I was listening to the radio a while back when something caught my ear. Dr. Charles Raison was talking about a crisis in the treatment and diagnosis of mental illnesses. As one of the roughly 27 million Americans taking antidepressants, I was alarmed by his claim that there is little scientific basis for the way we diagnose depression, and that the Diagnostic and Statistical Manual of Mental Disorders, the therapist’s bible, was mostly “folk wisdom.” He stated that most common pharmaceutical treatments don’t seem to work for roughly a quarter of the people who are prescribed them — and may even intensify symptoms. When they do work, there is concern that patients will get worse when they stop taking the medications. And there are no long-term studies of how antidepressants affect the brain when used indefinitely; most were approved based on studies that lasted only six to eight weeks. I had taken them for years.

A professor of psychiatry and human ecology at the University of Wisconsin–Madison, Raison believes depression isn’t a single thing but a cloud of related mental and physical states unique to each person; there is no one symptom that every depressed person experiences. “It’s all kind of hunt-and-peck,” he says. “We have an array of treatment options that we just start throwing at people because we don’t know why, biologically, they’re depressed.” Meanwhile depression is growing to epidemic proportions in the United States, with few truly novel treatments approved over the last three decades.

Growing up in California’s San Joaquin Valley, Raison started out as a journalist; his family had owned a small-town newspaper there for a hundred years. In 1984, while working on his PhD in English, he underwent psychotherapy, and the experience inspired him to become a psychiatrist. Though it meant going back to take all the undergrad science courses he had skipped, he accomplished his goal and later became part of a team that identified connections among the immune system, inflammation, and mental health. He has since been at the forefront of research into new treatments for depression, many of which have been a part of human cultures for millennia: compassion meditation, sweat lodges, fasting, and psychedelics — in particular psilocybin, the active ingredient in hallucinogenic mushrooms. He says experiments have shown that psilocybin can put people into a “state of resilience” against whatever is causing their depression.

Raison is the director of clinical and translational research for Usona Institute, a nonprofit medical-research organization conducting studies on psilocybin. If results are positive, their work would support FDA approval for psilocybin as a treatment for major depression. He’s also a visiting professor at Emory University in Atlanta, Georgia, where he serves as director of research on spiritual health and hosts Emory’s Health Is Everything podcast. He is the author, with Vladimir Maletic, of The New Mind-Body Science of Depression.

These discussions took place by phone, both before and during the isolation and upheaval from the coronavirus. In May 2020 The Washington Post reported that nearly half of Americans surveyed said the coronavirus pandemic was harming their mental health. Raison says data have shown that, over time, loneliness is as lethal as smoking two packs of cigarettes a day. Our conversation ranged from the evolutionary role of depression, to the validity of psychiatric diagnoses, to the potential of ancient practices to heal our modern malaise.


542 - Charles Raison


Conover: An April 2019 article in The Atlantic suggested that psychiatrists don’t want to admit mental illness is still a mystery. Do you agree with that?

Raison: Yes, that’s true. There have been significant advances in psychiatry since the first modern Diagnostic and Statistical Manual (DSM) came out in 1980, but we still haven’t been able to do two critical things.

The first is to identify and develop more-effective treatments for various conditions. Tom Insel, a former head of the National Institute of Mental Health, said that we as a country got very little out of the billions of dollars the NIMH spent during his tenure.

The other thing we haven’t been able to do is figure out what to give to whom. We can diagnose someone as depressed, for example, but there is no one thing that all depressed people have wrong with them. If I have a bad stomachache, the doctor is going to figure out whether it is a perforated bowel or a bacterial infection or my appendix that’s the problem. We don’t have that clarity in psychiatry. We’re not able to look at someone and say, “Ah! The cause of your depression is X, and here is the definitive treatment.”

Conover: You’ve been critical of the diagnoses in the DSM, saying it gets a lot wrong.

Raison: It’s not that the diagnoses in the DSM are worthless; there is wisdom in them. We know that if you have a manic episode, for instance, it’s very likely that you’re going to have a depressive episode, and also that you’re going to have more manic episodes when you’re young and more depressive episodes when you’re older, on average. The DSM is like folk wisdom — valuable, clinical folk wisdom. And nobody’s replaced it with anything better. This is why psychiatry is in a crisis. We’ve realized that it’s mostly bunk scientifically, but we haven’t figured out what to do next.

