research article phobia

January 1, 2014

Why Do We Develop Certain Irrational Phobias?

By Andrew Watts

Katherina K. Hauner , a postdoctoral fellow at the Northwestern University Feinberg School of Medicine, answers:

Under normal circumstances, fear triggers a natural fight-or-flight response that allows animals to react quickly to threats in their environment. Irrational and excessive fear, however, is typically a maladaptive response. In humans, an unwarranted, persistent fear of a certain situation or object, known as specific phobia, can cause overwhelming distress and interfere with daily life. Specific phobia is among the more prevalent anxiety disorders, affecting an estimated 9 percent of Americans within their lifetime. Common subtypes include fear of small animals, insects, flying, enclosed spaces, blood and needles.

For fear to escalate to irrational levels, a combination of genetic and environmental factors is very likely at play. Estimates of genetic contributions to specific phobia range from roughly 25 to 65 percent, although we do not know which genes have a leading part. No specific phobia gene has been identified, and it is highly unlikely that a single gene is responsible. Rather variants in several genes may predispose an individual to developing a number of psychological symptoms and disorders, including specific phobia.

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As for the environmental component, a person may develop a phobia after a particularly frightening event, especially if he or she feels out of control. Even witnessing or hearing about a traumatic occurrence can contribute to its development. For instance, watching a devastating airplane crash on the news may trigger a fear of flying. That said, discerning the origin of the disorder can be difficult because people tend to do a poor job of identifying the source of their fears.

Our understanding of how and why phobias crop up remains limited, but we have made great strides in abating them. Exposure therapy, a form of cognitive-behavior therapy, is widely accepted as the most effective treatment for anxieties and phobias, and the vast majority of patients complete treatment within 10 sessions. During exposure therapy, a person engages with the particular fear to help diminish and ultimately overcome it over time. An individual might, for example, look at a photograph of the dreaded object or become immersed in the situation he or she loathes. Fortunately for those plagued by irrational fears, we can treat a phobia rapidly and successfully without necessarily knowing its origin.

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Research Findings on the Genetics of Phobias

Daniel B. Block, MD, is an award-winning, board-certified psychiatrist who operates a private practice in Pennsylvania.

Phobias are extreme fears that make it impossible to function normally. Phobias may grow out of really negative experiences, but because they are overwhelming and often irrational, they become disabling. There are many different types of phobias; some of the most common include:

• Fear of specific animals (dogs, spiders, etc.)
• Fear of open spaces, enclosed space, or high places
• Fear of natural events, such as thunderstorms

While fears are an unavoidable part of being human, most fears can be controlled and managed. Phobias, however, cause psychological and physical reactions that are difficult if not impossible to manage. As a result, people with phobias will go to great lengths to avoid the object of their fears.

What Causes Phobias?

Why does someone react to a normal, everyday event — the bark of a dog, for example — with extreme fear and anxiety? Why do other people react to the same experience with mild anxiety or calm?​

The causes of phobias are not yet widely understood. Increasingly, however, research shows that genetics may play at least some role.

Studies show that twins who are raised separately have a higher than average rate of developing similar phobias. Other studies show that some phobias run in families, with first-degree relatives of phobia sufferers more likely to develop a phobia.

In “Untangling genetic networks of panic, phobia, fear, and anxiety,” Villafuerte and Burmeister reviewed several earlier studies in an attempt to determine what, if any, genetic causes can be identified for anxiety disorders.

Family Studies Suggest a Genetic Link

If a family member has a phobia, you are at an increased risk for a phobia as well.

In general, relatives of someone with a specific anxiety disorder are most likely to develop the same disorder. In the case of agoraphobia (fear of open spaces), however, first-degree relatives are also at increased risk for panic disorder, indicating a possible genetic link between agoraphobia and panic disorder .

Researchers have found that first-degree relatives of someone suffering from a phobia are approximately three times more likely to develop a phobia.

According to the findings, twin studies showed that when one twin has agoraphobia, the second twin has a 39% chance of developing the same phobia. When one twin has a specific phobia, the second twin has a 30% chance of also developing a specific phobia. This is much higher than the 10% chance of developing an anxiety disorder found in the general population.

Gene Isolation Suggests a Link Between Phobias and Panic Disorder

Although they were unable to specifically isolate the genetic causes of phobias, Villafuerte and Burmeister reviewed several studies that appear to demonstrate genetic anomalies in both mice and humans with anxiety disorders. The early research appears to show that agoraphobia is more closely linked to panic disorder than to the other phobias, but is far from conclusive.

More research will need to be performed in order to isolate the complex genetics involved in the development of phobias and other anxiety disorders. However, this study does support the theory that genetics play a major role.

• Villafuerte, Sandra and Burmeister, Margit. Untangling genetic networks of panic, phobia, fear and anxiety . Genome Biology . July 28, 2003. 4(8):224. 

By Lisa Fritscher Lisa Fritscher is a freelance writer and editor with a deep interest in phobias and other mental health topics.

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What is a phobia?

A phobia is an uncontrollable, irrational, and lasting fear of a certain object, situation, or activity. This fear can be so overwhelming that a person may go to great lengths to avoid the source of this fear. One response can be a panic attack. This is a sudden, intense fear that lasts for several minutes. It happens when there is no real danger.

Who is affected by phobias?

About 19 million Americans have one or more phobias that range from mild to severe. Phobias can happen in early childhood. But they are often first seen between ages 15 and 20. They affect both men and women equally. But men are more likely to seek treatment for phobias.

What causes phobias?

Research suggests that both genetic and environmental factors contribute to the start of phobias. Certain phobias have been linked to a very bad first encounter with the feared object or situation. Mental health experts don’t know if this first encounter is necessary or if phobias can simply occur in people who are likely to have them.

What are the main types of phobias?

Specific phobia, what is specific phobia.

Specific phobia is an extreme fear of an object or situation that typically isn't harmful.

Examples may include a fear of:

• Flying (fearing the plane will crash)
• Dogs (fearing the dog will bite or attack)
• Closed-in places (fear of being trapped)
• Tunnels (fearing a collapse)
• Heights (fear of falling)

What are the characteristics of specific phobia?

People with specific phobia know that their fear is extreme. But they can't overcome it. The problem is diagnosed only when the specific fear interferes with daily activities of school, work, or home life.

There is no known cause, although they seem to run in families. They are also found slightly more often in women. If the object of the fear is easy to avoid, people with phobias may not seek treatment. Sometimes, however, they may make important career or personal decisions to avoid a situation that includes the source of the phobia.

Treatment for specific phobia

When phobias interfere with a person's life, treatment can help. For specific phobias, cognitive-behavioral therapy (CBT) with exposure treatment is advised. In exposure therapy, people are gradually exposed to what frightens them until the fear starts to fade. Relaxation and breathing exercises also help to ease symptoms.

Social phobia

What is social phobia.

Social phobia is an anxiety disorder in which a person has significant anxiety and discomfort related to a fear of being embarrassed, humiliated, or scorned by others in social or performance situations. Even when they manage to confront this fear, people with social phobia usually:

• Feel very anxious before the event or outing
• Feel intensely uncomfortable throughout the event or outing
• Have lingering unpleasant feelings after the event or outing

Social phobia often happens with the following:

• Public speaking
• Meeting people
• Dealing with authority figures
• Eating in public
• Using public restrooms

What are the characteristics of social phobia?

Although this disorder is often thought of as shyness, they are not the same. Shy people can be very uneasy around others, but they don't have the extreme anxiety in anticipating a social situation. Also, they don't necessarily avoid circumstances that make them feel self-conscious. In contrast, people with social phobia are not necessarily shy at all, but can be completely at ease with some people most of the time.

Most people with social phobia will try to avoid situations that cause distress.

Diagnosing social phobia

Social phobia is diagnosed when the fear or avoidance significantly interferes with normal, routines, or is excessively upsetting.

Social phobia disrupts normal life, interfering with career or social relationships. It often runs in families and may be happen along with depression or alcoholism. Social phobia often starts in early adolescence or even younger. 

Treatment for social phobia

People with social phobia often find relief when treated with cognitive-behavioral therapy, medicine, or a mix of both.

Agoraphobia

What is agoraphobia.

Agoraphobia involves the fear of having a panic attack in a place or situation from which escape may be hard or embarrassing.

The anxiety of agoraphobia is so severe that panic attacks are not unusual. People with agoraphobia often try to avoid the location or cause of their fear. Agoraphobia involves fear of situations like the following:

• Being alone outside his or her home
• Being at home alone
• Being in a crowd
• Traveling in a vehicle
• Being in an elevator or on a bridge

People with agoraphobia typically avoid crowded places like streets, crowded stores, churches, and theaters.

What are the characteristics of agoraphobia?

Most people with agoraphobia get it after first suffering a series of panic attacks. The attacks happen randomly and without warning, and make it impossible for a person to predict what will trigger the reaction. This unpredictability of the panic causes the person to anticipate future panic attacks and, eventually, fear any situation in which an attack may happen. As a result, they avoid going into any place or situation where previous panic attacks have happened.

People with the disorder often become so disabled that they literally feel they cannot leave their homes. Others who have agoraphobia, do go into potentially "phobic" situations, but only with great distress, or when accompanied by a trusted friend or family member.

People with agoraphobia may also have depression, fatigue, tension, alcohol or drug abuse problems, and obsessive disorders, making treatment crucial. 

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Articles on Phobias

Displaying 1 - 20 of 26 articles.

