 20% [ 151 ].

2.4.3. Caffeine and Lung Cancer

Baker et al. [ 152 ] examined 993 individuals (624 male and 369 female) with primary, incident lung cancer and observed an elevated lung cancer risk for drinkers of at least two cups of caffeinated coffee per day, as confirmed in a meta-analysis conducted by Wang et al. [ 153 ]. The authors reported a linear relationship between coffee consumption and increased risk of lung cancer, especially for consumers of ≥3 cups coffee per day [ 153 ].

In summary, the importance of caffeine in the functioning of the respiratory system is great due to the important function this system plays not only for basic life functions, but also in the world of sports, where it seems important to consider caffeine as a means of increasing ventilation, tidal volume, and airway functions. Thanks to these effects, caffeine can be also used as a medication for people with asthma, but it should be considered that caffeine can also have negative effects on the respiratory system such as increasing the risk of COPD and lung cancer. Therefore, once again, we can see that although caffeine has many benefits, it is necessary to exercise moderation in consuming products that contain it.

2.5. Circulatory System

In general, an acute intake of caffeine stimulates a modest increase in blood pressure (both systolic and diastolic) [ 154 ]. In volunteers who abstained from caffeine-containing products, a bolus dose of 250 mg led to a 5–10% increase in both systolic and diastolic blood pressure for 1–3 h. Tolerance to this effect developed, however, when caffeine was given three times a day for seven days [ 155 , 156 ]. In another study, Van Dusseldorp et al. [ 157 ] reported that daily use of decaffeinated coffee (40 mg caffeine) instead of five cups of regular coffee (445 mg caffeine) for six weeks led to a small but significant decrease in systolic (by 1.5 mmHg) and diastolic (by 1.0 mmHg) blood pressure in 45 healthy volunteers. Moreover, scientists from Radboud University Nijmegen Medical Center observed that the dose of caffeine in coffee alone raised blood pressure less than an identical concentration given in the pill [ 158 ]. These effects suggest that the mechanism of caffeine action is an increase in intracellular calcium concentrations, the release of norepinephrine, and the sensitization of dopamine receptors, because caffeine has a positive inotropic effect [ 159 ]. Some studies have documented that coffee consumption and the type of coffee plays a role in lipid metabolism. Boiled coffee increases serum total and LDL cholesterol concentrations, but filtered coffee does not significantly change serum cholesterol levels [ 160 ]. A study of 32 healthy volunteers of both sexes (aged 25.2 ± 4.2) with body mass index (BMI = body mass (kg)/height 2 (m)) of 21.7 ± 2.2, conducted by Melik et al. [ 161 ], showed that 200 mg of caffeine consumption increased arterial pressure and decreased heart rate and resting cutaneous laser-Doppler flux. It was observed that myogenic activity also increased. In conclusion, the results of this study suggest that caffeine affects cutaneous microvascular function during rest and during a post-occlusive reactive hyperemia response [ 161 ].

Caffeine and Arrhythmia

One of the possible mechanisms of caffeine action is blocking ARs (mainly subtypes A 1 and A 2 ) [ 47 ] and causing a higher release of dopamine and noradrenalin [ 162 ]. It inhibits the action of natural adenosine, and can cause tachycardia and arrhythmias due to the increased activation of the β1-receptor [ 163 ]. As a nonselective competitive inhibitor of A 2A Rs, caffeine might attenuate the vasodilator effect of adenosine, and increase sympathetic activity, yielding to capillary de-recruitment and leading to decreased myocardial perfusion reserve [ 47 , 164 ]. Seitz et al. [ 165 ] in their study showed that caffeine reduced the myocardial perfusion reserve index (MPRI). The authors examined 25 patients (84% male, median age 69 years) with substantial myocardial ischemia and coffee addiction (3–4 cups per day), who underwent repeat adenosine stress perfusion imaging by cardiovascular magnetic resonance after a prior intake of two cups of coffee (about 200 mg of caffeine) 1 h before examination, which confirmed the need for abstinence from caffeine [ 165 ].

