How Do Psychedelic Treatments Work?

Special Series: Magic Mushrooms, MDMA, and the Promise of Psychedelic-Assisted Therapy

Illustration by Iris Johnson

By Paul Frysh

Jan. 4, 2022

"I think of it every day. It was the most meaningful experience I've ever had in my life."

This was reported to Roland Griffiths, PhD, in the 1990s from someone in a clinical trial on the psychedelic drug psilocybin, the active ingredient in magic mushrooms. Griffiths, a psychopharmacologist, would hear countless similar statements over the following 3 decades.

Since that response in the '90s, many researchers have combined psychedelics -- especially psilocybin and MDMA -- with psychotherapy to test a treatment called psychedelic-assisted psychotherapy. Some versions of the treatment have proven so effective in clinical trials that the FDA has fast-tracked them for consideration for approval.

On the surface, psychedelic-assisted psychotherapy looks like a simple combination of drugs and therapy. But it's more complex than that. The treatments don't even work very well unless you have both parts: medication and therapy.

And yet paired in the right way, this new approach seems to produce profound changes in behavior and outlook in a very short period of time.

"We've never had a tool of this sort that fundamentally changes that narrative structure of self and world view in the way this does," Griffiths says.

Are deep changes in perspective the reason these therapies work? Perhaps. But many researchers believe there may be more at work.

The Staying Power of the Psychedelic Experience

Since the 1970s, Griffiths had spent many hours giving other mind-altering drugs to people and observing the effects. (Don't worry, it's all perfectly legal when Griffiths does it. In fact, much of his research has been funded by the National Institute on Drug Abuse.)

He'd listened with great attention as study participants told him about their experiences with opioids, alcohol, amphetamines, cocaine, sedative-hypnotics, and many other drugs.

So in the 1990s, when the government finally reopened research on psychedelics like psilocybin, LSD, DMT, and others, Griffiths was intrigued. He knew about studies from the 1950s and '60s showing real promise for the use of psychedelic-assisted therapies in the treatment of addiction, trauma, and other mental illness. (Read more about the history of psychedelic research as part of this WebMD series.)

And yet when Griffiths, now a professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine and director of their Center for Psychedelic & Consciousness Research, first started to study these psychedelic therapies, he was taken aback. He had never come across such consistently ardent descriptions of a drug experience.

People would often describe a profound sense of awe, or love, or connectedness to the people and the world around them. And it wasn't just the descriptions that struck him, it was the persistence of the memory.

Even several months after taking psilocybin in a clinical trial, for example, more than half of participants reported it as one of the top five most meaningful experiences of their lives. They compared it to things like the birth of their first child or the death of a parent.

That just seemed, as Griffiths put it, "unreasonably improbable." People simply didn't say those kinds of things after other drug experiences.

For example, Griffiths says, if you give someone a high dose of alcohol or valium or cocaine, they might remember some of the details like the rush of pleasure, the lowering of inhibitions, and perhaps some behavior that is outside the norm for them, he says.

"But the memories of that experience -- and certainly the meaning of it -- get cloudy very quickly. And it certainly doesn't inform major life decisions."

So what made psychedelics different?

Cigarettes and Psychedelics

In 2013, Griffiths and research psychologist Matthew Johnson, PhD, a close colleague at Johns Hopkins, started to study psilocybin-assisted therapy for nicotine addiction. Therapists talked to each person in the trial about the process, guided them through their psilocybin sessions, and followed up with a few more hours of therapy.

As expected, people gave the typical hyperbolic descriptions of psychedelic experience. But because researchers were trying to help people quit cigarettes, not find the meaning of life, they put these descriptions aside and focused on results.

Though the study was small, with 15 participants, the results were striking. About 80% of people in the study were still smoke-free after 6 months. By comparison, standard quit-smoking treatments like talk therapy or nicotine replacement, which require far more time or ongoing medication, are below 35% and tend to hover around 20% after 6 months. (Further results have been good enough that in October 2021, the NIH awarded a major grant -- the first of its kind -- to Johns Hopkins to continue the research on psilocybin therapy for smoking.)