Back in the day, I was a true believer in the DSM. I would see patients, make a diagnosis, and give them a drug. And some patients did really well. Now we’ve lost that certainty. I see young doctors in training who don’t know what to do when a patient says she’s going to kill herself. We’ve replaced a fictitious certainty with an honest confusion. Maybe there is some good in knowing what you don’t know, but I worry about psychiatry becoming paralyzed.

Conover: Has the development of new psychiatric drugs contributed to the loss of faith in diagnoses?

Raison: Yes, starting in the 1990s Big Pharma developed atypical antipsychotics that worked just as well for bipolar disorder as they did for schizophrenia. And then the same medications turned out to have antidepressant effects. So all of a sudden there were these medicines that worked for everything. If something works for everything, then who needs to figure out which disorder a person has, right?

SSRIs [selective serotonin reuptake inhibitors] changed the treatment of depression around the same time. All of a sudden antidepressants were tolerable. Before that, people had a really hard time with unpleasant side effects. Nobody ever stayed on antidepressants if they didn’t have to. But many people could take SSRIs for a long time and not seem too much the worse for wear. And these SSRIs worked for depression, they worked for anxiety, they worked for obsessive-compulsive disorder, and on and on. It was a sea change.

What we didn’t understand until a couple of years ago is that, although antidepressants help most patients — the ones who are really, really depressed often start feeling a lot better — about 25 percent of people do worse on the antidepressant than on a placebo.

Another problem is that a lot of people who respond positively to an antidepressant lose that response over time. And when people with chronic depression stop taking an antidepressant, they are at a high risk of crashing back into depression again. It’s as if, over time, the brain tries to overcome the effects of the antidepressant and go back to being depressed. Take away the drug, and the brain overshoots its goal. So, many people are left with a choice: Do I stay on this antidepressant for the rest of my life, even though it’s not doing much for me? Or do I get off it and risk doing worse? Sometimes, when the drug starts to lose its effectiveness, you can up the dose, but the patient will ultimately become even more resistant over time. There is concern now that antidepressants make for a worse disease course in the long run.

Conover: Does going straight to a diagnosis in order to prescribe a drug undercut the relationship between a patient and a clinician?

Raison: Sometimes, definitely. Ironically psychiatrists often have less interaction with patients than other doctors do. We see people for about ten minutes, then write them a prescription. We’re like these pill-dispensing machines, especially in outpatient practices. There’s a different kind of psychiatry for inpatient services, where you’re dealing with people who are extremely ill. The sicker you are, the more likely psychiatry is to help you. It’s less effective for people who are out in the world.

Psychiatry may be too focused on getting rid of illness and not focused enough on enhancing wellness. Some negative emotions can add depth to life. There’s a great Tom Waits lyric: “If I exorcise my devils / Well, my angels may leave, too.” People on SSRIs sometimes complain that life is flatter, less intense. But getting rid of those negative symptoms can also be very helpful. Ultimately patients want wellness. The question is: How much wellness?

Conover: Most of us think of depression as a chemical imbalance in the brain, but you say it’s a disorder of consciousness.

Raison: There is a deep philosophical issue here. Some neurologists and psychologists believe that consciousness doesn’t really exist; it’s just an illusion produced by the brain. Then there’s the Western religious belief that consciousness is a soul or spirit that’s separate from the brain, and the brain is just a receiver. I don’t believe either. I think that consciousness is a product of the brain’s activity, but it can also influence brain function in some way. There’s a dialogue. Now, if consciousness is created by the activity of the brain, then of course consciousness is chemical, and so are mental illnesses. And so is feeling happy, and feeling scared, and enjoying a good movie. It’s all chemical. But the idea of depression as a simple chemical imbalance is unbelievably crude. The neurotransmitters that are most often targeted — norepinephrine, serotonin, and dopamine — aren’t always found at abnormal levels in depressed people.

The brain operates in circuits, and depression probably occurs when your circuits fire in repetitive ways that produce depressive, unhappy thoughts. But acting like we can identify a specific cause hides as much as it reveals.

Conover: A study published in Psychiatry Research suggests that psychiatric diagnoses are all worthless.

Raison: I don’t subscribe to that. It’s true that the diagnoses we have in psychiatry are just descriptions of symptoms. Kleptomania is a description of people who like to steal things; it doesn’t tell you the cause of their compulsion. But some psychiatric diagnoses do tell you that if a patient presents in a certain way, they’re likely to respond better to this drug, or they’re likely to develop this other symptom next. It’s not perfect, but it’s better than nothing.