Biophobia: search trends reveal a growing fear of nature

Ricardo Correia , University of Helsinki and Stefano Mammola , University of Helsinki

Innies, outies and omphalophobia: 7 navel-gazing questions about belly buttons answered

Sarah Leupen , University of Maryland, Baltimore County

Why are we so scared of clowns? Here’s what we’ve discovered

Sophie Scorey , University of South Wales ; James Greville , University of South Wales ; Philip Tyson , University of South Wales , and Shakiela Davies , University of South Wales

Scared of needles? Claustrophobic? One longer session of exposure therapy could help as much as several short ones

Bronwyn Graham , UNSW Sydney and Sophie H Li , UNSW Sydney

CBT? DBT? Psychodynamic? What type of therapy is right for me?

Sourav Sengupta , University at Buffalo

Pictures of COVID injections can scare the pants off people with needle phobias. Use these instead

Holly Seale , UNSW Sydney and Jessica Kaufman , Murdoch Children's Research Institute

Tokophobia is an extreme fear of childbirth. Here’s how to recognise and treat it

Julie Jomeen , Southern Cross University ; Catriona Jones , University of Hull ; Claire Marshall , University of Hull , and Colin Martin , Southern Cross University

Spider home invasion season: why the media may be to blame for your arachnophobia

Mike Jeffries , Northumbria University, Newcastle

Fear can spread from person to person faster than the coronavirus – but there are ways to slow it down

Jacek Debiec , University of Michigan

Anxiety in autistic children – why rates are so high

Keren MacLennan , University of Reading

Curious Kids: where do phobias come from?

Lara Farrell , Griffith University

Fear of the dentist: what is dental phobia and dental anxiety?

Ellie Heidari , King's College London

Get ‘inspidered’ – from fear of spiders to fascination

Gerhard J. Gries , Simon Fraser University and Andreas Fischer , Simon Fraser University

You can’t ‘erase’ bad memories, but you can learn ways to cope with them

Carol Newall , Macquarie University and Rick Richardson , UNSW Sydney

Tokophobia: what it’s like to have a phobia of pregnancy and childbirth

Catriona Jones , University of Hull ; Franziska Wadephul , University of Hull , and Julie Jomeen , University of Hull

Health Check: why are some people afraid of heights?

Bek Boynton , James Cook University and Anne Swinbourne , James Cook University

How virtual reality spiders are helping people face their arachnophobia

Why are some people afraid of cats?

Sally Shuttleworth , University of Oxford

From creepy clowns to the dancing plague – when phobias are contagious

Clare Glennan , Cardiff Metropolitan University

Fear of death underlies most of our phobias

Lisa Iverach , University of Sydney ; Rachel E. Menzies , University of Sydney , and Ross Menzies , University of Sydney

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Professor of Midwifery and Dean in the Faculty of Health Sciences, Southern Cross University

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4 Best Drinks for Lower Anxiety, Recommended by Dietitians

Feeling anxious? Try sipping on one of these drinks recommended by dietitians to soothe and calm your nervous system.

Deborah Murphy is a food and nutrition blogger, recipe developer, content creator and consulting dietitian. She is an expert in plant-based nutrition and has more than 10 years of experience providing medical nutrition therapy for the geriatric population.

Emily Lachtrupp is a registered dietitian experienced in nutritional counseling, recipe analysis and meal plans. She's worked with clients who struggle with diabetes, weight loss, digestive issues and more. In her spare time, you can find her enjoying all that Vermont has to offer with her family and her dog, Winston.

Photographer Victor Protasio, Food Stylist Ruth Blackburn, Prop Stylist Christina Daley

Stress and anxiety are a normal part of life. However, if you have anxiety disorder, these frazzled feelings do not go away. Over time, anxiety can impact your ability to participate in daily activities. As many as 19% of U.S. adults have experienced prolonged anxiety.  

Medication and therapy are the primary tools for tackling anxiety. However, diet may also play a role in supporting your mood. It’s not just what is on your plate that will make a difference to your stress levels either. Your overall hydration as well as what you drink can have a noticeable impact on your anxiety levels. Read on to learn more about the best beverages for easing anxiety, according to dietitians.

The 4 Best Drinks for Lowering Anxiety

1. chamomile tea.

If you’ve ever struggled with insomnia, there’s a good chance you’ve heard that chamomile may help you catch more zzz’s at night. The same calming effect that improves sleep may also ease anxiety. “Chamomile tea is beneficial for anxiety due to its active ingredient, apigenin. Apigenin is a flavonoid compound found in chamomile that has been shown to have anti-anxiety effects,” says Wan Na Chan, M.P.H., RD, owner of One Pot Wellness. In fact, she points to some research that shows that chamomile extract has been reported to alleviate anxiety, improve mood and relieve pain. Stick with consuming chamomile tea , though, which is generally considered safe, rather than other forms, like extracts.

2. Green Tea

Green tea is a widely popular beverage that has been linked to a host of health benefits like reduced inflammation, improved blood sugars and better digestion. Lower anxiety may be another benefit to add to the growing list. Green tea is rich in a specific amino acid called L-theanine, which has been associated with better mood and lower anxiety symptoms.

One review found that supplementing with 200 to 400 milligrams of L-theanine could significantly reduce anxiety and stress. And one small study found that people reported greater improvements in their sleep, depression and anxiety when they took 200 milligrams of L-theanine daily for four weeks versus a placebo group.

Although the research on L-theanine sounds promising, one thing to note about these studies is that the amount of L-theanine included in the supplements is much higher than what is in a cup of brewed green tea, which ranges from 8 to 30 milligrams. 

3. 100% Fruit Juice

We all know that eating your fruits and vegetables is good for your overall health, but did you know that they may improve your mood, too? Anxiety and depression have been associated with lower antioxidant levels in the body. Lower levels of antioxidants may mean higher levels of oxidative stress and inflammation, which can make you more prone to anxiety.

While we generally recommend consuming whole fruits and vegetables (hello, fiber !) over juice, there may be mood-boosting benefits to consuming a glass of 100% fruit juice. Data collected from over 62,000 adults about their mental health and diet found that those who regularly consumed 100% fruit juice reported fewer days of feeling anxious than non-juice drinkers. Worried about the sugar in a glass of juice? Combine fruit juice with unsweetened tea, like we did for this Hibiscus-Pomegranate Iced Tea , to reduce the overall sugar content per glass.

Feeling cranky and on-edge? Pour yourself a glass of water. “It keeps blood flowing throughout our body and is essential for delivering nutrients and energy sources to our brain,” says Laura M. Ali, M.S., RDN , a culinary nutritionist and the author of the cookbook MIND Diet for Two . “Research has shown increased rates of depression and anxiety in people who drink less water,” she says. Although it’s not quite known why, water may affect levels of norepinephrine, a neurotransmitter that plays a role in our body’s reaction to stress. In addition, even a small (1%) dip in hydration levels has been shown to be enough to trigger emotions such as anger, hostility, depression and tension. Don’t like drinking plain water? Try this Strawberry, Basil & Lime Infused Water or incorporate more hydrating foods into your diet.

3 More Stress-Relieving Beverages

Eating a calcium-rich diet may be helpful for your mood. A study on more than 1,200 college students found that those who consumed more calcium reported less stress and anxiety. Score some extra calcium in your diet by sipping on a glass of milk. One cup of low-fat milk provides nearly 25% of your Daily Value for calcium.

2. Fermented Drinks 

As we learn more about the brain-gut connection every day, note that some drinks like kombucha and kefir pack probiotics that may be helpful for improving mood. “Kefir is a naturally fermented dairy drink that contains active healthy bacteria, Lactobacillus , that are important for keeping your GI tract healthy and may also have a role in supporting brain health. Lactobacillus has been shown in some early research to help reduce anxiety,” says Ali. “These probiotic bacteria tamp down inflammation in our brain, which increases signaling in our brain to release the hormone serotonin, known for its calming effect,” she explains.

3. Ginger Tea

Ginger is well-known for its ability to combat inflammation . We know that anxiety and inflammation are linked, so sipping on a warm cup of ginger tea may help improve your mood. Try this Soothing Ginger-Lemon Tea or a cup of Orange-Ginger Tea . 

The Bottom Line

Diet alone won’t solve your anxiety. If you have chronic anxiety, it’s important to work with a licensed, qualified health care practitioner to talk about your options for treatment. However, certain elements in your diet, including what you drink, can be a useful tool for helping to find calm in your day-to-day life. When you’re feeling stressed, leveling up your hydration can be a first step for lifting your mood. Water is great, but we also love the anxiety-fighting drinks from this list like tea and fruit juice. As we learn more about the connection between our gut health and mood, fermented drinks like kombucha and kefir may also deserve a spot in your beverage lineup.

National Institute of Mental Health. Any Anxiety Disorder.

Kramer DJ, Johnson AA. Apigenin: a natural molecule at the intersection of sleep and aging . Front Nutr . 2024;11:1359176. doi:10.3389/fnut.2024.1359176

Amsterdam JD, Li QS, Xie SX, Mao JJ. Putative antidepressant effect of Chamomile ( Matricaria chamomilla L.) oral extract in subjects with comorbid generalized anxiety disorder and depression. J Altern Complement Med . 2020;26(9):813-819. doi:10.1089/acm.2019.0252

National Center for Complementary and Integrative Health. Chamomile.