Deep in the data was an interesting wrinkle: The people who claimed to have the most meaningful and memorable experience on psilocybin were the ones most likely to stay off cigarettes.

Since then, many clinical trials on psychedelic therapies -- especially those that use psilocybin and MDMA -- have shown great promise for the treatment of a broad range of mental health issues like PTSD, depression, alcoholism, OCD, and cocaine addiction.

And the pattern continues: People who have more memorable experiences tend to have better results.

The Mystical Experience Questionnaire

Each person chosen for a clinical trial at the Hopkins Center for Psychedelic & Consciousness Research answers something called the Mystical Experience Questionnaire. That's because successful psychedelic-assisted therapy links especially well with one type of meaningful and memorable experience called mystical experience. And many people who get better credit their improvement to this phenomenon.

You need not be religious to have such an experience. Author Michael Pollan, who calls himself "a staunch materialist" in his book How To Change Your Mind, describes his psilocybin experience as "numinous" and "spiritual."

After his experience, Pollan wrote, "I had always assumed access to a spiritual dimension hinged on one's acceptance of the supernatural -- but now I'm not so sure."

Pradeep Bansal, MD, (featured as part of this series), who's agnostic, says psilocybin-assisted psychotherapy led him to a kind of sacred and spiritual transformation.

"I'm a hard scientist more than anything else," Bansal says. "But this experience has taught me that there are so many things science does not understand and cannot explain."

Griffiths and his team at the Johns Hopkins Center for Psychedelic & Consciousness Research are trying to explain it. They emphasize three main aspects of mystical experience:

A sense of unity. It's a feeling of belonging in the world and of connectedness to other people, creatures, and even the universe.

A sense of sacredness. This isn't necessarily religious. It can simply be the overwhelming sense of preciousness about an experience.

A "noetic" sense. This is a deep feeling that the experience is "authoritatively true." For some people, it feels more true than normal waking consciousness.

Many people also report having a positive mood, feelings of love and connection to others, sudden psychological insights, and a loss of the sense of time and place.

But although there's lots of overlap in the experiences people have on a particular psychedelic drug, there can be wide differences as well. And psychedelic-assisted therapies can also work well in some people who don't have what scientists would term a "mystical experience."

Plus, some of these experiences aren't easy to categorize.

For example, at a 2021 trial for cancer-related depression at the Aquilino Cancer Center in Rockville, MD, one woman told lead investigator Manish Agrawal, MD, about a vision she had during psilocybin therapy in a clinical trial.

She saw a tree that died and broke down into a rich soil that then helped nurture new life. The vision helped her realize she would continue to nourish and guide her children even after she died. That eased her anxiety about her illness and mortality and gave her an immense sense of peace in her daily life.

"It's not a psychological insight exactly. It's not necessarily spiritual or mystical," Agrawal says.

"And yet it had deep meaning and staying power for this particular person."

Matthew Johnson at Johns Hopkins points to something scientists call "self-efficacy" in his trials to break smoking addiction. He calls them "duh moments."

It's hard to put into words, Johnson says. After treatment, people will often tell him some version of "My God, I really can just quit."

"It sounds stupid when you say it out loud," says Johnson, but it's a real thing.

"It's almost like these things that they've been saying to themselves for so long become so emotionally anchored -- they're feeling it in their heart and their bones -- and it's so compelling that it sticks with them."

-- Matthew Johnson, PhD

Typically, these people have said the exact same thing to themselves countless times before, sometimes at profound moments of insight during therapy.

And yet somehow with psychedelics in the mix, it's different.

There are countless stories like this in the world of psychedelic-assisted psychotherapy. Their connection to successful outcomes is clear. And yet their variation makes it harder to figure out exactly what unites them.