Obviously in medicine we need to know what’s causing the problem and to have a means of treating the cause. But, as I said, with a diagnosis of major depression, there is no one thing causing the problem. The problem itself can be different for different patients. According to the DSM you have to have five out of nine possible symptoms to be diagnosed with major depression. That means two people can both have major depression and have only one symptom in common.

My coauthor, Vlad Maletic, talks about a study in which researchers tried to count how many different presentations of depression there were in a large patient population. Among four thousand patients there were two thousand different presentations. Some people slept too much; others, too little. Some enjoyed life but felt horrible about themselves. Others felt fine about themselves but said life seemed empty. Unhappiness, a loss of interest in the world, anxiety, physical pain, sleep problems, exhaustion — depression symptoms are what we experience when adversity gets the better of us, and we see them across cultures. About six years ago a group of anthropologists went to the jungles of Bolivia to study the Tsimané, one of the last remaining aboriginal tribes there. The anthropologists developed a questionnaire in the native language to assess depression, and damned if the Tsimané didn’t have exactly the same symptoms that we do in the developed Western world.

Clearly humans evolved the capacity to become depressed, but why? Why has nature allowed depression to be so common? It must be doing something good for us. That doesn’t mean depression feels good or typically results in good outcomes nowadays, but it has served enough of an adaptive purpose that it’s been maintained in human populations. One possibility is that it’s telling us to make a change. Sometimes, though it’s hard when you are depressed, it’s useful to ask, What is this depression trying to tell me?

Conover: Are brain scans and genetic tests useful in treating depression?

Raison: Brain scans are good if you have a stroke or multiple sclerosis, which cause big injuries to the brain. For depression? No. The brain is super complex. Yes, some depressed people seem to have a certain type of brain activity, but lots of them don’t have that pattern. For a test to be clinically useful, it has to produce reliable and consistent results. We are just not there.

Some genetic tests that have become popular are beginning to fall apart on closer examination. No single gene is going to predict depression. Genes are so dependent on conditions that they are essentially unpredictable — or maybe they’re predictable, but you’d have to be God to decipher them.

Conover: You’ve been researching the effects of the psychedelic psilocybin on depression. Are your findings promising?

Raison: One fascinating thing about psychedelics is that the experiences they often induce seem to change people’s narratives about themselves, and about the world, for the better. Depression has elements of a narrative disorder, one that arises from the stories we tell ourselves about our lives: difficult childhood stories; stories of adversity and loss, of not getting the love we need at key points. Studies suggest that a psychedelic experience, if done in a proper, clinical context, radically changes people’s personal stories. Sometimes they realize that it’s just a story. Other times they come away with a more positive story, the feeling that they are contributing to something much larger than themselves. Someone’s narrative may become “I’m meant to be here. Things that are difficult are part of life.”

It also affects people spiritually. Fundamentalists become more universalist. Atheists become more agnostic. Agnostics often become believers. One study recruited people who wanted to meditate. Half were given the drug, and half got a placebo. The people who got the psilocybin meditated more and reported more satisfaction with meditation. A Swiss colleague of mine named Franz Vollenweider gave Zen Buddhist monks at a monastery psilocybin, and many of them said they had arrived at what they were looking for.

Robin Carhart-Harris at Imperial College London has shown that, after taking psychedelics, participants in the study were less enamored of authoritarian power structures. They came into the study thinking we need a strongman to lead us and left thinking we need to have more openness.

Conover: Do you have any solid findings from your own research about psilocybin?

Raison: We are still in the middle of our study. At this point there have been just five completed studies in the scientific literature looking at high-dose psilocybin for the treatment of depression. The first two were published four or five years ago, one from New York University and the other from Johns Hopkins. Both enrolled people with potentially life-threatening cancer and clinically significant anxiety and depression. They didn’t just give these people a psilocybin pill and tell them to take it at home and see what happens. Participants got six to eight hours of psychological preparation, and they had two therapists or facilitators with them when they took the dose. Half of them got a placebo, and half got a single high dose of psilocybin — enough to guarantee a powerful psychedelic experience. Their depression was measured beforehand and again about five weeks later. Then the researchers did a crossover, which means they ran the experiment again, and everybody who got the placebo the first time got active treatment the second time, and vice versa.

The results were quite striking: In both studies a single dose of psilocybin induced a powerful antidepressant response that was maintained for five weeks. Six months after the crossover, 70 to 80 percent of people were in remission from their depression without other treatments. This is unheard of in psychiatry! NYU has followed up with sixteen of its participants for four years now. A couple of them got a little psychotherapy, and one or two went on antidepressants, but none of them has had severe depression or anxiety since.