Caffeine is also a nonspecific inhibitor of phosphodiesterases that is able to intensify production of cAMP and cGMP, which affects cardiac contractility, and this may predispose to arrhythmias [ 163 ]. The meta-analysis conducted by Greenland [ 166 ] was based on 22 studies, and the author showed that drinking at least five cups of coffee per day may enhance the risk of myocardial infraction or coronary death.

In conclusion, the circulatory system is one of the most vulnerable to the negative effects of caffeine because of its effects on blood pressure (both systolic and diastolic), which can be rapidly increased. It should be emphasized that the type of coffee (caffeinated or decaffeinated) and the way that caffeine is served influence blood pressure, and it was suggested that the stimulating effect of caffeine action is associated with an increase in intracellular calcium concentrations, the release of norepinephrine, and the sensitization of dopamine receptors. Caffeine is able to inhibit ARs and PDEs and activate the β1-receptor, which can lead to problems related to cardiac function such as tachycardia and arrhythmia and, consequently, to death.

2.6. Urinary Tract

The well-known diuretic effect of caffeine is related to the maintenance of the water–salt balance in different segments of the nephron in which adenosine plays a complex role, depending on the differential expression of its receptors. Therefore, caffeine increases the rate of glomerular filtration, counteracting by the vasoconstriction of renal afferent arteriole mediated by adenosine via type 1 AR during tubuloglomerular feedback. It should also be emphasized that caffeine inhibits Na + reabsorption at the level of the proximal renal tubules and disrupts the hepatorenal reflex through sensory nerves in Mall’s intrahepatic spaces [ 167 ]. Caffeine may increase urine production [ 8 ], and excessive caffeine intake (more than 400 mg/day) may increase the risk of detrusor instability (unstable bladder) in women [ 168 ]. In the kidneys, caffeine induces diuresis and natriuresis [ 169 ]. Wu et al. [ 170 ] showed that there was a positive correlation between several urinary caffeine metabolites, especially paraxanthine, theobromine, and caffeine and urine flow rate. Moreover, the number of metabolites showing certain flow-dependency was higher in males than females and was higher in young participants compared to elderly participants [ 170 ]. A study by Lohsiriwat et al. [ 171 ] on nine women and three men (aged 21–40 years) with overactive bladder symptoms who drank 8 mL/kg body weight of water with or without caffeine at two separate sessions showed that caffeine at 4.5 mg/kg body weight caused diuresis and decreased the threshold of sensation at the filling phase, with an increase in flow rate and voided volume. In conclusion, caffeine can promote early urgency and frequency of urination [ 171 ]. The main effects of caffeine on kidney action are shown in Figure 5 .

The main effects of caffeine action on the kidneys. ↓↓↓—decrease, ↑↑↑—increase.

2.6.1. Caffeine and Urinary Incontinence

Jura et al. [ 172 ] conducted a prospective cohort study of 65,176 women (37–39 years old) without urinary incontinence, using questionnaires to measure caffeine intake. The authors associated risk for urgency incontinence with high caffeine intake and showed that this risk was higher in patients who consumed more than 450 mg of caffeine, and 25% of incident urgency incontinence may be attributable to caffeine consumption. One year later, in 2012, Hirayama et al. [ 173 ] showed that caffeine was not associated with a higher risk of urinary incontinence in a group of 683 men and 298 women (aged 40–75 years) from Japan. On the other hand, Townsend et al. [ 174 ], who examined 21,564 women (aged 39–81 years) with moderate urinary incontinence showed that long-term caffeine intake over one year was not associated with urinary incontinence progression over two years among women, either when 150 mg nor 450 mg of caffeine per day were given. In 2013, Gleason et al. [ 175 ] examined 4309 non-pregnant women (>20 years old) with urinary incontinence (from mild to severe forms) and showed that caffeine intake ≥204 mg/day was associated with urinary incontinence, but not with severe forms of it.

