Psychedelic-Assisted Psychotherapy: What We Know, and Still Don’t Know

Posted: September 15, 2021
Psychedelic-Assisted Psychotherapy: What We Know, and Still Don’t Know

PATHWAYS TO THE FUTURE - from Brain & Behavior Magazine, September 2021 issue

On May 9th of this year, a front-page headline in The New York Times announced: “The Psychedelic Revolution Is Coming. Psychiatry May Never Be the Same.” According to the story’s subheadline,”Psilocybin and MDMA are poised to be the hottest new therapeutics since Prozac.” Six days earlier, a story appearing on the inside of the newspaper had reported “A Psychedelic Drug Passes a Big Test for PTSD Treatment.”

Readers who could remember the 1960s might well have done a double-take. Psychedelics? A “revolution”? Hadn’t society “been there, done that”—over half a century ago?

In a way, yes. “Excitement over psychedelic drugs led to extravagant claims about their vast potential to expand human consciousness, elucidate the psychological architecture of the brain, and treat mental disorders,” recalls Dr. Jeffrey Lieberman, a BBRF Scientific Council member, 2-time BBRF Distinguished Investigator and 2006 Lieber Prize winner, in a recent editorial in the New England Journal of Medicine. By the mid-1960s, LSD had been prescribed to approximately 40,000 U.S. patients and spawned over 1,000 scientific papers. At the same time, as noted by Dr. Lieberman, “recreational use of these drugs, encouraged by countercultural icons like Dr. Timothy Leary, spread. “Appeals to ‘tune in, turn on, and drop out’ propelled unsupervised use to leap-frog medical research,” while “people experiencing ‘bad trips’ filled emergency departments.”

Widespread, unregulated use of psychedelics was one factor leading Congress in 1970 to pass the Controlled Substances Act, under which psychedelic compounds including psilocybin (the psychoactive ingredient in “magic mushrooms”) and MDMA (a type of amphetamine sold since the 1980s as the “club” drug “Ecstasy,” also known as “Molly”) were listed as Schedule I substances—unlawful to possess and officially regarded as “having no currently accepted medical use.”

The 1970 law has not since reclassified psilocybin, MDMA, or other psychedelic substances including mescaline, LSD, and DMT (the active ingredient in ayahuasca). But around the year 2000, research in a few academic labs did resume, legally, on all of these psychedelics— most influentially, psilocybin and MDMA.

Since then, a new body of data has been building about how consciousness-altering psychedelic substances affect the operation of the brain. Among other impacts, psychedelics act upon the serotonin neurotransmitter system, which plays an important role in mood regulation. Psilocybin is known to stimulate several types of neural serotonin receptors, especially the serotonin 2A receptor; such stimulation has a wide range of “downstream” pharmacologic effects in the brain and body, which remain poorly understood but could impact symptoms of mood disorders such as depression and anxiety.

Animal studies have shown that MDMA, which has a distinct mechanism of action, induces serotonin release by binding to serotonin transporter proteins. There is evidence the drug may enhance the extinction of fear memories and modulate fearmemory reconsolidation and thus it holds promise in treating PTSD and anxiety, among other disorders.

While the pharmacology and mechanisms of action of psychedelics continue to be a subject for study, their impact on human consciousness has often been described: pronounced changes in sensory perception, including euphoria, sensory illusions, and auditory and visual hallucinations— which are experienced variably in different users and on different occasions, on a wide scale ranging from “magical” and “revelatory” to deeply sad and terrifying.

In recent years, researchers have begun to scrutinize, some under rigorous clinical trial conditions, how psychedelics might be used in conjunction with psychotherapy to treat a variety of mental health conditions.

Both psilocybin and MDMA have been given “fast-track” designation by the U.S. Food and Drug Administration (in 2018 and 2017, respectively) as potential treatments in psychiatric disorders. Dozens of U.S. -registered clinical trials are under way in a wide range of mental health conditions, some partly funded by the government and others by independent advocacy foundations and/or small drug companies with a financial interest in the research. Leaders of some of the new studies include established investigators at major academic and research institutions including Johns Hopkins University, New York University, and The University of California in the U.S., and Imperial College London and the Medical Research Council in the U.K.

Several recently published studies have received widespread public attention. In November 2020, a study of psilocybin-assisted psychotherapy appearing in JAMA Psychiatry and led by Drs. Roland Griffiths and Alan Davis of Johns Hopkins University, reported “large, rapid, and sustained antidepressant effects” in a group of 27 participants with major depressive disorder.