In the Carhart-Harris psilocybin study at Imperial College London, the participants didn’t have cancer, but they were classified as treatment-resistant for depression. Each had failed at least two antidepressant trials. These patients got essentially the same result as those in the other studies: their depression decreased considerably. Even six months later their symptoms were cut in half. The effect was not as durable as in the cancer-patient studies. After five or six months a number of the participants went back on antidepressants, but they were getting more benefit than they had before. This suggests a prolonged beneficial effect even in a difficult-to-treat population.

More recently the same people who did the cancer study at Johns Hopkins did a small study with people who had regular major depression. They did not have to be treatment-resistant, although many of them were. This study was published, and it shows the same pattern of results: a huge and long-lasting impact of high-dose psilocybin in reducing depression.

At Usona Institute we are in the middle of what’s called a Phase 2 study of psilocybin. Our hope is that, if our study succeeds, psilocybin will be approved by the FDA for treatment of major depression.

My colleagues at MAPS, the Multidisciplinary Association for Psychedelic Studies, are prescribing MDMA, also known as ecstasy or Molly, for post-traumatic stress disorder, and it’s showing promise. When combined with psychotherapy, there’s profound improvement that can last for years.

Clearly humans evolved the capacity to become depressed, but why? Why has nature allowed depression to be so common?

Conover: Are MDMA and psilocybin similar drugs?

Raison: No, they’re different agents. Classic psychedelics like psilocybin, mescaline, ayahuasca, and LSD work mostly by interacting with a postsynaptic serotonin receptor. They produce vivid psychedelic states: you see hallucinations, your sense of time can change, and you often have mystical experiences.

MDMA is mostly a serotonin releaser, and it tends to produce profound emotional experiences — feelings of love, kindness, and being connected with everybody. That’s why it’s been called the “love drug.” In the MAPS studies patients also undergo twelve psychotherapy sessions, three of which are conducted after receiving either MDMA or a placebo. These sessions are extremely powerful. People are able to look at their trauma without negative emotions flooding them. They’re able to hold the trauma in this open, loving space.

Conover: Could a bad experience with a psychedelic push some people deeper into depression?

Raison: Almost certainly yes, just as there is compelling evidence that some people are made much worse by antidepressants like Prozac and Zoloft. Anything that has a beneficial effect on the brain in some can have the opposite effect in others. There are people who become agitated when you give them a drug to relax them. That’s just the nature of the brain.

There is not going to be a magic pill. Depression is a hardwired response to adversity. To get rid of it, I think we’d have to rebuild who we are as human beings. I sometimes worry that psychedelics are being oversold. The hopes being pinned on them are so great that there’s going to be disillusionment and backlash when they don’t solve everyone’s problems.

Conover: But you’ve also said people report that psychedelics are like “a year of psychotherapy in a day.”

Raison: That’s just a metaphor, an attempt to get across the fact that people can have profound psychological experiences. But let’s talk about psychotherapy. I’ve got a colleague at the University of California, San Francisco, who is studying how people with depression get better through psychotherapy: They don’t get a little bit better every day. Rather they tend to experience sudden gains. They have a particularly good session where all of a sudden something clicks, and they’re way better. Then they have a couple of sessions that are sort of ho-hum before something clicks again. What psychedelics do, when they work, is induce a massive sudden gain. People are more likely to quit smoking and drinking; they’re less likely to feel anxious. Those outcomes are associated with the quality of the psychedelic experience. In general those who experience a sense of oneness with others or with the universe are more likely to report feeling happier overall.

When people have an emotional breakthrough in a psychedelic session, that, too, seems to predict well-being. It means that you confronted your personal problems and either resolved them or came to some sort of acceptance of them.

Conover: What is psilocybin doing for people in biological terms? What happens in the brain?

Raison: Classic psychedelics like psilocybin cause a rapid change in brain activity. Normally there are many more connections within brain areas than there are across brain areas, and areas of the brain that are farther apart don’t talk to each other nearly as much as areas that are side-by-side. When you give people psilocybin, that changes. All of a sudden widely divergent parts of the brain start talking to one another. Parts of the deep temporal lobe that aren’t usually connected with consciousness become connected.

