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

A Long, Strange Trip: Psychedelics Meet Mainstream Medicine

Psychedelics

Illustration by Iris Johnson

By Paul Frysh

Jan. 4, 2022


Psychedelic drugs seem to be everywhere lately. The Silicon Valley glitterati are all a-twitter about "microdosing" with LSD and magic mushrooms to improve creativity. Nicole Kidman's character in the fictional Hulu series Nine Perfect Strangers doses her guests' morning smoothies with psilocybin. And new documentary films on psychedelics seem to drop almost monthly.

In real life, much of this is of questionable scientific rigor, and ... well ... illegal.

But there is also a growing body of medical research behind this psychedelic renaissance. Psychedelic drugs, when combined with therapy, have shown great promise for treatment of a variety of mental health issues. Scientists call the new treatment "psychedelic-assisted psychotherapy."

But would the FDA really approve drugs for medical use that are mainly known as party drugs? The answer may surprise you.

Psychedelics Meet Psychotherapy

The word psychedelic literally means "mind revealing," which is one way to describe the powerful effects of psychedelic drugs (sometimes also called hallucinogens or entheogens). They cause a profound shift in your sense of self and consciousness. 

But so do lots of other drugs, like alcohol, cocaine, and opiates. What makes psychedelics different? 

It is "their capacity reliably to induce states of altered perception, thought, and feeling that are not experienced otherwise except in dreams or at times of religious exaltation," according to a definition, often cited by scientists, from Jerome Jaffe, MD, of the University of Maryland School of Medicine. These states of "religious exaltation" are not limited to traditional religious practice, but may stem from meditation, fasting, deep breathing, and other disciplines. 

In fact, psychedelics have been used for thousands of years as part of religious and cultural rituals to induce mystical experience. And it is this uncanny effect that may be part of what helps with so many mental health conditions. (WebMD explores these effects in depth in How Do Psychedelic Treatments Work?)

Most of the medical research on psychedelics has examined two drugs: psilocybin, which is the active ingredient in magic mushrooms, and MDMA, which you may know better as ecstasy or molly. There's also growing research on LSD, mescaline, DMT, and other psychedelics.

A number of universities, including Johns Hopkins, NYU, the University of California San Diego, and Imperial College London in the U.K., are doing in-depth research on these medicines. And early results, while limited in size, have been impressive.

What the Research Shows

A 2021 study published in the journal Nature Medicine looked at 91 people with severe, chronic PTSD. Half of them got MDMA-assisted therapy, and the rest got a placebo. Almost 90% who got MDMA had a "clinically significant" reduction in symptoms, and 67% no longer qualified for a PTSD diagnosis. 

Compare that to standard talk therapies where 30% of people simply drop out of treatment and even after that, only around 40% get well enough to no longer have PTSD. Or compare it to other FDA-approved meds for PTSD, which only help lessen symptoms around 25% of the time.

Barbara Rothbaum, PhD

But it was a small 2012 study in the Journal of Psychopharmacology that first got the attention of clinician psychologist Barbara Rothbaum, PhD, a psychiatry professor at Emory University.

That study tracked the long-term effects of MDMA-assisted psychotherapy in 19 people with PTSD that were resistant to other treatments. It showed that after a single course of treatment, most of the people in the study still had clinically significant gains in symptom relief, with no harmful effects reported.

But the kicker for Rothbaum was that the effects persisted in most people even 4 years or more after treatment.

She often worked with people with PTSD and knew how important these therapies could be for people who didn't respond to approved treatments.

"Suicide rates for people with untreated PTSD are unusually high, as are risks of substance misuse, addiction, and depression," Rothbaum says. "It disrupts relationships and lowers quality of life." MDMA-assisted therapy looked like a lifeline, Rothbaum says. "And it still does."

Oncologist Manish Agrawal, MD, was equally taken with research on people with anxiety and depression due to a cancer diagnosis.

People with life-threatening disease who got psilocybin-assisted psychotherapy had "significant decreases" in anxiety and depression as long as 12 months after the treatment, according to studies published in 2011, 2014, and 2016. And as with MDMA, there were few, if any, harmful effects in people in these clinical trials.

Agrawal, now co-director of clinical research at the Aquilino Cancer Center in Rockville, MD, had long sought a more effective way to help his patients and their families deal with the mental and emotional effects of a cancer diagnosis. He would send people for therapy or group sessions or support groups. But too many people remained psychologically shattered after their diagnosis.

"This research was the first time I saw something that looked like it could really move the needle," Agrawal says.

Manish Agrawal, MD

Agrawal was so impressed that he decided to get certified in psychedelic-assisted therapies. In 2021, Agrawal and his colleagues at Aquilino finished collecting data for their own trial of psilocybin-assisted therapy for depression in people with cancer. It's the first psychedelic research in cancer patients in several years. And initial results look promising, he says.

Half of all people in the study no longer had clinical depression 8 weeks after a single dose of psilocybin and accompanying therapy, says Agrawal. "That's a very encouraging result." (Learn more about Agrawal's work and follow one man through his psychedelic trip in One Man's Psychedelic Journey to Confront His Cancer).