What Psychedelics Do in the Brain

It's important to keep in mind that correlation is not causation. That is, just because the sky is blue when you sneeze, doesn't mean the blue sky caused your sneeze. (Nor did your sneeze cause the blue sky!)

And just because your psychedelic experience felt memorable or meaningful doesn't mean those particular qualities of the experience are what made you get better.

That's certainly the view of some scientists who think psychedelics simply change the physical brain. Some of them believe that any subjective altered states or deep mystical insights could just be interesting side effects.

There is an argument to be made for this. Scientists already know psychedelics typically stimulate the brain's serotonin system. And that they seem to quiet the brain's default mode network (responsible for repeating thought patterns) and stimulate the creation of new neural pathways (neural plasticity).

The problem is that lots of things can cause these effects. A meditation session might quiet the default mode network. A long run in the woods might increase serotonin activity. A snort of cocaine might boost some types of neural plasticity.

And yet, at least in the short term, none of these has been shown to match the dramatic clinical effects of just one administration of psychedelic-assisted psychotherapy.

Still, though in its infancy, there is some research that aims to uncover the particular physical changes in the brain from psychedelic drugs that help people get better. Some scientists think it could work even without psychotherapy.

For example, at his UC Davis laboratory, chemical neuroscientist David E. Olson, PhD, has zeroed in on a particular type of neuroplasticity in the prefrontal cortex. He believes this type of neural growth could be the cause of improvement in people with a wide variety of mental illnesses, like depression, anxiety, and PTSD.

Olson's lab has developed several drugs that they believe stimulate this type of neural growth without causing the subjective effects often linked to classic hallucinogenic drugs. They have already tested these compounds in animals and are performing additional safety studies. If all goes well, they hope to test two of these compounds in humans later this year.

It may be, Olson says, that one day, drugs like this could be prescribed for home use, perhaps even without psychotherapy.

But scientists will need to do much more research to see if this is possible.

Reopening a Window for Healing

Neuroscientist Gul Dolen, MD, PhD, has a theory that she says bridges the psychological and physical effects of psychedelic-assisted therapies.

Dolen and her team at the Johns Hopkins Dolen Lab base their psychedelic research on the well-established scientific concept of "critical periods." These are certain time windows of optimal learning as animals and humans grow from infancy to adulthood.

In one famous example, baby ducks (and other wild birds) will "imprint" on whatever moving object they see about 15 hours after birth and start following it around. That's usually the mommy duck, but in unusual circumstances it could be some other animal. And if the baby duck doesn't see any moving object in that time frame, they won't imprint on anything.

In humans, there's a language critical period that opens at birth and closes around age 8, as is clear to anyone who's watched in wonder at the speed that kids can pick up a new language.

More recent research suggests there may be a period of "social reward learning" when teens learn to value group interaction. And there are a number of other periods related to social, emotional, and even physical learning.

Once the window for a particular critical period begins to close, it becomes much harder for your brain to learn and adapt in that particular area.

Dolen and her team think MDMA, and perhaps other psychedelics, temporarily "reopen" a number of these critical periods -- maybe all of them.

"A memory isn't just in one place," Dolen says. "It's a complex web of synaptic connections that crisscrosses the brain." A single memory might involve multiple areas of social, physical, and psychological learning, each with its own now-closed critical period.

"You can't just take a psychedelic and go to the club and cure your PTSD."

-- Gul Dolen, MD, PhD

Reopening these periods with psychedelic medications, says Dolen, could prime the brain to be able to reorganize and adjust the meaning of a traumatic memory or unhealthy thought pattern.

But Dolen is careful to point out that this priming is just the first step. "You can't just take a psychedelic and go to the club and cure your PTSD," says Dolen. You also need to activate the right memory or memories in a safe and appropriate setting and with a well-trained therapist as your guide -- the "set and setting" of psychedelic-assisted therapy.

If Dolen is right, the physiological and psychological aspects of the treatment are so integrated as to be almost impossible to pull apart.

A New Mode of Treatment

In some ways, to understand how psychedelics work, you first need to understand how they don't work. That is, they don't work in the same way as most other available psychiatric drugs.