Depression is a sort of rigid brain state in which people have negative thoughts over and over again. One possibility is that psilocybin disrupts that brain activity, and when it re-forms, it comes together differently. Another possibility — and these are not mutually exclusive — is that areas of the brain that don’t usually have a voice suddenly get heard. Psychedelics give the unconscious a chance to speak. People often describe a psychedelic experience as if it were coming from outside of them. I think that when parts of your brain you don’t normally listen to start speaking right to you, it feels like it’s coming from the outside. That’s what happens with schizophrenia and psychotic disorders — people hear voices that seem to be coming from outside of their head. Of course it’s just their brain talking to them. All the feelings they pushed down and didn’t know they felt are all of a sudden right in front of them.

Another thing that happens with psychedelics is ego dissolution. Many people get the sense that the boundaries of the self have blurred, and their consciousness has become part of a larger whole.

Conover: Consciousness is a complex concept. What does it mean to you?

Raison: Philosopher David Chalmers famously spoke of the “hard problem of consciousness.” It’s not hard to figure out the brain patterns that produce consciousness; it’s just hard to understand how physical reactions can produce something nonphysical. That is the mysterious part. Nobody really has an answer for it scientifically.

The work I do has made me aware of how precious consciousness is. It’s everything we value in life. One of the scary possibilities with artificial intelligence is we might invent these hyperbrilliant entities, but there’s nobody home, so to speak. Computers are getting smarter and smarter, but there’s no indication that they are going to develop consciousness.

I think consciousness is far more ephemeral than most of us realize. I see it as this evanescent, miraculous thing that provides sort of an illusion of continuity, a sense of a continuous stream of presence.

One of the great questions about consciousness is whether it’s an emergent quality of certain material systems or a fundamental element of the physical world. The latter view is called panpsychism. It has strong detractors, but I find it an interesting concept. Perhaps there are some basic building blocks of consciousness, just as matter is made of atoms.

What I’m attempting to do with psilocybin is engage consciousness directly using a pharmacological agent. All the data we have so far suggest that the intense experiences psychedelics provide do change consciousness. To the degree that subjects in our psychedelic studies have a sort of unitary mystical experience — connecting with “God” or “the universe” — they become less depressed.

Conover: You started your career in the field of immunopsychiatry, which didn’t work out as you expected. What is it?

Raison: Immunopsychiatry grew out of the discovery that the immune system plays a surprisingly large role in how we think and feel and respond to stress. Back in the late nineties Andy Miller, my mentor at Emory University in Atlanta, thought that maybe depression was an inflammatory state. There’s a logic to this. A lot of the symptoms of a fever resemble symptoms of depression — you sleep a lot, lose your appetite, are exhausted all the time — and a fever is nothing but an inflammatory response caused by the immune system.

He and I and others did a series of studies that showed how interferon — which your body’s immune system uses to fight disease — produced most of the same changes to hormones and brain function that you see in depressed people. This was pretty powerful evidence that inflammation could cause depression. The problem was that if depression is an inflammatory disorder, then anti-inflammatories should work as antidepressants, and we found that they don’t. In fact, in our study the placebo did better than the anti-inflammatory. I often tell people that maybe we should have been studying saline, because that was our placebo, and it worked wonders!

The immune system and its interactions with the brain are way more complicated than we thought — no big surprise there. At lower levels inflammatory molecules appear to protect against depression.

I feel depression might have evolved as a protective response to infection. Depressed people usually run a mildly elevated body temperature, which helps the body beat infections. Also many genes that have been associated with depression seem to provide some protection against various pathogens.

Early in human evolution, one of the primary causes of death was infection from wounding. Over time the brain evolved to link stress with wounding, and it began to activate the immune system in response to stress to prepare for the impending wounding-caused infection. Nowadays if we get stressed, we still get inflammation, even when we don’t need the protection from wounding.

We’re finding that, in Western nations, people tend to maintain mildly elevated levels of inflammation all the time. The same pattern does not appear in people living more traditional human lifestyles. The anthropologist Thom McDade, at Northwestern, went down to the Amazon rain forest, where infection is still a common way to die, and he drew blood repeatedly on people who were mostly agriculturalists and foragers. He found that, when they get sick, their inflammation goes through the roof, but if they recover, their inflammation goes down to almost zero. In the U.S., on the other hand, we just walk around with chronic mild elevation, which has been shown to increase the risk of heart attack, diabetes, cancer, dementia, and depression.

Conover: Psychologist James Hillman theorized that people in modern Western societies often get sick because our buildings are sick, the institutions we live within are sick — everything surrounding us is sick. Do you agree?