Williams JL, Everett JM, D’Cunha NM, et al . The effects of green tea amino acid L-Theanine consumption on the ability to manage stress and anxiety levels: a systematic review. Plant Foods Hum Nutr 75, 12–23 (2020). doi:10.1007/s11130-019-00771-5

Hidese S, Ogawa S, Ota M, Ishida I, Yasukawa Z, Ozeki M, Kunugi H. Effects of L-Theanine administration on stress-related symptoms and cognitive functions in healthy adults: a randomized controlled trial. Nutrients . 2019; 11(10):2362. doi:10.3390/nu11102362

Wang H, Jin M, Xie M, et al. Protective role of antioxidant supplementation for depression and anxiety: A meta-analysis of randomized clinical trials. J Affect Disord . 2023;323:264-279. doi:10.1016/j.jad.2022.11.072

Agarwal S, Fulgoni VL III, Jacques PF. Association of 100% fruit juice consumption with cognitive measures, anxiety, and depression in US adults. Nutrients . 2022; 14(22):4827. doi:10.3390/nu14224827

Haghighatdoost F, Feizi A, Esmaillzadeh A, et al. Drinking plain water is associated with decreased risk of depression and anxiety in adults: Results from a large cross-sectional study . World J Psychiatry . 2018;8(3):88-96. doi:10.5498/wjp.v8.i3.88

Maydych V. The interplay between stress, inflammation, and emotional attention: relevance for depression. Front Neurosci . 2019;13:384. doi:10.3389/fnins.2019.00384

Du C, Hsiao PY, Ludy M-J, Tucker RM. Relationships between dairy and calcium intake and mental health measures of higher education students in the United States: outcomes from moderation analyses. Nutrients . 2022; 14(4):775. doi:10.3390/nu14040775

U.S. Department of Agriculture. FoodData Central. Milk, lowfat, fluid, 1% milkfat, with added vitamin A and vitamin D .

Merkouris E, Mavroudi T, Miliotas D, Tsiptsios D, Serdari A, Christidi F, Doskas TK, Mueller C, Tsamakis K. Probiotics’ effects in the treatment of anxiety and depression: a comprehensive review of 2014–2023 clinical trials. Microorganisms . 2024; 12(2):411. doi:10.3390/microorganisms12020411

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Guest Essay

The Happiness Gap Between Left and Right Isn’t Closing

By Thomas B. Edsall

Mr. Edsall contributes a weekly column from Washington, D.C., on politics, demographics and inequality.

Why is it that a substantial body of social science research finds that conservatives are happier than liberals?

A partial answer: Those on the right are less likely to be angered or upset by social and economic inequities, believing that the system rewards those who work hard, that hierarchies are part of the natural order of things and that market outcomes are fundamentally fair.

Those on the left stand in opposition to each of these assessments of the social order, prompting frustration and discontent with the world around them.

The happiness gap has been with us for at least 50 years, and most research seeking to explain it has focused on conservatives. More recently, however, psychologists and other social scientists have begun to dig deeper into the underpinnings of liberal discontent — not only unhappiness but also depression and other measures of dissatisfaction.

One of the findings emerging from this research is that the decline in happiness and in a sense of agency is concentrated among those on the left who stress matters of identity, social justice and the oppression of marginalized groups.

There is, in addition, a parallel phenomenon taking place on the right as Donald Trump and his MAGA loyalists angrily complain of oppression by liberals who engage in a relentless vendetta to keep Trump out of the White House.

There is a difference in the way the left and right react to frustration and grievance. Instead of despair, the contemporary right has responded with mounting anger, rejecting democratic institutions and norms.

In a 2021 Vox article, “ Trump and the Republican Revolt Against Democracy ,” Zack Beauchamp described in detail the emergence of destructive and aggressive discontent among conservatives.

Citing a wide range of polling data and academic studies, Beauchamp found:

More than twice as many Republicans (39 percent) as Democrats (17 percent) believed that “if elected leaders won’t protect America, the people must act — even if that means violence.”

Fifty-seven percent of Republicans considered Democrats to be “enemies,” compared with 41 percent of Democrats who viewed Republicans as “enemies.”

Among Republicans, support for “the use of force to defend our way of life,” as well as for the belief that “strong leaders bend rules” and that “sometimes you have to take the law in your own hands,” grows stronger in direct correlation with racial and ethnic hostility.

Trump has repeatedly warned of the potential for political violence. In January he predicted bedlam if the criminal charges filed in federal and state courts against him damaged his presidential campaign:

I think they feel this is the way they’re going to try and win, and that’s not the way it goes. It’ll be bedlam in the country. It’s a very bad thing. It’s a very bad precedent. As we said, it’s the opening of a Pandora’s box.

Before he was indicted in New York, Trump claimed there would be “potential death and destruction” if he was charged.

At an Ohio campaign rally in March, Trump declared, “If I don’t get elected, it’s going to be a blood bath for the whole country.”

In other words, Trump and his allies respond to adversity and what they see as attacks from the left with threats and anger, while a segment of the left often but not always responds to adversity and social inequity with dejection and sorrow.

There are significant consequences for this internalization.

Jamin Halberstadt , a professor of psychology at the University of Otago in New Zealand and a co-author of “ Outgroup Threat and the Emergence of Cohesive Groups : A Cross-Cultural Examination,” argued in his emailed reply to my inquiry that because “a focus on injustice and victimhood is, by definition, disempowering (isn’t that why we talk of ‘survivors’ rather than ‘victims’?), loss of control is not good for self-esteem or happiness.”

But, he pointed out:

this focus, while no doubt a part of the most visible and influential side of progressive ideology, is still just a part. Liberalism is a big construct, and I’m reluctant to reduce it to a focus on social justice issues. Some liberals have this view, but I suspect their influence is outsized because (a) they have the social media megaphone and (b) we are in a climate in which freedom of expression and, in particular, challenges to the worldview you characterize have been curtailed.

Expanding on this line of argument, Halberstadt wrote:

I’m sure some self-described liberals have views that are counterproductive to their own happiness. One sub-ideology associated with liberalism is, as you describe, a sense of victimhood and grievance. But there is more than one way to respond to structural barriers. Within that group of the aggrieved, some probably see systemic problems that cannot be overcome, and that’s naturally demoralizing and depressing. But others see systemic problems as a challenge to overcome.

Taking Halberstadt’s assessment of the effects of grievance and victimhood a step farther, Timothy A. Judge , the chairman of the department of management and human resources at Notre Dame, wrote in a 2009 paper, “ Core Self-Evaluations and Work Success ”:

Core self-evaluations (C.S.E.) is a broad, integrative trait indicated by self-esteem, locus of control, generalized self-efficacy and (low) neuroticism (high emotional stability). Individuals with high levels of C.S.E. perform better on their jobs, are more successful in their careers, are more satisfied with their jobs and lives, report lower levels of stress and conflict, cope more effectively with setbacks and better capitalize on advantages and opportunities.

I asked Judge and other scholars a question: Have liberal pessimists fostered an outlook that spawns unhappiness as its adherents believe they face seemingly insurmountable structural barriers?

Judge replied by email:

I do share the perspective that a focus on status, hierarchies and institutions that reinforce privilege contributes to an external locus of control. And the reason is fairly straightforward. We can only change these things through collective and, often, policy initiatives — which tend to be complex, slow, often conflictual and outside our individual control. On the other hand, if I view “life’s chances” (Virginia Woolf’s term) to be mostly dependent on my own agency, this reflects an internal focus, which will often depend on enacting initiatives largely within my control.

Judge elaborated on his argument:

If our predominant focus in how we view the world is social inequities, status hierarchies, societal unfairness conferred by privilege, then everyone would agree that these things are not easy to fix, which means, in a sense, we must accept some unhappy premises: Life isn’t fair; outcomes are outside my control, often at the hands of bad, powerful actors; social change depends on collective action that may be conflictual; an individual may have limited power to control their own destiny, etc. These are not happy thoughts because they cause me to view the world as inherently unfair, oppressive, conflictual, etc. It may or may not be right, but I would argue that these are in fact viewpoints of how we view the world, and our place in it, that would undermine our happiness.

Last year, George Yancey , a professor of sociology at Baylor University, published “ Identity Politics, Political Ideology, and Well-Being : Is Identity Politics Good for Our Well-Being?”

Yancey argued that recent events “suggest that identity politics may correlate to a decrease in well-being, particularly among young progressives, and offer an explanation tied to internal elements within political progressiveness.”

By focusing on “political progressives, rather than political conservatives,” Yancey wrote, “a nuanced approach to understanding the relationship between political ideology and well-being begins to emerge.”

Identity politics, he continued, focuses “on external institutional forces that one cannot immediately alleviate.” It results in what scholars call the externalization of one’s locus of control, or viewing the inequities of society as a result of powerful if not insurmountable outside forces, including structural racism, patriarchy and capitalism, as opposed to believing that individuals can overcome such obstacles through hard work and collective effort.

As a result, Yancey wrote, “identity politics may be an important mechanism by which progressive political ideology can lead to lower levels of well-being.”

Conversely, Yancey pointed out, “a class-based progressive cognitive emphasis may focus less on the group identity, generating less of a need to rely on emotional narratives and dichotomous thinking and may be less likely to be detrimental to the well-being of a political progressive.”

Yancey tested this theory using data collected in the 2021 Baylor Religion Survey of 1,232 respondents.

“Certain types of political progressive ideology can have contrasting effects on well-being,” Yancey wrote. “It is plausible that identity politics may explain the recent increase well-being gap between conservatives and progressives.”

Oskari Lahtinen , a senior researcher in psychology at the University of Turku in Finland, published a study in March, “ Construction and Validation of a Scale for Assessing Critical Social Justice Attitudes ,” that reinforces Yancey’s argument.