2.6.2. Caffeine and Kidney Stones

Studies by Curhan et al. [ 176 ] showed that there is an association between intake of caffeinated drinks and risk of kidney stones. The authors based their data on the study of 553,081 women, of which 719 had documented kidney stones. They reported that risk for stone formation decreased by 10% for caffeinated coffee and 8% for tea for each 240 mL serving consumed daily. Peerapen and Thongboonkerd [ 177 ] in their study investigated the formation of calcium oxalate monohydrate (COM) (which is one of the main causes of kidney stones) in vitro after use of different doses of caffeine (1 to 10 μM). The authors examined the crystallization process, crystal growth, and crystal-cell adhesion, and found that caffeine reduced the crystal number and crystal-binding capacity of renal tubular cells in a dose-dependent manner. The study results showed significantly decreased levels of annexin A1 in the apical surface (a protein that belongs to the annexin family of calcium-dependent phospholipid-binding proteins that plays a significant role in controlling intercellular calcium release), because this protein is translocated into the cytoplasm of the caffeine-treated cells. This mechanism may decrease the crystal-binding capacity of renal tubular epithelial cells [ 177 ]. Caffeine has anti-fibrotic activity not only against liver fibrosis, but also against renal fibrosis. Nilnumkhum et al. [ 178 ] studied the protective effect of caffeine against renal fibroblast activation induced by hypoxia. The authors used the baby hamster kidney (BHK-21) fibroblast cell line (ATCC) as an in vitro model and inducted hypoxia by transferring them to a hypoxic chamber for 12 h. The control sample were fibroblasts grown under normoxic conditions. Hypoxia increased levels of fibronectin, α-smooth muscle actin, actin stress fibers, intracellular reactive oxygen species (ROS), and oxidized proteins, but caffeine preserved all these markers to their basal levels. Additionally, cellular catalase (CAT) activity (reduced by hypoxia) could be reactivated by caffeine. The authors showed that caffeine eliminated intracellular ROS and therefore exhibited an anti-fibrotic effect against hypoxia-induced renal fibroblast activation [ 178 ].

2.6.3. Caffeine and Bladder Cancer

The protective role of caffeinated coffee in bladder cancer is still being considered. Some meta-analysis studies showed no correlation between coffee consumption and risk of bladder cancer [ 179 ], but other meta-analyses of case-control studies provide opposing data, suggesting a linear increase in the risk of bladder cancer along with the amount of coffee intake (15–29% increase for 2–4 cups of coffee a day, proportionally) [ 180 ]. Moreover, Huanhuan et al. [ 144 ] examined the effect of caffeine in the inhibition of renal cell carcinoma (RCC) and showed that caffeine may target glucose-6-phosphate dehydrogenase (G6PDH), inhibit G6PDH activity, and disrupt redox homeostasis, and through this, may inhibit RCC tumor growth, which is dependent on G6PDH activity. This discovery opens the gates to the therapeutic effects of caffeine in kidney diseases, even cancer [ 181 ].

In summary, the effect of caffeine on the urinary system may be direct or indirect, and caffeine can act through the products of its metabolism, which are excreted by the kidneys, and this process depends on age and sex. Women are more likely to experience urinary incontinence problems. There are also positive effects such as a reduction in kidney stone formation thanks to a decrease in the crystal-binding capacity of renal tubular epithelial cells, and lower renal fibrosis because of its ability to eliminate ROS. The role of caffeine in bladder cancer is still under investigation, but there are premises that caffeine increases the risk of this ailment.

2.7. Skeletal and Muscular System

Caffeine’s capacity to improve exercise performance and cognitive functions makes it a very common dietary supplement in sports nutrition [ 182 ]. It is suggested that the most important mechanism of caffeine activity in muscle work is antagonism of ARs. Preventing the decrease in neuronal activity by blocking the ARs is associated with the possibility of increasing muscle fiber recruitment [ 183 ]. Another mechanism of the caffeine effect is the opening of the ion channel RyRs, especially in muscles and myocytes [ 184 ]. There is a reserve of Ca 2+ in the sarcoplasmic reticulum (SR), which can be additionally released in the presence of caffeine, resulting in improved muscle speed and strength [ 185 ]. Caffeine can increase contractility during submaximal contractions through induction calcium release from SR and inhibition of its reuptake [ 163 ]. The ability of caffeine to boost adrenaline rush, release calcium ions, improve Na⁺/K⁺-ATPase, and reduce pain perception [ 186 ] seems to be directly related to improved sports performance. Caffeine may also have a direct positive effect on the mechanical activity of skeletal muscle. This was demonstrated by Domaszewski et al. [ 187 ], who studied 40 professional male handball players (age: 23.13 ± 3.51 years, body mass: 93.51 ± 15.70 kg, height: 191 ± 7.72 cm, BMI: 25.89 ± 3.10) who regularly consumed products rich in caffeine by giving them caffeine at a dose of 9 mg/kg body weight. The authors observed improved contraction time and reduced maximal displacement in the tested group [ 187 ].