In November 2021, COMPASS Pathways released initial data on a study on psilocybin-assisted therapy for treatment-resistant depression. It showed that 30% of people appeared to be in complete remission from their symptoms 3 weeks after treatment.

And this is just the tip of the iceberg. There have also been excellent outcomes for obsessive-compulsive disorder (OCD), anxiety, alcohol use disorder, smoking, and more.

For two conditions -- PTSD and treatment-resistant depression -- the FDA has designated psychedelic-assisted treatments as "breakthrough therapies" that show "substantial improvement over available therapy" for a "serious condition."

Approval for the first of these, MDMA-assisted psychotherapy for PTSD, could be less than 2 years away, experts say. And an approved form of psilocybin-assisted psychotherapy for treatment-resistant depression could be as little as 4 years away, according to experts at the Johns Hopkins Center for Psychedelic & Consciousness Research.

How We Got Here

So where did this research suddenly come from? 

"There's nothing sudden about it," says Rick Doblin, PhD, who founded the Multidisciplinary Association for Psychedelic Studies (MAPS), which is working to bring MDMA-assisted therapy to the market.

Doblin has been involved in the study of psychedelic medications for decades. Since its founding in 1986, the mission of MAPS has been to prove beneficial medical uses of psychedelics and other drugs in a therapeutic setting and get the FDA to approve them. 

It has not been easy.

The excesses of the 1960s, says Doblin, did much to shut down years of fascinating and promising research on psychedelic medications.

Before that, psychologists and psychiatrists treated tens of thousands of people with "psychedelic psychotherapy" over a period of about 15 years, starting in the early 1950s. This was due in part to reports of effects of LSD in test patients, but also to positive results reported by researchers and doctors. For much of that time, these substances were perfectly legal.

But things got "complicated," says Doblin, after psychedelic drugs became integrated into '60s counterculture and the anti-war movement.

1960s San Francisco crowd

In 1967, thousands gathered in San Francisco's Golden Gate Park (see above) to hear former Harvard psychologist and professor Timothy Leary who famously told the crowd of mostly young people to "turn on, tune in, and drop out."

Leary, a larger-than-life counterculture icon, clad in flowing white robe, beaded necklaces, and flowers in his hair, was a great advocate of psychedelics. But in the midst of deep cultural and political division, many look back on Leary's famous pronouncement as the death knell for mainstream acceptance of psychedelics.

Three years later, in 1970, President Richard Nixon signed the Controlled Substances Act that made LSD and psilocybin illegal. Psychedelics were now a "Schedule I" controlled substance. Psychedelic research and mental health treatments effectively came to a standstill, not only in the U.S. but around the world.

A 'Recent' Renaissance?

The current boom in psychedelic research actually started in 1990. That's when the FDA allowed a single researcher to study DMT (the active ingredient in the drink ayahuasca). Then in 1992, the FDA and an FDA Advisory Committee cracked the door for some more limited research.

The success of early studies combined with a growing awareness that psychedelics were far less toxic than other Schedule I drugs like cocaine, heroin, and fentanyl also has helped clear the way for more robust research.

And even these early studies only came about because of die-hard believers like Doblin and organizations like MAPS who thought the government had thrown the baby out with the bathwater. You don't put a stop to promising research just because of a few bad actors, Doblin says. That's why, says Doblin, they never stopped trying.

"The promise was all there in the research from the '50s and '60s," he says. "All you had to do was look."

When scientists finally started to do just that, they could not look away. Though this early research was often less rigorous by today's standards, the possibilities for future research were clear.

Of course, it didn't hurt, says Doblin, that there was a real lack of new and effective therapies for conditions like PTSD, depression, addiction, OCD, and more. The medical community -- and the public -- were on the lookout for something new.

This Time It's Different

After all that time in the scientific wilderness, Doblin and others at the forefront of psychedelic-assisted therapy are doing everything they can to make sure they don't repeat the mistakes of the 1960s.

That means strict rules about how to train the doctors who prescribe these treatments and the therapists who administer them.

The MAPS trials require 6 to 8 hours of training for the doctors who prescribe the medication and 100 hours of training for the therapists who give the treatments. A prescribing doctor who also wants to administer the treatment must do both parts of the training.

Rick Doblin, PhD

"We're the sponsor. We're the pharmaceutical company," Doblin says. "If something goes wrong, the FDA will pull the drug from the market. So we want to make sure that the therapists are properly trained."

"Eventually," Doblin says, "I believe people will be trained in traditional medical and therapeutic education to do psychedelic psychotherapy."

MAPS already has a training program for therapists who hope to do MDMA-assisted therapy if the FDA approves it, which Doblin says should be sometime in 2023.

The Therapy is Part of the Treatment

You probably don't give much thought to where you are when you take medication to ease your headache, or clear your sinuses, or lower your blood pressure. You simply check the dosage, take the pill, and get back to your daily business.

Psychedelic medications work differently. They require certain conditions, including psychotherapy before, during, and after the dosing.

This helps prepare the "set and setting" of psychedelic-assisted therapy. "Set" is your mindset going into the day of your psychedelic dosing. And "setting" describes the space and people around you when you take your dose and experience its effects.