Lahtinen conducted two surveys of a total of 5,878 men and women to determine the share of Finnish citizens who held “critical social justice attitudes” and how those who held such views differed from those who did not.

Critical social justice proponents, on Lahtinen’s scale,

point out varieties of oppression that cause privileged people (e.g., male, white, heterosexual, cisgender) to benefit over marginalized people (e.g., woman, Black, gay, transgender). In critical race theory, some of the core tenets include that (1) white supremacy and racism are omnipresent and colorblind policies are not enough to tackle them, (2) people of color have their own unique standpoint and (3) races are social constructs.

What did Lahtinen find?

The critical social justice propositions encountered

strong rejection from men. Women expressed more than twice as much support for the propositions. In both studies, critical social justice was correlated modestly with depression, anxiety, and (lack of) happiness, but not more so than being on the political left was.

In an email responding to my inquiries about his paper, Lahtinen wrote that one of the key findings in his research was that “there were large differences between genders in critical social justice advocacy: Three out of five women but only one out of seven men expressed support for the critical social justice claims.”

In addition, he pointed out, “there was one variable in the study that closely corresponded to external locus of control: ‘Other people or structures are more responsible for my well-being than I myself am.’”

The correlation between agreement with this statement and unhappiness was among the strongest in the survey:

People on the left endorsed this item (around 2 on a scale of 0 to 4) far more than people on the right (around 0.5). Endorsing the belief was determined by political party preference much more than by gender, for instance.

Such measures as locus of control, self-esteem, a belief in personal agency and optimism all play major roles in daily life.

In a December 2022 paper, “ The Politics of Depression : Diverging Trends in Internalizing Symptoms Among U.S. Adolescents by Political Beliefs,” Catherine Gimbrone , Lisa M. Bates , Seth Prins and Katherine M. Keyes , all at Columbia’s Mailman School of Public Health, noted that “trends in adolescent internalizing symptoms diverged by political beliefs, sex and parental education over time, with female liberal adolescents experiencing the largest increases in depressive symptoms, especially in the context of demographic risk factors, including parental education.”

“These findings,” they added, “indicate a growing mental health disparity between adolescents who identify with certain political beliefs. It is therefore possible that the ideological lenses through which adolescents view the political climate differentially affect their mental well-being.”

Gimbrone and her co-authors based their work on studies of 85,000 teenagers from 2005 to 2018. They found that

while internalizing symptom scores worsened over time for all adolescents, they deteriorated most quickly for female liberal adolescents. Beginning in approximately 2010 and continuing through 2018, female liberal adolescents reported the largest changes in depressive affect, self-esteem, self-derogation and loneliness.

In conclusion, the authors wrote, “socially underprivileged liberals reported the worst internalizing symptom scores over time, likely indicating that the experiences and beliefs that inform a liberal political identity are ultimately less protective against poor mental health than those that inform a conservative political identity.”

From another vantage point, Nick Haslam , a professor of psychology at the University of Melbourne, argued in his 2020 paper “ Harm Inflation: Making Sense of Concept Creep ” that recent years have seen “a rising sensitivity to harm within at least some Western cultures, such that previously innocuous or unremarked phenomena were increasingly identified as harmful and that this rising sensitivity reflected a politically liberal moral agenda.”

As examples, Haslam wrote that the definition of “trauma” has been

progressively broadened to include adverse life events of decreasing severity and those experienced vicariously rather than directly. “Mental disorder” came to include a wider range of conditions, so that new forms of psychopathology were added in each revision of diagnostic manuals and the threshold for diagnosing some existing forms was lowered. “Abuse” extended from physical acts to verbal and emotional slights and incorporated forms of passive neglect in addition to active aggression.

Haslam described this process as concept creep and argued that “some examples of concept creep are surely the work of deliberate actors who might be called expansion entrepreneurs.”

Concept expansion, Haslam wrote, “can be used as a tactic to amplify the perceived seriousness of a movement’s chosen social problem.” In addition, “such expansion can be effective means of enhancing the perceived seriousness of a social problem or threat by increasing the perceived prevalence of both ‘victims’ and ‘perpetrators.’”

Haslam cited studies showing that strong “correlates of holding expansive concepts of harm were compassion-related trait values, left-liberal political attitudes and forms of morality associated with both.” Holding expansive concepts of harm was also “associated with affective and cognitive empathy orientation and most strongly of all with endorsement of harm- and fairness-based morality.” Many of these characteristics are associated with the political left.

“The expansion of harm-related concepts has implications for acceptable self-expression and free speech,” Haslam wrote. “Creeping concepts enlarge the range of expressions judged to be unacceptably harmful, thereby increasing calls for speech restrictions. Expansion of the harm-related concepts of hate and hate speech exemplifies this possibility.”

While much of the commentary on the progressive left has been critical, Haslam takes a more ambivalent position: “Sometimes concept creep is presented in an exclusively negative frame,” he wrote, but that fails to address the “positive implications. To that end, we offer three positive consequences of the phenomenon.”

The first is that expansionary definitions of harm “can be useful in drawing attention to harms previously overlooked. Consider the vertical expansion of abuse to include emotional abuse.”

Second, “concept creep can prevent harmful practices by modifying social norms.” For example, “changing definitions of bullying that include social exclusion and antagonistic acts expressed horizontally rather than only downward in organizational hierarchies may also entrench norms against the commission of destructive behavior.”

And finally:

The expansion of psychology’s negative concepts can motivate interventions aimed at preventing or reducing the harms associated with the newly categorized behaviors. For instance, the conceptual expansion of addiction to include behavioral addictions (e.g., gambling and internet addictions) has prompted a flurry of research into treatment options, which has found that a range of psychosocial treatments can be successfully used to treat gambling, internet and sexual addictions.

Judge suggested an approach to this line of inquiry that he believed might offer a way for liberalism to regain its footing:

I would like to think that there is a version of modern progressivism that accepts many of the premises of the problem and causes of inequality but does so in a way that also celebrates the power of individualism, of consensus and of common cause. I know this is perhaps naïve. But if we give in to cynicism (that consensus can’t be found), that’s self-reinforcing, isn’t it? I think about the progress on how society now views sexual orientation and the success stories. The change was too slow, painful for many, but was there any other way?

The Times is committed to publishing a diversity of letters to the editor. We’d like to hear what you think about this or any of our articles. Here are some tips . And here's our email: [email protected] .

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Thomas B. Edsall has been a contributor to the Times Opinion section since 2011. His column on strategic and demographic trends in American politics appears every Wednesday. He previously covered politics for The Washington Post. @ edsall

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‘Money pervades everything’: the psychotherapist delving into our deep anxiety about finances

Do you find it hard to budget or, conversely, difficult to spend? Vicky Reynal reveals what our financial choices reveal about our psyches – and what can be done to ease our money worries

I am a generous tipper. I’ve always thought, to the extent that I have thought about it at all, that this is a positive trait. Recently, however, I’ve begun to wonder. Is it normal to feel a deep sense of anxiety after ordering a takeaway pizza, then realising there is no change in the house? Does everyone spend their spare time searching Google to find out if one should tip the Waitrose delivery driver – or whether to do so might cause offence? Are hotel stays meant to be such a stressful experience, requiring constant calculations to determine the appropriate amount of cash to reward every personal interaction?

These are the kinds of questions that arise while I’m reading Money on Your Mind: The Psychology Behind Your Financial Habits . Written by Vicky Reynal, Britain’s first self-styled “financial psychotherapist”, the book outlines a wide range of unhelpful financial behaviours, offering something that will resonate with almost every reader, and makes a convincing case that these are rooted in our emotions – driven by fears and desires – and influenced by past experiences. Perhaps we struggle to spend money on ourselves or others. What do we fear might happen if we do? Some of us are incapable of budgeting. What do we gain from our overspending? We may see our colleagues rewarded with salary increases while we languish on the same pay grade. Why do we struggle to ask for a raise? Are we battling with doubts about our self-worth?

I’m fascinated by what my own financial choices might reveal about my psyche. So, when I go to meet Reynal at her consulting space in Vauxhall, London, I take the opportunity to ask her. Reynal greets me in the manner one would expect from someone who deals with money matters: with a firm handshake and a businesslike demeanour. Smartly dressed in black trousers and shirt under a monochrome patterned blazer, she would not look out of place in any boardroom in the City. After we take our seats, she encourages me to think more deeply about my behaviour. What is behind my compulsion to express gratitude for small acts of service? What do I fear might happen if I don’t? “Is it about wanting to be liked by the other, or wanting the other to think positively of you, even if it is just for a few minutes?” she asks. “I guess the question that pops into my mind would be: is there a part of you that expects people to be critical, so you choose to appease them upfront to avoid that feeling?” I have to admit, this sounds like a definite possibility.

Ten years ago, Reynal started practising psychotherapy and began to notice how often clients’ problems were linked to finances. We tend to think of money in terms of cold hard numbers: the size of our bank balance, the interest rate on our savings account or credit card debt, the number of years it will take to save a house deposit. We believe our financial decisions to be rooted in rationality. Having worked with enough clients for whom money was the source of emotional distress, Reynal sees things differently. Five years ago, she began describing herself as a financial psychotherapist, helping people explore their money troubles as a formal part of her practice.

In the book, Reynal cites a series of statistics to illustrate how money is causing us all kinds of problems. One UK poll found that 32% of us find it stressful talking about our finances with family and friends. Another found a third of couples had argued about money. People with substantial debt are reportedly more likely to suffer from ulcers and migraines, and six times more likely to experience anxiety and depression. Clearly, an absence of money can have a serious impact on the quality of our relationships and our health. But Reynal sees money troubles among the wealthy, too. “If anything, they feel guiltier about their unhappiness, because there is this conception that money should buy happiness,” she says. “And so, if you’re unhappy despite having a lot of wealth, it brings up a lot of shame and guilt.”