2.7.1. Caffeine and Bones

The connection between caffeine and osteogenic activity was examined by Shin et al. [ 188 ] in a study on 51 two-week-old male rats. The authors showed that high-caffeine consumption (120 and 180 mg/kg/day) for four weeks led to a significant decrease in body mass gain with proportional decreases in lean body mass and body fat. Additionally, in dual-energy X-ray and F-NaF positron emission tomography, a decrease in bone mass and in vivo osteogenic activity was observed—a shorter and lighter tibia, femur, and vertebral column. Caffeine intake may have a small negative effect on calcium levels, but there is not enough evidence to show an association between coffee consumption and risk of osteoporosis [ 189 ].

2.7.2. Caffeine Action on Muscle Filaments and Muscular Strength

Caffeine, an activator of the calcium and cAMP/protein kinase A (cAMP/PKA) pathway, enhances glucose uptake, fat oxidation, and mitochondrial biogenesis in skeletal muscle cells. Yokokawa et al. [ 190 ] reported that caffeine may increase myoglobin expression via the cAMP/PKA pathway in skeletal muscle by using L6 myotubes. The authors showed that caffeine increased myoglobin expression and activated the cAMP/PKA pathway in muscle cells. Moreover, cAMP increased myoglobin expression [ 190 ]. Tazzeo et al. [ 191 ] proved that caffeine decreases actin filament binding to phosphorylated myosin heads and increases the ratio of globular to filamentous actin in pre-contracted tissues, and concluded that caffeine interferes with actin function (decreased binding by myosin, possibly with depolymerization), and for this reason, relaxes smooth muscle [ 191 ].

Caffeine in a dose of 3 mg/kg body weight induced changes in muscle oxygen saturation during submaximal workloads [ 143 ]. Wilk et al. [ 192 ] examined 16 healthy strength-trained male athletes (age: 24.2 ± 4.2 years, body mass: 79.5 ± 8.5 kg, BMI: 24.5 ± 1.9, bench press 1RM: 118.3 ± 14.5 kg), who were habitual caffeine consumers (411 ± 136 mg of caffeine per day). In the study, the athletes’ response to caffeine was examined (9 mg/kg body mass and 11 mg/kg body mass) after strength and muscle endurance tests. The authors showed that the dose of caffeine was associated with peak velocity and reported its significant decrease when 11 mg/kg body weight of caffeine was used, but no other changes were observed. Cesareo et al. [ 193 ] in 2019 achieved similar results in their study based on 12 resistance-trained men (aged 20–29 years) and showed that a caffeine-like compound (TeaCrine ® 300 mg) with a caffeine content of 300 mg did not improve muscular strength, power, or endurance performance [ 193 ]. However, future studies should confirm the above findings and also analyze the inter-subject variations in response to different doses of caffeine.

In conclusion, the influence of caffeine on the functioning of muscular and skeletal systems is important in sport, mainly because of its ability to improve exercise performance and cognitive functions by antagonism of ARs, opening RyRs channels and induction of calcium release. Scientists have focused their attention on athletes to demonstrate or exclude the potential dose-dependent doping nature of caffeine, however, its action should also be analyzed in the context of other strength sports. Regarding the contribution of caffeine to some diseases, it has not been possible to show an effect on the risk of muscle and bone disease (e.g., osteoporosis), but this area of research has still not been completely explored, and a great deal of further research is needed in order to be able to draw more constructive conclusions.