For example, methadone targets specific opiate receptors to help prevent withdrawal symptoms from heroin addiction. Varenicline attaches to nicotine receptors to curb cigarette cravings. SSRIs (antidepressant meds) make more serotonin available to improve brain cell messaging.

Each of these drugs works in a different way to treat a particular condition. And the effects stop when you stop taking the drug.

In psychedelic-assisted therapy, a single drug, like psilocybin, works in the same way to treat a wide range of mental health conditions. The effects often last far beyond the acute effects of the medication, and the therapy, instead of being separate from the drug, is an integral part of the treatment.

This represents a fundamentally new mode of mental health treatment that simply does not fit easily into prior treatment dualities like "drugs vs. therapy."

If a psychedelic-assisted therapy helps people quit smoking, does the psychedelic drug acutely change the physical brain, which in turn changes perspective and behavior? Or is there something about the psychedelic experience itself that changes perspective and behavior?

The answer is not yet clear.

The Fruits of Psychedelic Therapies

So what do we know for sure about the way psychedelic-assisted therapies work?

At best, says Griffiths, we can say that psychedelic therapies seem to change consciousness in some unique way. But even that's on shaky ground because, notwithstanding the huge advances in brain science and technology, scientists still can't really explain the basic nature of consciousness.

And so, if we limit ourselves to looking for reductionist explanations in the physiology of the brain, says Griffiths, then we are likely to come up short. We may get a bit closer to a full understanding if we combine that with psychological and even philosophical explanations. But the full mechanism of psychedelic therapies may always remain, to some extent, shrouded in mystery.

And perhaps that's OK.

Scholar William James said the value of a transcendent experience should be judged by its fruits -- that is, the way in which your outlook or behavior changes after the experience. By that standard, the fruits of psychedelic-assisted psychotherapy -- at least in current clinical trials -- are impressive indeed.

Maybe, at least for now, the fruits are enough.

Psychedelics FAQ

Can psychedelics help people? Growing evidence says yes, especially for PTSD, addiction, and depression -- with strict medical supervision as part of psychotherapy. These are not treatments you can give yourself. More research is needed to determine who will benefit most from these treatments. Initially, doctors will likely try other treatments first before they try one of the new psychedelic-assisted psychotherapies.

Are psychedelics legal? No. The FDA hasn't approved psilocybin or MDMA for medical uses outside of clinical trials. They are Schedule I illegal substances under the federal Controlled Substances Act. Simple possession of them is a violation of federal law as well as laws in many states.

How much would these treatments cost? The cost could run into the hundreds or thousands of dollars, according to scientists involved in the research. MAPS, a nonprofit research organization that is working to bring MDMA-assisted psychotherapy to market, estimates their treatment cost at $14,000 per case for PTSD, no matter the seriousness. But estimates for some other treatments are lower. That's compared to an annual cost for conventional PTSD treatments that ranges between $5,000 and $24,000, depending on the seriousness of the case. MAPS estimates that insurers would almost certainly save money on most cases 3 years into treatment.

Those costs might come down in protocols like the latest cancer and depression research, which uses group therapy instead of one-on-one therapy before and after the dosing sessions.

But it's not yet clear if insurance would cover these treatments. Then again, other treatments for mental health conditions have their own costs and insurance issues. Ketamine, electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and even a typical round of talk therapy can cost thousands of dollars. And insurance coverage can be uncertain even with these approved treatments.

Who would have access to these treatments? "It may be that the people most in need of these treatments are those least likely to have access, especially at first," says Steven Huang, a psychedelic diversity equity and inclusion consultant who works with MAPS and other companies involved in psychedelic research.

The complexity of mental health issues in underserved communities like people of color, LGBT, and the financially disadvantaged are the very things that could bar some members from the current round of clinical trials. Careful screening, Huang says, has led to a homogenous group that is overwhelmingly upper middle class, middle-aged, and white.