Reynal remembers a conversation in her consulting room that drove this point home. A client came to her with what he described as a “£2m problem”. Reynal assumed the man had somehow run up a huge debt. In fact, it emerged he had been granted an unexpected windfall. “They were completely distraught over it,” she recalls, “and who could they tell that to, hoping to find empathy and understanding and to really help them unpick what’s behind that? There was this real fear of people’s envy, how it would spoil the children, how it would ruin his marriage trying to decide what to spend all this money on. It was a person in distress, even if some people might find it difficult to empathise with that.”

Listening to this story, I do find it a little hard to empathise. I don’t doubt that to this particular client this was a very real problem. On the other hand, to many people struggling through a cost of living crisis, a £2m problem will not sound like much of a problem at all. Reynal’s case is that, while money can cause us real problems, for some, the way we feel about money can be just as challenging. And aren’t all money problems relative? No doubt my own money anxieties would cause some eyes to roll. But by focusing so intently on our individual relationship with money, I wonder if we risk ignoring the factors that create inequality and leave so many people facing financial hardship. “Well, they definitely relate, because what is going on at a macro scale often affects the individual,” says Reynal. “But ultimately, all we can do is manage our own experience of what is going on out there in the world.”

Reynal believes financial literacy can only take us so far. “I do make the point in the book that we have to teach children about money, because it’s not an innate skill. A lot of books out there tell people how they should behave with money and what they should do with money. But, for many, something gets in the way of being the way they want to be with money. So they end up overspending, or being overly greedy, or keeping financial secrets from their partners. And what I tried to do in this book is go to the roots of what experiences, what feelings, what longings, sit behind our money behaviours. It’s only by understanding these that we stand the chance of changing them.”

It won’t surprise you to learn that the process often involves looking back to childhood. Here, Reynal’s own story is illuminating. She is cagey about revealing certain personal details, in case that affects the way clients relate to her in her practice. (When I ask about her accent, she declines to say where it’s from, explaining that clients’ assumptions about her background can often be revealing.) She is happy, however, to reveal certain biographical information. After completing a psychotherapy degree, she studied for an MBA at the London Business School. Why the MBA? “Family pressures?” she laughs. “I think that in itself says a lot about the meaning of money in my family.”

Reynal learned early in life how money can cause heartbreak. “My father had two very difficult experiences with money that involved loss, betrayal and deceit,” she says. “The consequences of that – both financial and emotional – affected the whole family negatively.” Through therapy, she explored the meaning of those experiences, which she now describes as “financial trauma”, and their broader ramifications. “Unpacking all the different aspects of that was important to move on from it and to make different choices.” She felt drawn to the idea that she could help others do the same.

Still, for some time, Reynal felt torn between her passion for psychology and the expectation that she go into business – to forge a career in the world of money. Gradually, she began to wonder if the two paths needed to be distinct. She was fascinated by the aspects of her MBA studies that touched on psychology, such as behavioural finance. Fittingly, it was a piece of advice from one of the world’s richest men that encouraged Reynal to combine her two interests. As part of her MBA studies, she was invited to Nebraska to meet the legendary investor Warren Buffett . She asked him how to make such a pivotal decision as how to spend one’s professional life. His message? “Follow your passion, because only by doing something you love, can you ever be good at it.”

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Buffett’s advice stuck. After spending some time in the corporate world, Reynal returned to study psychotherapy at postgraduate level. Just as she had been struck by the psychological aspects of finance, she observed how discussions about money were largely absent in therapeutic circles. “If you look at the psychoanalytic literature, there’s thousands of papers written about the relationship with sex, with food, with other objects,” she says. “And so little written about money.” Reynal saw a way to bridge a gap between her two passions – and also, perhaps, to meet both her family’s expectations and her own.

Sometimes, we need to hear advice in terms we’re primed to understand. In the face of family pressure, it took some words of encouragement from Warren Buffett for Reynal to act in her own interests. Intriguingly, she saw something similar happening when she started calling herself a financial psychotherapist, attracting clients who finally had permission to seek help. “More men started coming,” she says. “I think you can interpret that in a number of ways. But I think, especially for some of the older men I saw, who might have grown up in a generation that wasn’t open-minded to psychotherapy, calling it financial psychotherapy might have enabled them to access it with less shame than if they were just going to a psychotherapist.”

The behaviour Reynal hears about in the consulting room and which she describes in Money on Your Mind , ranges from the mundane to the extreme. Some people engage in unsustainable shopping habits, others steal from their employers or blow their life savings engaging in “findom” (financial domination), a sexual kink in which the participant derives pleasure from giving money for nothing tangible in return. On the spectrum of money troubles, I feel reassured that my anxiety around tipping must fall at the less troubling end of the scale. Nevertheless, Reynal’s questions point to the way even my seemingly mundane behaviour may still be emotionally revealing. What does tipping represent for me? What does my anxiety say about the way I see myself and what I expect of others?

Addressing the way money affects our relationships, Reynal writes: “Arguments about money are rarely about money.” I think about the times my partner and I have argued about money. Were these disagreements really about money or were they about other things, such as fearing the loss of independence – or coming to terms with new responsibilities? Thinking about these questions, I realise how many of our relationships have a financial aspect to them. Money pervades everything. Examining our emotions may give us a way to understand how we feel about it. But should we all be thinking about money in order to understand our emotions? “It’s a window into something, you know?” says Reynal. “By being curious about why you behave a certain way with money, you can find out something about yourself.”

There are rarely easy answers when it comes to self-discovery, says Reynal. Regular readers of financial self-help literature may be disappointed to find Money on Your Mind lacking in investment tips or simple saving strategies. That’s an attitude Reynal has encountered among money-minded people who seek therapy. “It takes a bit of time to break through that so that we can get into a more reflective space,” she says. “We can get into: ‘What is this really about?’” Then there are those who seek to avoid money discussions altogether. For Reynal, the remedy is the same: “Understanding it more, understanding our relationship with it more, will ease our anxiety,” she says. “But to do that, we need to start talking and thinking about it.”

Money on Your Mind: The Psychology Behind Your Financial Habits by Vicky Reynal is published by Lagom at £16.99

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• Published: 08 May 2024

Structural pharmacology and therapeutic potential of 5-methoxytryptamines

• Audrey L. Warren   ORCID: orcid.org/0000-0002-1538-8648 1   na1 ,
• David Lankri   ORCID: orcid.org/0000-0002-1210-5673 2   na1 ,
• Michael J. Cunningham 2 ,
• Inis C. Serrano   ORCID: orcid.org/0000-0002-3588-821X 2 ,
• Lyonna F. Parise   ORCID: orcid.org/0000-0002-7527-8977 3 ,
• Andrew C. Kruegel 2 ,
• Priscilla Duggan   ORCID: orcid.org/0000-0002-9728-282X 2 ,
• Gregory Zilberg 4 ,
• Michael J. Capper   ORCID: orcid.org/0000-0003-0102-6993 1 ,
• Vaclav Havel   ORCID: orcid.org/0000-0002-6911-4669 2 ,
• Scott J. Russo   ORCID: orcid.org/0000-0002-6470-1805 3 ,
• Dalibor Sames   ORCID: orcid.org/0000-0001-6911-2260 2 , 4 &
• Daniel Wacker   ORCID: orcid.org/0000-0003-4951-7230 1 , 3  

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• Cryoelectron microscopy
• Molecular neuroscience
• Receptor pharmacology
• Stress and resilience

Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders 1 , 2 , 3 . These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT 2A (ref. 4 ). However, 5-HT 1A also plays a part in the behavioural effects of tryptamine hallucinogens 5 , particularly 5-methoxy- N,N -dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads 6 . Although 5-HT 1A is a validated therapeutic target 7 , 8 , little is known about how psychedelics engage 5-HT 1A and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT 1A , systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure–activity relationship analyses of 5-methoxytryptamines at both 5-HT 1A and 5-HT 2A enable the characterization of molecular determinants of 5-HT 1A signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT 1A agonists. We show that a 5-HT 1A -selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT 1A -targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.

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Structure-activity relationships of serotonergic 5-MeO-DMT derivatives: insights into psychoactive and thermoregulatory properties

(2-Aminopropyl)benzo[β]thiophenes (APBTs) are novel monoamine transporter ligands that lack stimulant effects but display psychedelic-like activity in mice

Data availability.

Density maps and structure coordinates have been deposited into the Electron Microscopy Data Bank (EMDB) and the PDB with the following accession identifiers: EMD-29560 and PDB 8FY8 for 5-MeO-DMT–5-HT 1A –Gα i1 –Gβ 1 –Gγ 2 ; EMD-29597 and PDB 8FYT for LSD–5-HT 1A –Gα i1 –Gβ 1 -Gγ 2 ; EMD-29571 and PDB 8FYE for 4-F,5-MeO-PyrT–5-HT 1A –Gα i1 –Gβ 1 –Gγ 2 ; EMD-29585 and PDB 8FYL for vilazodone–5-HT 1A –Gα i1 –Gβ 1 –Gγ 2 ; and EMD-29599 and PDB 8FYX for buspirone–5-HT 1A –Gα i1 –Gβ 1 –Gγ 2 .   Source data are provided with this paper. Additional data from this study are available upon request.

Carhart-Harris, R. L. et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology   235 , 399–408 (2018).