3. Caffeine and Oxidative Stress

Oxidative stress is the result of the negative effect of reactive oxygen (ROS) and nitrogen (RNS) species, which, under favorable circumstances, are a cause of the disruption of oxidative–antioxidant balance. ROS and RNS are produced continuously in the human body through oxidative metabolism, mitochondrial bioenergetics, and immune function. Indirectly, nutrients that induce inflammation are also involved in the development and maintenance of oxidative stress. There are different types of sources of nutrient-mediated oxidative stress that play a key role in the development of many human diseases [ 194 ]. Caffeine can indicate oxidative stress of varying severity depending on the person’s sex, age, health, body weight, BMI, and lifestyle, and also depending on type, dose, and mode of preparation of coffee [ 195 ]. In some studies, caffeine showed concentration-dependent non-enzymatic antioxidant potential by decreasing the levels of free radical generation and reducing superoxide dismutase (SOD) and CAT activities [ 196 ]. Caffeine protects against cell damage, exerts antioxidant effects, and reduces oxidative stress markers [ 197 ]. Chu et al. [ 198 ] investigated the effect of coffee (both caffeinated and decaffeinated) on oxidative stress induction by using primary neuronal cell culture and H 2 O 2 and showed that the high levels of chlorogenic acid lactones (CGLs) and lipophilic antioxidants included in roasted coffee could protect neuronal cells against the oxidative stress induced by H 2 O 2 by modulation of the ERK1/2 (extracellular signal-regulated kinases 1/2) and JNK (c-Jun N-terminal kinases) signaling pathways. Moreover, the authors indicated that only the roasted coffee extract inhibited JNK activation, while both roasted and green coffees inhibited ERK1/2 activation and showed a neuroprotective effect on neurodegenerative processes [ 198 ].

Li et al. [ 199 ] examined the role of caffeine in skin protection. Their study showed that a low dose of caffeine (<10 μM) could suppress skin damage induced by dihydrochloride or ultraviolet, which they used to induce oxidative stress in transformed skin cells and normal human epidermal keratinocytes. Caffeine can also mechanistically facilitate the elimination of ROS by activating autophagy through the inhibition of AR, increasing the level of sirtuin 3 (SIRT3) and the activation of 5′ adenosine monophosphate-activated protein kinase [ 199 ]. Similar investigations were also conducted by Xu et al. [ 200 ], and the authors showed that caffeine (4–512 μM) promoted SIRT3 activity and reduced SOD2 (superoxide dismutase 2) acetylation. The results of the above studies show that caffeine targets SIRT3 to enhance SOD2 activity and protect skin cells from UV irradiation-induced oxidative stress. Thus caffeine, as a small-molecule SIRT3 activator, could be a potential agent to protect human skin against UV radiation [ 200 ].

In summary, it should be emphasized that caffeine, acting as an antioxidant, counteracts the negative effects of oxidative stress and oxidative–antioxidant imbalances. Caffeine, by decreasing the levels of free radical generation, protects neuronal cells against oxidative stress and damage, and has a neuroprotective effect on neurodegenerative processes. Additionally, caffeine can suppress skin damage induced by ultraviolet and can mechanistically facilitate the elimination of ROS, and thus protect skin cells from UV irradiation-induced oxidative stress. The proven protective function of caffeine against the harmful effects of UV radiation and the free radicals generated by it on the skin is an interesting topic for future research including studies aimed at using scientific discoveries not only in pharmacology, but also in cosmetology.

4. The Association between Caffeine Consumption and All-Cause and Cause-Specific Mortality

Caffeine consumption may be associated with positive health influence, but also with side effects. The worst case scenario directly related to the consumption of gram amounts of caffeine is death, usually in attempted suicide, although in these cases, it is also rare. The increased risk of adverse effects of caffeine should be considered in poor metabolizers, people with liver disease, and people with heart disease, who may die from ingesting caffeine at levels well below what is normally considered toxic [ 32 ].