To include a wider variety of people going forward, scientists and study sponsors will have to look for better recruitment and screening strategies, he says. Not only will this serve a more diverse population, says Huang, it will also provide a more varied, and so more accurate, set of data to help shape psychedelic treatments.

Another problem is cost. A likely cost of several thousand dollars could bar many underserved communities that may lack financial resources. That's why, says Huang, in the absence of widespread insurance provider coverage, pharmaceutical companies and mental health providers have an obligation to make sure that successful psychedelic-assisted therapies, once approved, are made available to underserved communities and those most in need.

What is microdosing and does it work? It's when you take regular tiny doses (about 1/10th of a standard dose) to improve mood or creativity. Though some people swear by it, the evidence is so far lacking. The results reported by researchers come from full dosing in carefully controlled settings with guidance from trained professionals.

Are psychedelics the "new medicinal marijuana"? Not really. Marijuana currently treats pain and nausea in limited cases. Psychedelics, if approved by the FDA, would be part of treatment for serious mental health issues and require extensive supervision and therapeutic support.

What are the risks and side effects? The physical risks are few as long as you take them in the right dose and in a safe, medically controlled setting. But they can be unsafe for people with serious heart issues. They tend to raise heart rate and blood pressure though usually not much more than vigorous exercise or sexual activity.

Other possible side effects commonly reported in trials on psilocybin and MDMA include mild to moderate headache, nausea, fatigue, loss of appetite, and insomnia. But these don't typically last much longer than the effects of the drugs themselves.

The psychological risks are low as well, but they are more complex. Some reports suggest that "classic psychedelics" like psilocybin (and to a lesser extent MDMA) could trigger psychosis and even schizophrenia in certain people. So trials try to screen out anyone who's ever had a psychotic episode or schizophrenia in their family.

Some clinical studies on psilocybin also try to screen for people who've had bipolar disorder and even some personality disorders, though these are harder to find during screening.

Further studies may uncover other, more serious risks and side effects and home in on those who are most likely to get them.

How do I find a clinical trial? Go to ClinicalTrials.gov to find out more about drug-assisted psychotherapy trials for MDMA, psilocybin, LSD, DMT, and other psychedelic medications.

Hear more about the potential medical uses of psychedelics on this episode of WebMD's podcast, Health Discovered.

More in this series:

A Long, Strange Trip: Psychedelics Meet Mainstream Medicine

Are psychedelics on the verge of becoming approved treatments?

One Man's Psychedelic Journey to Confront His Cancer

What it's like to get psilocybin-assisted therapy in a clinical trial.

Reviewed by Jennifer Casarella, MD, on November 21, 2021

Sources

Roland Griffiths, PhD, director, Center for Psychedelic & Consciousness Research; professor of psychiatry and behavioral sciences, Johns Hopkins University School of Medicine.

Boadie Dunlop, MD, director, Mood and Anxiety Disorders Program; associate professor of psychiatry and behavioral sciences, Emory University.

Matthew W. Johnson, PhD, professor of psychiatry and behavioral sciences, Johns Hopkins University School of Medicine.

Manish Agrawal, MD, medical oncologist and co-director of clinical research, Aquilino Cancer Center, Rockville, MD.

Rick Doblin, PhD, founder and executive director, Multidisciplinary Association for Psychedelic Studies (MAPS).

John Krystal, MD, professor of psychiatry and neuroscience; co-director, Yale Center for Clinical Investigation; chief of psychiatry, Yale-New Haven Hospital.

Steven Huang, diversity, equity, and inclusion consultant.

Barbara Rothbaum, PhD, ABPP, professor of psychiatry and behavioral neuroscience; associate vice chair of clinical research,

Department of Psychiatry, Emory University School of Medicine.

Gül Dölen, MD, PhD, assistant professor of neuroscience, director, Dolen Lab, Johns Hopkins University School of Medicine.

David E. Olson, PhD, chemical neuroscientist, associate professor, UC Davis.

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