Article   CAS   PubMed   Google Scholar  

Armstrong, S. B. et al. Prospective associations of psychedelic treatment for co-occurring alcohol misuse and posttraumatic stress symptoms among United States Special Operations Forces veterans. Mil. Psychol. https://doi.org/10.1080/08995605.2022.2156200 (2023).

Goodwin, G. M. et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N. Engl. J. Med. 387 , 1637–1648 (2022).

Cameron, L. P. et al. 5-HT 2A Rs mediate therapeutic behavioral effects of psychedelic tryptamines. ACS Chem. Neurosci. https://doi.org/10.1021/acschemneuro.2c00718 (2023).

Krebs-Thomson, K., Ruiz, E. M., Masten, V., Buell, M. & Geyer, M. A. The roles of 5-HT 1A and 5-HT 2 receptors in the effects of 5-MeO-DMT on locomotor activity and prepulse inhibition in rats. Psychopharmacology 189 , 319–329 (2006).

Schwelm, H. M. et al. Qualitative and quantitative analysis of tryptamines in the poison of Incilius alvarius (Amphibia: Bufonidae). J. Anal. Toxicol. 46 , 540–548 (2022).

Hughes, Z. A. et al. Neurochemical evaluation of the novel 5-HT 1A receptor partial agonist/serotonin reuptake inhibitor, vilazodone. Eur. J. Pharmacol. 510 , 49–57 (2005).

Loane, C. & Politis, M. Buspirone: what is it all about? Brain Res. 1461 , 111–118 (2012).

Winter, J. C., Filipink, R. A., Timineri, D., Helsley, S. E. & Rabin, R. A. The paradox of 5-methoxy- N , N -dimethyltryptamine: an indoleamine hallucinogen that induces stimulus control via 5-HT1A receptors. Pharmacol. Biochem. Behav. 65 , 75–82 (2000).

Davis, A. K., So, S., Lancelotta, R., Barsuglia, J. P. & Griffiths, R. R. 5-Methoxy- N , N -dimethyltryptamine (5-MeO-DMT) used in a naturalistic group setting is associated with unintended improvements in depression and anxiety. Am. J. Drug Alcohol Abuse 45 , 161–169 (2019).

Article   PubMed   PubMed Central   Google Scholar  

Reckweg, J. T. et al. The clinical pharmacology and potential therapeutic applications of 5-methoxy- N , N -dimethyltryptamine (5-MeO-DMT). J. Neurochem. 162 , 128–146 (2022).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Chauhan, M., Parry, R. & Bobo, W. V. Vilazodone for major depression in adults: pharmacological profile and an updated review for clinical practice. Neuropsychiatr. Dis. Treat. 18 , 1175–1193 (2022).

Kim, K. et al. Structure of a hallucinogen-activated Gq-coupled 5-HT 2A serotonin receptor. Cell 182 , 1574–1588.e19 (2020).

Wacker, D. et al. Crystal structure of an LSD-bound human serotonin receptor. Cell 168 , 377–389.e12 (2017).

Cameron, L. P. et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 589 , 474–479 (2021).

Article   ADS   CAS   PubMed   Google Scholar  

Kaplan, A. L. et al. Bespoke library docking for 5-HT 2A receptor agonists with antidepressant activity. Nature 610 , 582–591 (2022).

Article   ADS   CAS   PubMed   PubMed Central   Google Scholar  

Carhart-Harris, R. L. & Nutt, D. J. Serotonin and brain function: a tale of two receptors. J. Psychopharmacol. 31 , 1091–1120 (2017).

Olsen, R. H. J. et al. TRUPATH, an open-source biosensor platform for interrogating the GPCR transducerome. Nat. Chem. Biol. 16 , 841–849 (2020).

Nichols, D. E. Chemistry and structure–activity relationships of psychedelics. Curr. Top. Behav. Neurosci. 36 , 1–43 (2018).

CAS   PubMed   Google Scholar  

Glennon, R. A. et al. Binding of β-carbolines and related agents at serotonin (5-HT 2 and 5-HT 1A ), dopamine (D 2 ) and benzodiazepine receptors. Drug Alcohol Depend. 60 , 121–132 (2000).

Halberstadt, A. L. & Geyer, M. A. Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology 61 , 364–381 (2011).

Xu, P. et al. Structural insights into the lipid and ligand regulation of serotonin receptors. Nature 592 , 469–473 (2021).

Ballesteros, J. A. & Weinstein, H. Integrated methods for the construction of three-dimensional models and computational probing of structure–function relations in G protein-coupled receptors. Methods Neurosci. 25 , 366–428 (1995).

Article   CAS   Google Scholar  

Rasmussen, S. G. et al. Crystal structure of the β 2 adrenergic receptor–Gs protein complex. Nature 477 , 549–555 (2011).

Wacker, D. et al. Structural features for functional selectivity at serotonin receptors. Science 340 , 615–619 (2013).

Nichols, D. E., Monte, A., Huang, X. & Marona-Lewicka, D. Stereoselective pharmacological effects of lysergic acid amides possessing chirality in the amide substituent. Behav. Brain Res. 73 , 117–119 (1996).

Speeter, M. E. & Anthony, W. C. The action of oxalyl chloride on indoles—a new approach to tryptamines. J. Am. Chem. Soc. 76 , 6208–6210 (1954).

Shulgin, A. T. & Shulgin, A. Tihkal: The Continuation (Transform Press, 1997).

Kozell, L. B. et al. Pharmacologic activity of substituted tryptamines at 5-hydroxytryptamine (5-HT) 2A receptor (5-HT 2A R), 5-HT 2C R, 5-HT 1A R, and serotonin transporter. J. Pharmacol. Exp. Ther. 385 , 62–75 (2023).

Blair, J. B. et al. Effect of ring fluorination on the pharmacology of hallucinogenic tryptamines. J. Med. Chem. 43 , 4701–4710 (2000).

Laban, U., Kurrasch-Orbaugh, D., Marona-Lewicka, D. & Nichols, D. E. A novel fluorinated tryptamine with highly potent serotonin 5-HT 1A receptor agonist properties. Bioorg. Med. Chem. Lett. 11 , 793–795 (2001).

Wang, C. et al. Structural basis for molecular recognition at serotonin receptors. Science 340 , 610–614 (2013).

Gasser, P., Kirchner, K. & Passie, T. LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects. J. Psychopharmacol. 29 , 57–68 (2015).

Article   PubMed   Google Scholar  

Halberstadt, A. L., Koedood, L., Powell, S. B. & Geyer, M. A. Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice. J. Psychopharmacol. 25 , 1548–1561 (2011).

Darmani, N. A., Martin, B. R., Pandey, U. & Glennon, R. A. Do functional relationships exist between 5-HT 1A and 5-HT 2 receptors. Pharmacol. Biochem. Behav. 36 , 901–906 (1990).

Arnt, J. & Hyttel, J. Facilitation of 8-OHDPAT-induced forepaw treading of rats by the 5-HT 2 agonist DOI. Eur. J. Pharmacol. 161 , 45–51 (1989).

Ermakova, A. O., Dunbar, F., Rucker, J. & Johnson, M. W. A narrative synthesis of research with 5-MeO-DMT. J. Psychopharmacol. 36 , 273–294 (2022).

Bagot, R. C. et al. Ketamine and imipramine reverse transcriptional signatures of susceptibility and induce resilience-specific gene expression profiles. Biol. Psychiatry 81 , 285–295 (2017).

Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311 , 864–868 (2006).

Donahue, R. J., Muschamp, J. W., Russo, S. J., Nestler, E. J. & Carlezon, W. A. Jr. Effects of striatal ΔFosB overexpression and ketamine on social defeat stress-induced anhedonia in mice. Biol. Psychiatry 76 , 550–558 (2014).

Golden, S. A., Covington, H. E. 3rd, Berton, O. & Russo, S. J. A standardized protocol for repeated social defeat stress in mice. Nat. Protoc. 6 , 1183–1191 (2011).

Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131 , 391–404 (2007).

Willner, P., Towell, A., Sampson, D., Sophokleous, S. & Muscat, R. Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology 93 , 358–364 (1987).

Li, N. et al. Glutamate N -methyl- d -aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol. Psychiatry 69 , 754–761 (2011).

Hesselgrave, N., Troppoli, T. A., Wulff, A. B., Cole, A. B. & Thompson, S. M. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2022489118 (2021).

Shao, L. X. et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron 109 , 2535–2544.e4 (2021).

de la Fuente Revenga, M. et al. Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice. Cell Rep. 37 , 109836 (2021).

Savalia, N. K., Shao, L. X. & Kwan, A. C. A dendrite-focused framework for understanding the actions of ketamine and psychedelics. Trends Neurosci. 44 , 260–275 (2021).

Bickle, J. G. et al. 5HT 1A receptors on dentate gyrus granule cells confer stress resilience. Biol. Psychiatry https://doi.org/10.1016/j.biopsych.2023.10.007 (2023).

Newman-Tancredi, A. et al. NLX-112, a highly selective 5-HT 1A receptor agonist, mediates analgesia and antidepressant-like activity in rats via spinal cord and prefrontal cortex 5-HT 1A receptors, respectively. Brain Res. 1688 , 1–7 (2018).

Becker, A. M. et al. Ketanserin reverses the acute response to LSD in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects. Int. J. Neuropsychopharmacol. https://doi.org/10.1093/ijnp/pyac075 (2022).

Strassman, R. J. Human psychopharmacology of N , N -dimethyltryptamine. Behav. Brain Res. 73 , 121–124 (1996).