Raison: Life in the modern world may be better than in the 1700s and the 1800s, but the modern world has its own set of issues. There’s a lot of separation from nature, for example. There’s some evidence that mental illnesses increase the farther you are from green spaces. Literally having a park nearby reduces the risk of psychosis and depression. Now, we don’t know whether the cause is psychological or if it’s because green spaces are a rich source of microorganisms that modulate the immune system. But it’s safe to say humans have a preference for the kind of natural spaces in which they evolved. I think one of the great stressors, and one that nobody’s studied adequately, is the loss of our natural world. It used to be that the world you were born into looked the same when you died. I can think of very few places that are the same now as they were when I was a kid. Even national parks don’t look the same. There is some unrecognized grief over all this loss. Novelist John Spivey says that we’re disconnected from a sense of place and have come to rely on each other too much. Earlier Indigenous people were able to have a relationship with their home turf that met some of their emotional needs; now we have to lean on each other for that.

Conover: And we end up disappointed.

Raison: Yes, because people are inconstant. The problem is that, because of climate change, the mountains are now inconstant, too. Fields are inconstant. If I love a place, I grieve it already, because I know that in a few years it won’t look the same.

Conover: You have some familiarity with ancient wisdom traditions and spiritual practices. Are there any that could be helpful to people with depression?

Raison: I think many have promise. There’s been a lot of work with compassion meditation [a form of mindfulness meditation focused on nonjudgmental awareness and alleviation of suffering — Ed.]. Emory University has one of the most interesting Tibetan Buddhist programs in the United States right now. Recently they had scientists go to India and teach at monasteries, and they have monks on campus. They’re starting a K-12 compassion program for schools both in the slums of India and in Aspen, Colorado. I serve as the director of research on spiritual health at Emory. We’ve been teaching compassion meditation to hospital chaplains, and the initial results are that patients feel less depressed when they see chaplains who’ve had this training.

There’s evidence that fasting, which is widely practiced in spiritual traditions, has antidepressant effects. If you deprive yourself of food, it sponsors elevated states of mind. This might be why some people who get depressed don’t eat: it’s an attempt at self-treatment.

Hyperthermia, or overheating the body, is also a powerful antidepressant. The use of heat for spiritual purposes and healing — sweat lodges, for example — is widespread, especially in Indigenous societies.

There is not going to be a magic pill. Depression is a hardwired response to adversity. To get rid of it, I think we’d have to rebuild who we are as human beings.

Conover: How do these nondrug approaches like heat or fasting work?

Raison: They are what I call “adaptive stressors.” Survival was difficult for our ancestors. You had to work for your food and shelter. If you have to run down your meal, or get to it before a scavenger, you’re more likely to be successful if your brain gives you an emotional reward for running. Now, instead of spending six hours chasing down a gazelle, you can go to the grocery store and buy meat, but you will not get the same emotional boost, because evolution paired that payoff with the hard way of achieving the goal. When we achieve goals via shortcuts, our achievements don’t fully satisfy, because we are deprived of those adaptive stressors. I believe this goes a long way toward explaining the ennui of the modern world.

Psychedelics are physical stressors, too: Your heart rate goes up. Your blood pressure goes up. And they are psychological stressors. Many people who have a mystical experience during their session will first go through a dark night of the soul, in which they confront their demons. They’re brought face-to-face with things they do not want to think about, and they’re forced to experience them fully, which produces a beneficial change in their mental state.

Conover: Does the anesthetic ketamine help with depression?

Raison: Ketamine has been rigorously studied, and it does have an effect compared to a placebo. Many people who are very depressed will feel considerably better within an hour or two after a ketamine treatment. It’s been approved by the FDA. Ketamine doesn’t work for everyone, but it works for a lot of people for whom the standard antidepressants fail.

It produces strange psychological effects. Many people feel they are floating out of their body. It’s not a psychedelic, but at high doses it can produce hallucinations.

Because ketamine is legal, some psychiatrists are starting to use it the way we use psychedelics in our studies: to give patients a high dose and sit with them and help them through the experience, then have them do psychotherapy. But it is also clear that ketamine has direct effects on the brain that reduce depression whether or not the drug is paired with psychotherapy.

Conover: What about other psychedelics like ayahuasca?

Raison: Ayahuasca has been used ritually in shamanic ceremonies in South America for centuries. There are now a couple of small studies — fifteen to twenty people — showing that ayahuasca has antidepressant effects. That shouldn’t be surprising. A lot of vets with PTSD go down to South America for ayahuasca ceremonies, but I hear that scene has gotten seedy. In the Peruvian Amazon you can drive down the street and see signs saying, Ayahuasca Here.