In normal condition, caffeine is supposed to be associated with lower risk of death. The mechanism by which it may reduce mortality are not well-known, but it is suggested that it could be due to its antioxidant and anti-inflammatory effects [ 201 ]. Tsujimoto et al. [ 202 ] conducted a prospective cohort study based on the data from the National Health and Nutrition Examination Survey 1999–2010 of about 17,594 participants. The authors compared hazard ratios (HR) for death among participants with a caffeine intake of 10–99, 100–199 and 200 mg/day or more with those whose caffeine consumption was less than 10 mg/day. In their main analysis, caffeine intake was associated with lower risk of all-cause mortality. They also performed an additional analysis among patients with diabetes and reported a non-significant association between caffeine intake and mortality among participants with this disease, but this conclusion was challenged by Neves et al. [ 203 ], who, after taking into account sex, presence of kidney disease, and dietary habits of participants, showed a dose-dependent protective effect of caffeine intake among women with diabetes and may reduce their mortality. An inverse relationship between caffeine consumption and all-cause mortality has also been reported among people with chronic kidney disease (CKD) by Vieira et al. [ 204 ]. The authors analyzed 4863 adults with CKD and showed that patients who consumed >213.5 mg/day of caffeine were less exposed to death from CKD than those who consumed <28.2, 28.2–103.0, and 103.01–213.5 mg/day of this purine alkaloid. In a meta-analysis conducted by Li et al. [ 205 ], composed of 21 cohort studies, the consumption of caffeinated coffee was also associated with decreased all-cause mortality.

Caffeine is widely viewed as a safe stimulant, and is consumed in a variety of forms from pure caffeine to caffeinated drinks and food. However, it should be noted that excessive caffeine consumption may be hidden. For example, herbal medicines and herbal supplements for weight loss with high caffeine content may not disclose these concentrations on the product label, which may be an underestimated source of caffeine in this context. In addition, interactions between caffeine and other ingredients in caffeine-containing products may also increase the risk of side effects [ 32 ]. Nevertheless, caffeine intake is associated with lower risk of all-cause mortality and for this reason may be useful in life extension, especially among women with diabetes and patients with CKD. These results lead to the promising consideration of the use of caffeine as an agent in the treatment of many diseases and should be taken into consideration in further research, not forgetting the negative effects of its activity.

5. Conclusions

It is not easy to define unequivocally whether caffeine has a positive or negative effect on the human organism. Through interaction with receptors such as ARs, RyRs, and GABA receptors and inhibition of PDEs, caffeine’s action is multi-directional and reaches most of the human body systems. Its prevalence in plants, medicinal and other products means that most people are exposed to its use, and its rapid absorption and complex metabolism contribute to its effects on cell function. Caffeine’s action depends on age, sex, source, and consumed dose. At low doses, caffeine is said to have a positive effect on cognitive performance, memory, and brain function, but at high doses, it may be responsible for nervousness, anxiety etc. The positive effects of caffeine are observed in many diseases (AD, PD, asthma, cirrhosis, fibrogenesis, kidney stones, some cancers, etc.) as well as negative effects (Huntington’s disease, arrythmia, tachycardia, lung cancer etc.). Caffeine is also considered to have a therapeutic impact on pain. Thanks to its anti-inflammatory and antioxidant properties, it may be useful medication not only in pharmacology, but also in cosmetology. Many studies have focused on caffeine’s ability to improve motor and respiratory functions, which seems to be important in sport. The multi-directional action of caffeine is a very interesting research direction, and therefore this topic was, is, and will continue to be investigated, which will contribute to the development of new medicines, increasing social awareness of the effects of caffeine consumption, and constantly expanding knowledge about this commonly used stimulant.

Author Contributions

Conceptualization, K.R. and I.K.; Methodology, K.R.; Writing—original draft preparation, K.R., I.K. and E.M.K.; Writing—review and editing, K.R., I.K. and E.M.K.; Visualization, K.R.; Supervision, I.K. and E.M.K.; Funding acquisition, K.R. and E.M.K. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Institutional Review Board Statement

Informed consent statement, data availability statement, conflicts of interest.

The authors declare no conflict of interest.

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