Pokorny, T., Preller, K. H., Kraehenmann, R. & Vollenweider, F. X. Modulatory effect of the 5-HT 1A agonist buspirone and the mixed non-hallucinogenic 5-HT 1A/2A agonist ergotamine on psilocybin-induced psychedelic experience. Eur. Neuropsychopharmacol. 26 , 756–766 (2016).

Reckweg, J. et al. A phase 1, dose-ranging study to assess safety and psychoactive effects of a vaporized 5-methoxy- N , N -dimethyltryptamine formulation (GH001) in healthy volunteers. Front. Pharmacol. 12 , 760671 (2021).

Shapiro, D. A. et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 28 , 1400–1411 (2003).

Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14 , 331–332 (2017).

Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14 , 290–296 (2017).

Punjani, A., Zhang, H. & Fleet, D. J. Non-uniform refinement: adaptive regularization improves single-particle cryo-EM reconstruction. Nat. Methods 17 , 1214–1221 (2020).

Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66 , 486–501 (2010).

Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. D Struct. Biol. 75 , 861–877 (2019).

Yamashita, K., Palmer, C. M., Burnley, T. & Murshudov, G. N. Cryo-EM single-particle structure refinement and map calculation using Servalcat. Acta Crystallogr. D Struct. Biol. 77 , 1282–1291 (2021).

The PyMOL Molecular Graphics System v.2.0 (Schrödinger, 2017).

Kroeze, W. K. et al. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat. Struct. Mol. Biol. 22 , 362–369 (2015).

Henke, A. et al. Toward serotonin fluorescent false neurotransmitters: development of fluorescent dual serotonin and vesicular monoamine transporter substrates for visualizing serotonin neurons. ACS Chem. Neurosci. 9 , 925–934 (2018).

Rodrı́guez, P. et al. A single administration of the atypical psychedelic ibogaine or its metabolite noribogaine induces an antidepressant-like effect in rats. ACS Chem. Neurosci. 11 , 1661–1672 (2020).

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Acknowledgements

This work was supported by NIH grant R35GM133504, a Sloan Research Fellowship in Neuroscience, an Edward Mallinckrodt, Jr Foundation Grant, a McKnight Foundation Scholars Award, an Irma T. Hirschl/Monique Weill-Caulier Trust Research Award (all to D.W.); an NIH F31 MH132317 (A.L.W), and T32 Training Grant GM062754 and DA053558 (A.L.W and G.Z.); the G. Harold & Leila Y. Mathers Charitable Foundation, the NIH grant R01DA050613, G.L. Freeman, and Columbia University for support of this work (all to D.S.); and the following NIH grants: R01MH127820 and R01MH104559 (S.J.R.). L.F.P is supported by the Leon Levy Foundation and the Brain and Behavior Research Foundation. Some of this work was performed at the National Center for CryoEM Access and Training (NCCAT) and the Simons Electron Microscopy Center located at the New York Structural Biology Center, supported by the NIH Common Fund Transformative High Resolution Cryo-Electron Microscopy program (U24 GM129539) and by grants from the Simons Foundation (SF349247) and NY State Assembly. We further acknowledge cryo-EM resources at the National Resource for Automated Molecular Microscopy located at the New York Structural Biology Center, supported by grants from the Simons Foundation (SF349247), NYSTAR, and the NIH National Institute of General Medical Sciences (GM103310) with additional support from Agouron Institute (F00316) and NIH (OD019994). For additional data collection, we are grateful to staff at the Laboratory for BioMolecular Structure (LBMS), which is supported by the DOE Office of Biological and Environmental Research (KP160711). This work was supported in part through the computational and data resources and staff expertise provided by Scientific Computing and Data at the Icahn School of Medicine at Mount Sinai and supported by the Clinical and Translational Science Awards (CTSA) grant ULTR004419 from the National Center for Advancing Translational Sciences. We thank B. Bechand for early examination of in vivo pharmacology of the described compounds assisted by V. C. Galicia; C. Hwu for assistance with synthesis and purification of several compounds (all at Columbia University); and F. Zandkarimi from the Columbia University Chemistry Department Mass Spectrometry Core Facility for conducting the high-resolution mass spectrometry experiments.

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These authors contributed equally: Audrey L. Warren, David Lankri

Authors and Affiliations

Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Audrey L. Warren, Michael J. Capper & Daniel Wacker

Department of Chemistry, Columbia University, New York, NY, USA

David Lankri, Michael J. Cunningham, Inis C. Serrano, Andrew C. Kruegel, Priscilla Duggan, Vaclav Havel & Dalibor Sames

Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Lyonna F. Parise, Scott J. Russo & Daniel Wacker

Zuckerman Institute of Mind, Brain, Behavior, Columbia University, New York, NY, USA

Gregory Zilberg & Dalibor Sames

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Contributions

D.S., A.C.K, M. J. Cunningham and D.L. conceived and initiated the project. A.L.W. designed experiments, expressed and purified protein for grid freezing, collected data, refined structures with help from M. J. Capper, performed signalling and uptake assays, and co-wrote the manuscript. D.L. designed, synthesized, purified and characterized compounds with assistance from V.H., and co-wrote the manuscript. M. J. Cunningham designed, synthesized, purified and characterized compounds. D.L., V.H. and D.S. designed and supervised the pharmacokinetics study. L.F.P. performed the chronic SD stress assay and subsequent behavioural analyses supervised by S.J.R. I.C.S. designed and performed in vivo pharmacology assays, including the open-field and HTR assays, with assistance from P.D. G.Z. prepared grids for structure determination and assisted with data collection. D.S. and D.W. conceptualized the overall project and designed experiments, analysed the data, supervised the project and management, and wrote the manuscript.

Corresponding authors

Correspondence to Dalibor Sames or Daniel Wacker .

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Competing interests.

The authors declare the following competing financial interests: D.S. and A.C.K. are co-founders of Gilgamesh Pharmaceuticals and Kures. M. J. Cunningham is a co-founder of Gilgamesh Pharmaceuticals. A.L.W., D.L., I.C.S., L.F.P., S.J.R., D.S. and D.W. are inventors on a patent application related to the featured compound class. D.W. has consulted for Otsuka Pharmaceutical, Longboard Pharmaceuticals and Ocean Bio on the design of psychedelic-based therapeutics. None of the companies listed herein contributed to the funding or experimental design. All other authors declare no competing interests.

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Extended data figures and tables

Extended data fig. 1 cryo-em structure determination of drug-bound 5-ht 1a -gαi1/gβ1/gγ2 complexes..

a , Representative structure determination of 5-MeO-DMT-bound 5-HT 1A signalling complex. Top Left , Analytical size exclusion chromatography and SDS-PAGE show monodisperse and pure protein of intact complex and its components. Right , representative Cryo-EM micrograph (white bar indicates scale) of 4680 total micrographs and data processing schematic exemplified by 5-MeO-DMT-bound 5-HT 1A -Gi1 structure: After particle picking, 2D classification and multiple rounds of 3D classification, the final particle stack was refined using non-uniform refinement. A final map was obtained and resolutions were estimated applying the 0.143 cutoff in GS-FSC. Initial models were built in COOT, and then further refined in PHENIX for the generation of final coordinates shown in this manuscript. b , Local resolution map of a 5-MeO-DMT-bound 5-HT 1A -Gi1 complex ( left ) and FSC curves ( right ) calculated based on the final reconstruction in cryoSPARC. c , 5-MeO-DMT (yellow) in the orthosteric binding pocket from the side ( left ) and rotated 45° towards the top of the receptor ( right ) with the map of ligand and surround residue densities shown at 5σ.

Source data

Extended data fig. 2 comparison of different 5-ht 1a structures and differences in binding of lsd to 5-ht 1a and 5-ht 2a ..

a , Superposition of herein reported 5-MeO-DMT-bound 5-HT 1A -Gi complex with the previously reported 5-HT-bound 5-HT 1A -Gi structure (PDB ID: 7E2Y ) shows similar conformations. Additional residues in 5-HT 1A ’s EL2 and G proteins not observed in previous structures are highlighted in red. b , Lipids (blue) and cholesterol hemisuccinate (dark blue) are bound to similar sites as observed before. c , Local resolution map of a LSD-bound 5-HT 1A -Gi1 complex ( left ) and FSC curves ( right ) calculated the final reconstruction in cryoSPARC. d , LSD (grey) in the orthosteric binding pocket from the side ( top ) and rotated 45° towards the top of the receptor ( bottom ) with the map of ligand and surround residue densities shown at 5σ. e , LSD shows distinct binding modes bound to 5-HT 1A -Gi signalling complex and 5-HT 2A (PDB ID: 6WGT ). Left , 5-HT 1A -bound LSD (grey) sits deeper in the binding pocket compared to 5-HT 2A -bound LSD (orange). Zoom in of LSD in 5-HT 1A -Gi structure ( middle ) and 5-HT 2A structure ( right ) highlights differential stereochemistry and receptor-specific interactions of diethylamide moiety. Hydrogen bonds are indicated as grey dashed lines.