Conover: Why isn’t it being used instead of psilocybin in the U.S.?

Raison: Because it’s a botanical brew. To get psilocybin approved, we have to have a purity of .1 percent — only one part in a thousand can be off. Ayahuasca is like a soup. There’s no way the FDA can approve it. It also produces a lot of nausea and is a harder experience for people. It’s more intense and can be darker, although some swear by it.

Something researchers are very interested in is the venom of the Sonoran Desert toad, which contains a potent psychedelic agent called 5-MeO-DMT. Last I heard, it’s going for a hundred dollars a gram down in Mexico, and the toads are in danger of extinction because people are hunting them down. It’s not that hard to synthesize 5-MeO-DMT, though. You can’t make it into a pill, but you can take it as an intermuscular injection or an IV, or you can smoke it, in which case the effect comes on in about five seconds.

Conover: Are researchers interested in it just because it’s more potent?

Raison: It reportedly has a very different psychological effect than other psychedelics. One of the leaders in the field says it’s not a psychedelic; it’s a transcendelic. It often puts people into a state where everything goes white. There’s no ego, no self, only this core basic awareness.

Conover: Where does LSD fit in relation to the other psychedelics we’ve discussed?

Raison: There has been renewed interest in it from drug companies, but it’s less studied than psilocybin, in part because LSD got a bad rap as a counterculture drug. It’s also a very long-lasting experience — like twelve hours. On the other hand, it has an effect on the dopamine system that’s not apparent in other psychedelics. Dopamine is a neurotransmitter connected to the brain’s reward system. There is probably untapped therapeutic potential there.

Conover: There have been no new accepted treatments for depression in a while. Is it a lack of new candidates, or is it because new drugs aren’t accepted by the psychiatric field?

Raison: It’s the lack of new pharmaceuticals. In fact, until ketamine came along, all antidepressants operated on some combination of norepinephrine, serotonin, and dopamine. None of these antidepressants is appreciatively different from the others when tested on large groups. Still, it’s good to have many options available, because people respond idiosyncratically to antidepressants. It can take some trial and error before you hit upon one that really makes a difference for you. I recently saw someone who was on Zoloft, and it really helped with anxiety, but it turned them into a zombie. So they went on vortioxetine, and — boom — it was like a miracle.

Conover: Do you think we’re overprescribing antidepressants?

Raison: Hard to say. Depression seems to have gotten more common since 1990. Depression also used to be a relapsing-remitting condition, and now it seems more often to be chronic. I wonder whether the increased use of antidepressants has helped make the disease more intractable. That’s never been proven, but I worry about it.

Conover: If someone reading this has depression, what would you suggest they do?

Raison: Clearly I am critical of psychiatry. Having said that, I would tell them to try to find a psychiatrist who seems to care about you, who has time for you, and with whom you feel a connection. If the doctor sees you for six minutes and spends her or his entire time typing on the computer, keep moving.

If you are really depressed and want to try an antidepressant, try it. If it works well for you, count yourself lucky. You’ve been given a reprieve. Now you have to decide whether you’re going to take this medication for the rest of your life. If you want to go off it, get into therapy. Studies show that tapering off an antidepressant while in therapy may protect against relapse.

If you fail with one antidepressant, try another. If you fail on more than a couple, the best data suggest that you’re not likely to find a pill that works for you, but there are other things that might work. The one I think is the least disruptive is transcranial magnetic stimulation, or TMS. It helps a lot of people who don’t do well on meds. You sit in a chair, and the doctor uses electromagnets to deliver magnetic pulses to your brain. It’s not uncomfortable.

For people who are really, really depressed, the best treatment is still electroconvulsive therapy, or ECT. It’s got a bad reputation, but it can work. I don’t recommend it for someone who’s just unhappy. This is for people who have not responded to medicines and are really up a creek. I could tell you stories of people who got back into the world because of ECT. Not everyone has access to TMS or ECT because of geography, or insurance, or whatever, but it’s amazing to me that more people don’t use those treatments.

We’ve been talking about some interesting possibilities that are on the horizon. Something they all share is that, rather than taking a pill every day, the treatments are infrequent, because the person feels better for an extended period afterward. Psychedelics work like that. Our research suggests hyperthermia has that quality. With ketamine people can go for a few weeks or a month before they need another treatment, so you aren’t bathing your brain in a chemical all the time.