Set and Setting

A 2021 psilocybin trial for treatment-resistant depression required 6 to 8 hours of preparatory talk therapy about mental health issues and what to expect during the dosing session, which can be quite intense, emotional, and even scary.

The dosing session itself took about 8 hours and required two psychotherapists in a closed room with a nurturing physical environment to ensure full safety and support. Later, there were three sessions of "integration," where a therapist helped participants process their psychedelic experience in order to get the most out of it.

The MAPS trials for MDMA-assisted psychotherapy for PTSD have similar requirements, as do many other proposed psychedelic-assisted therapies.

Part of the reason for this is safety. These are powerful medications. And because of their long history of recreational use, there is some risk of misuse, or at the very least, unsafe use.

In a club where you're dancing for hours or using other drugs, a high dose of MDMA could make you overheat and pass out, or even damage parts of your brain. And for some people, the psychological effects of psychedelics can be frightening or trigger risky behavior, especially in an unstable environment without trained support. Psychedelics may also be unsafe for people with serious heart conditions or a family history of psychosis.

In a controlled clinical setting with proper screening, doctors can minimize these risks.

But it's not just about safety, says Boadie Dunlop, MD, associate professor of psychiatry and behavioral sciences and director of the Mood and Anxiety Disorders Program at Emory University.

Set and setting are actually key to the success of the treatments.

Boadie Dunlop, MD

"If psychedelic drugs worked on their own to treat mental health issues, people would already be using them," Dunlop says.

"Word of mouth would have spread about the power to treat these very common conditions and people would just take them."

Sure, Dunlop says, psychedelics can lift mood for a short time in some people. But for long-lasting effects -- what scientists call "enduring benefit" -- patients need to take them in a psychotherapy setting.

But nothing is set in stone. As research builds, the treatments will continue to evolve, Dunlop says.  

"There's no doubt that we're going to have to keep fine-tuning it."

Is Approval Possible?

Would the federal government ever seriously consider approving such seriously mind-altering substances better known at clubs and parties than in any kind of medical setting?

"It's already happened," says John Krystal, MD, chairman of the psychiatry department at the Yale School of Medicine.

John Krystal, MD

He's talking about esketamine (Spravato), a nasal-spray form of ketamine that got the FDA's nod in 2019 for treatment-resistant depression. Ketamine is known in recreational settings as "special K."

In a clinical setting, you take esketamine at a doctor's office, and a prescription typically means you also need to be on an antidepressant medication like selective serotonin reuptake inhibitor (SSRI). Of course, unlike proposed psychedelic-assisted treatments, esketamine doesn't require psychotherapy along with it.

Still, Krystal says, esketamine takes a similar approach: It changes consciousness temporarily to treat depression over a longer term. And its approval has helped open the doors for study of psychedelic-assisted therapies.

But Krystal is wary of moving too quickly to FDA approval. He notes that many psychedelic studies have been fairly small. He wants to see bigger studies and more of them.

And there are other limitations.

The gold standard for scientific research -- the randomized, double-blind, placebo-controlled study -- requires that neither the giver nor the receiver of a medication in a study know for certain what it is. But it is very hard to hide, or "blind," psychedelic drugs because they cause such deep, distinct, and well-known effects. That makes it much harder to do these studies in an effective way.

Still, Krystal is optimistic. Psychedelic research, he says, has shed new light on the way certain mental health conditions seem to work in the brain and it offers new hope for some conditions, like treatment-resistant depression, which he calls "a devastating medical condition that shortens life span by over 5 years."

That's why he applauds psychedelic research, even when it pushes the limits with studies that might be politically unpopular or hard to administer -- just as long as there's no rush to approve.

"I am hopeful that the FDA will exert its usual cautious approach to the approval of new medications. As they used to say about wine, 'We want no drug approved before its time.'"

A Tipping Point

A quick search on ClinicalTrials.gov shows hundreds of active clinical trials on psychedelic medications. There are more than 50 studies on psilocybin alone, and similar numbers for MDMA, LSD, DMT, and other psychedelics.

"We are no longer investigating whether psychedelics can help. The evidence is pretty clear."

-- Rick Doblin, PhD

And there has been an explosion of interest in the private sector from companies that want to get approval for psychedelic treatments and bring them to market. MAPS is one such organization. But there are many others, like COMPASS Pathways, who recently secured a new U.S. patent (it already has 8 others) for a form of psilocybin to treat major depressive disorder.

B.More and Awakn are working on psychedelics to treat alcoholism and other addictions. Usona Institute, another nonprofit, is working on forms of psilocybin and DMT for other psychedelic therapies.

In August 2021, a company called Cybin became the first psychedelics company to list its stock on the New York Stock Exchange. And there are quite a number of psychedelic pharmaceutical companies (including COMPASS, listed on NASDAQ) that are traded around the world.

Rick Doblin, for one, sees this as a tipping point.

Psychedelic research today is far more advanced than at the height of the 1960s, he says, and prescription approval is well within range.

"We are no longer investigating whether psychedelics can help," says Doblin. "The evidence is pretty clear."

The question now, he says, is where do we go from here?

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.

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