Extended Data Fig. 3 Global structure-activity landscape of tryptamine psychedelics at 5-HT 1A and 5-HT 2A receptors and their synthesis.

a , Overview of the cryo-EM structure of the 5HT 1A receptor-Gi signalling complex bound to 5-MeO-DMT ( center ). Classic psychedelics such as the prototypical compounds DMT and LSD are agonists of both 5-HT 1A and 5-HT 2A receptors ( left semi-circle ). 5-MeO-DMT ( top of the circle ), a major psychoactive compound found in toad secretions, shows comparable potency and efficacy at both 5-HT 1A and 5-HT 2A receptors. Systematic structural mapping via elaboration of the core 5-MeO-DMT structure identifies a class of 5-MeO-tryptamines with increasing 5-HT 1A selectivity ( right hemi-circle ). 5-MeO-DMT can be viewed as a deconstruction of ibogaine, a oneirogen with a complex polycyclic tryptamine structure ( bottom of the circle ). Iboga compounds show no activity at 5-HT 1A and 5-HT 2A receptors, but this activity re-emerges by deconstruction of the isoquinuclidine core to simple mono-cyclic tryptamines such as 5-MeO-PipT (5-methoxypiperidinyl-tryptamine) and 4-F,5-MeO-PyrT (4-fluoro, 5-methoxypyrrolidinyl-tryptamine, right hemi-circle). Images of peyote, mushrooms, ayahuasca, and toad are from iStock and ShutterStock, and Tabernanthe iboga schematic is adapted from previous work 65 .  b , General synthesis methodology of tryptamines. a. oxalyl chloride, b. MeOH, LAH, c. PPh3, CBr4, d. Amine, TEA, e. Amine, f. LAH.

Extended Data Fig. 4 Structural comparison of 5-MeO-DMT 5-HT1A-selective analog 4-F, 5-MeO-PyrT bound to 5-HT 1A .

a , Local resolution map of a 4-F,5-MeO-PyrT-bound 5-HT 1A -Gi1 complex ( left ) and FSC curves ( right ) calculated from the final reconstruction in cryoSPARC. b , 4-F,5-MeO-PyrT (dark blue) in the orthosteric binding pocket from the side ( left ) and rotated 45° towards the top of the receptor ( right ) with the map of ligand and surrounding residue densities shown at 5σ. c , structural side-by-side comparison of 5-HT 1A orthosteric site bound to 5-MeO-DMT (yellow) and 4-F,5-MeO-PyrT (dark blue). d , cAMP accumulation assays using wildtype and mutant 5-HT 1A , and different drugs. Concentration-response experiments reveal different sensitivities of distinct drugs to F361L mutation. All signalling studies were performed in triplicates and are averaged from two to three independent experiments. Data have been normalized against 5-HT and errors bars denote s.e.m.

Extended Data Fig. 5 Comparison of 4-F,5-MeO-PyrT binding pose to that of different clinical 5-HT 1A drugs.

a , b , Local resolution maps of vilazodone-bound ( a ) and buspirone-bound ( b ) 5-HT 1A -Gi1 complexes and corresponding FSC curves calculated from the final reconstructions in cryoSPARC. c , d , Vilazodone ( c , green) and buspirone ( d , teal) in the orthosteric binding pocket from the side ( left ) and rotated 45° towards the top of the receptor ( right ) with the density map of ligand and surrounding residues shown at 5σ. e-h , Extracellular view of 4-F,5-MeO-PyrT ( e , dark blue), Vilazodone ( f , green), Aripiprazole ( g , magenta, PDB ID: 7E2Z ), and Buspirone ( h , teal) binding poses in 5-HT 1A ’s orthosteric site.

Extended Data Fig. 6 Selectivity of different 5-MeO-DMT analogs and off-target activity of 4-F,5-MeO-PyrT.

a , 5-HT 1A -Gi and 5-HT 2A -Gq BRET of 5-HT, 5-MeO-DMT, 5-MeO-MET, and 4-F,5-MeO-PyrT with respective potencies and 5-HT 1A  > 5-HT 2A selectivities. b , Off-target inhibition of transporters SERT, PMAT, OCT1, and OCT2 by 4-F,5-MeO-PyrT and known inhibitors. SERT uptake was performed in triplicates and data was averaged from two independent experiments showing data as mean+s.e.m. PMAT, OCT1, and OCT2 uptake was performed once in quadruplicate. c, Arrestin-recruitment of 5-HT and 4-F,5-MeO-PyrT at all human 5-HT receptor subtypes except for 5-HT 7A , whose activation was measured via cAMP stimulation. All functional studies were performed in triplicates and are averaged from two to three independent experiments. Data have been normalized against 5-HT, Citalopram, and Decynium-22, and errors bars denote the s.e.m.

Extended Data Fig. 7 Effects of 5-MeO-DMT derivatives on rodent behavior.

a , Evaluation of 4-F,5-MeO-PyrT in open field for two hours (n = 3-4/group). b , Exemplary traces of the ambulatory distance traveled in open field following 4-F,5-MeO-PyrT (1 mg/kg, s.c.) administration and with and without WAY-100635 pre-treatment (1 mg/kg, s.c., 15 min prior). Panel was created with BioRender.com. c , Effect of WAY-100635 (1 mg/kg, s.c., 15 min prior) on 4-F,5-MeO-PyrT’s and 5-MeO-MET’s effect on total locomotion (n = 7 - 8/group, 30 min). d , Determination of optimal inhibitory WAY-100635 dose via administration of 1 mg/kg and 2 mg/kg WAY-100635 prior to studying 4-F,5-MeO-PyrT’s effects on total locomotion (n = 7 - 8 /group) and HTR (n = 6/group). Analysis was done using one-way ANOVA with multiple comparisons with Tukey’s post hoc test, and exact p values have been denoted in the Figure. e-g , Effects of saline or 4-F,5-MeO-PyrT administration on control (Control) or chronically defeated mice (Stress). Determination of e , distance moved as a measure of locomotor activity, f , social interaction as a measure of anxiety- and depression-related phenotype, g , corner time as a measure of anxiety-like behavior. Analysis was done in a sub-cohort of the animals reported in Fig. 5d . Number of mice for each group is indicated below the data for each respective cohort. Differences were determined by two-way ANOVA with multiple comparisons using Fisher’s LSD post hoc test, and exact p values have been denoted in the Figure. h , Vehicle- and drug-treated stressed mice shown in Fig. 5d were divided into susceptible (SI ratio<1) and resilient (SI ratio>1) populations. Significance in the population shift was determined by a two-sided Fisher’s exact test and p value and number of mice have been denoted in the Figure. Error bars denote the s.e.m.

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Warren, A.L., Lankri, D., Cunningham, M.J. et al. Structural pharmacology and therapeutic potential of 5-methoxytryptamines. Nature (2024). https://doi.org/10.1038/s41586-024-07403-2

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Imaging response to immune checkpoint inhibitors in patients with advanced melanoma a retrospective observational cohort study.

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The association between objective imaging response and first line immune checkpoint inhibitor (ICI) therapy regimes in advanced melanoma remains uncharacterized in routine practice.We conducted a multi-center retrospective cohort analysis of advanced melanoma patients receiving first line ICI therapy from August 2013-May 2020 in Alberta, Canada. The primary outcome was likelihood of RECIST v1.1 assessed objective imaging response between patients receiving antiprogrammed cell death protein 1 (anti-PD1) monotherapy and those receiving combination ipilimumabnivolumab. Secondary outcomes were identification of baseline characteristics associated with nonresponse and the association of imaging response with overall survival (OS) and time to next treatment (TTNT).Results: 198 patients were included, 41/198 (20.7%) had complete response, 86/198 (43.4%) had partial response, 23/198 (11.6%) had stable disease, and 48/198 (24.2%) had progressive disease. Median OS was not reached (NR) (95% CI 49.0-NR) months for complete responders, NR (95%CI 52.9-NR) months for partial responders, 33.7 (95%CI 15.8-NR) months for stable disease, and 6.4 (95%CI 5.2-10.1) months for progressive disease (log-rank p<0.001). Likelihood of objective imaging response remained similar between anti-PD1 monotherapy and ipilimumab-nivolumab groups (OR 1.95 95%CI 0.85-4.63, p=0.121).Elevated LDH level (OR 0.46; 95%CI 0.21-0.98, p=0.043), mucosal primary site (OR 0.14; 95%CI 0.03-0.48, p=0.003), and BRAF V600E mutation status (OR 0.31; 95%CI 0.13-0.72, p=0.007) were associated with decreased likelihood of response.No significant difference in likelihood of imaging response between anti-PD1 monotherapy and combination ipilimumab-nivolumab was observed. Elevated LDH level, mucosal primary site, and BRAF V600E mutation status were associated with decreased likelihood of response. Given that pivotal clinical trials of ipilimumab-nivolumab did not formally compare ipilimumab-nivolumab with nivolumab monotherapy, this work adds context to differences in outcomes when these agents are used. These results may inform treatment selection, and aid in counseling of patients treated with first-line ICI therapy in routine clinical practice settings.

Keywords: Melanoma, Immunotherapy, RECIST = Response Evaluation Criteria in Solid Tumors, Survival, prognosis

Received: 12 Feb 2024; Accepted: 13 May 2024.

Copyright: © 2024 Gupta, Stukalin, Meyers, Heng, Monzon, Cheng and Navani. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Igor Stukalin, Tom Baker Cancer Centre, Calgary, T2N 4N2, Alberta, Canada Daniel E. Meyers, Tom Baker Cancer Centre, Calgary, T2N 4N2, Alberta, Canada Daniel Y. Heng, Tom Baker Cancer Centre, Calgary, T2N 4N2, Alberta, Canada Jose Monzon, Tom Baker Cancer Centre, Calgary, T2N 4N2, Alberta, Canada Tina Cheng, Tom Baker Cancer Centre, Calgary, T2N 4N2, Alberta, Canada Vishal Navani, Tom Baker Cancer Centre, Calgary, T2N 4N2, Alberta, Canada

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