There is a new drug, a hormone called brexanolone. Depressed people take it every day for two weeks, then stop. The ongoing antidepressant effect may last for many weeks afterward. Nobody knows why, but it does seem to have that pattern. The FDA is requiring a yearlong study.

I am optimistic about these treatments. I believe over time they will prove much more effective than regular antidepressants.

Conover: Some of my friends who are general practitioners tell me their patients see antidepressants as no big deal.

Raison: One of the rules of the universe is that there’s no free lunch. Medicines come with costs. Of course, there are plenty of people for whom the costs are well worth it. If your life is falling apart and you’re thinking about killing yourself, taking an antidepressant is a hell of a lot better than being in that state.

But sometimes maybe depression is something you need to go through, because it can teach you something. This is why people get frustrated with me: I can’t give a single answer! What I see are situation-specific choices. The goal of much of my work has been to give people some alternative to taking a pill every day, because there seems to be mounting evidence that it’s not beneficial for the brain. For depression and anxiety, I talk about using an antidepressant as a stabilizing mechanism while we think about how to build up a patient’s resilience in other ways.

One place we’ve gone wrong in the treatment of depression is that we treat it like a bacterial infection. Antibiotics directly kill the bacteria but do nothing to strengthen the immune system. In fact, antibiotics can weaken immunity because they do all the work for us.

Like antibiotics, antidepressants don’t seem to strengthen what is already inside us. When they work, they directly “kill” depressive symptoms. What we need to do is treat depression like a virus and develop “vaccines,” which work by strengthening the immune system.

In mental health a vaccine-like treatment would induce changes in how we think and feel — and, presumably, how our brain functions — that would far outlast the drug’s presence in the body. A patient’s well-being would be self-sustaining and generated by the natural activity of the brain and body rather than by the ongoing impact of a foreign substance. We already know that good psychotherapy has this characteristic. People maintain protection from depression long after the therapy is finished. We’ve also shown that ancient wellness practices like hyperthermia produce a long-lasting antidepressant effect. Other things like meditation and exercise you have to do regularly to get the effect, but they certainly produce improvements in mood that outlast the activities themselves. And all the data so far suggest that a single treatment, or two treatments, with psychedelics can relieve depression for an extended period, because the psychedelics cause the patient to see the world differently.

I want to be clear that, like antibiotics, antidepressants are lifesavers for many patients and should be used without hesitation when the depression has not responded to other interventions or when it has gotten so problematic that the patient needs outside help to keep themselves together. But in an ideal future we would use “vaccine” types of treatment first, and we’d discover more approaches that build resiliency.

One of the rules of the universe is that there’s no free lunch. Medicines come with costs. Of course, there are plenty of people for whom the costs are well worth it.

Conover: Is depression just a result of the modern world, something we have to deal with now?

Raison: Depression is not a modern phenomenon. It is ancient. But it’s becoming more common and more persistent in much of the modern world, which suggests that, for all modernity’s opportunities and pleasures, it’s likely producing more depression. An obvious culprit is smog. We don’t usually talk about pollution and depression in the same breath, but study after study has shown that smog is a serious risk factor. So is secondhand smoke. And many of us consume diets shown to increase the risk of depression. The speed that computers have brought to our lives produces chronic stress, which is a major risk factor for depression. We know that these things are bad for us, yet we can’t help ourselves.

Conover: Smartphones and social media have become dopamine dispensers. Are they making us more depressed?

Raison: I don’t know the answer to that. My theory is yes. It goes back to the adaptive stressors we were talking about. These technologies are shortcuts, easy alternatives to the older, more arduous ways of reaching our goals. With Facebook you’re suddenly connected with everybody in a way you never could have been before. It’s easy. You get a hundred likes on something, and you feel important. You get dissed on Facebook, and you get depressed. These things have an addictive quality. You get just enough of what you want that you get hooked on it, but you don’t get the full satisfaction of sitting down with people, smelling them, and seeing them in a three-dimensional space. And that’s the problem.

One reason the modern world may be so depressing is that many of its aspects play off of our evolutionary needs. We have a need to be connected with other people, so the online world gives us thousands of “friends.” We evolved to have a need for high-calorie foods, so we get hooked on sweets. When food was not always easy to find, we needed to conserve energy, so now we spend our days sitting down. The list goes on and on, but at its heart is the fact that we live largely artificial lives, filled with plentiful but insipid substitutes for the types of experiences that bring more solid and long-lasting well-being.