In April 2021, a team led by Drs. Robin Carhart-Harris and David Nutt of Imperial College London reported in the New England Journal of Medicine on a phase 2 trial involving 60 patients with major depressive disorder, half of whom received psilocybin and half the conventional SSRI antidepressant escitalopram (Lexapro) over 6 weeks. While both groups, with psychotherapeutic support, showed improvements, the trial “did not show a significant difference in antidepressant effects between psilocybin and escitalopram,” although results tended to favor psilocybin in a number of “secondary” measures, the team said.

In May 2021, as reported in the Times, a team led by Dr. Jennifer Mitchell of the University of California, San Francisco reported in Nature Medicine results of the first-ever Phase 3 trial using MDMA to treat patients with severe PTSD. Among the those in the MDMAassisted therapy group, 67% no longer qualified for PTSD diagnosis after their three MDMA-assisted therapy sessions and 88% of participants experienced a clinically significant reduction in symptoms.

What to make of these recent studies, each involving the use of psychedelic-assisted psychotherapy in fewer than 100 individuals? Those most hopeful about the potential benefits of psychedelics in psychiatry point to reports of their positive effects on mood and outlook—some proposing that they can “open the mind” to new insights in psychotherapy that can lead to significant therapeutic gains. But science has yet to explain exactly how this might occur or which individuals are most likely to benefit.


As evidence about psychedelic-assisted psychotherapy has steadily grown, generating much discussion but no consensus, the American Psychiatric Association (APA) formed a study group to perform “an evidence-based summary of the literature of the clinical application of psychedelic drugs in psychiatric disorders.” In May 2020, the group published a paper in the American Journal of Psychiatry (AJP) reviewing the evidence.

Of the AJP paper’s eight named authors, six have BBRF affiliations: corresponding author William McDonald, M.D., 1999 BBRF Independent Investigator; Ned Kalin, M.D., BBRF Scientific Council member and AJP’s Editor-in-Chief; Carolyn Rodriguez, M.D., Ph.D., BBRF Scientific Council member and 2014 and 2009 BBRF Young Investigator; Charles Nemeroff, M.D., Ph.D., BBRF Scientific Council member, 2003 and 1996 BBRF Distinguished Investigator, and 1996 BBRF Selo Prize winner; Alik Widge, M.D., Ph.D., 2014 BBRF Young Investigator; and Linda Carpenter, M.D., 1997 BBRF Young Investigator.

The recent resurgence of interest in psychedelics is traced to several studies. One of these was led by Dr. Griffiths of Johns Hopkins, reporting in 2006 that a single high dose (25mg) of psilocybin, given in a psychotherapeutic setting, produced long-lasting positive changes in mood and wellbeing in healthy volunteers. This led Dr. Griffiths and others to question whether depressed individuals would have a similar experience.

Also influential were several brain-imaging studies conducted in the 2010s, led by Drs. Carhart-Harris and Nutt. These suggested that psilocybin produced “profound and meaningful alterations in brain function, especially of the default mode network (DMN), consistent with an antidepressant effect.”

The DMN is a circuit connecting a number of brain areas whose activity reflects “baseline” activity when an individual is not actively performing a conscious mental task. In depressed individuals, DMN connectivity is elevated compared with non-depressed individuals. It may reflect looping, self-referential, “ruminative” thinking that is seen in many depressed individuals. DMN activity has been shown to be lowered in individuals under the influence of psilocybin, as it has been in individuals experiencing successful antidepressant treatments.

Observations such as these begin to suggest in biological terms what users of psychedelic substances have historically described in emotional and experiential terms. Plant-derived psychedelics have been used for thousands of years for medicinal and religious purposes in traditional cultures of Mexico and Central and South America, among others, but have carried an aura of profound mystery which science now seeks to penetrate.

Comments about the importance of the psychedelic experience in the larger context of users’ lives have been generated in many early studies of the drugs. Such testimonials were especially impressive in preliminary trials of psilocybin in advanced-stage cancer patients, whose poor prospects had plunged them into deep depression and/or anxiety. In 2011, a small pilot study led by Dr. Charles Grob of UCLA was conducted in 12 individuals with advanced-stage cancer, all suffering from anxiety. Each received two treatments, weeks apart: one with a moderate dose of psilocybin, the other with niacin, which served as an “active placebo” (niacin has a “flushing” effect, sometimes also experienced after ingestion of psychedelics). Cancer patients’ anxiety scores didn’t change in the 2 weeks following treatments, but were significantly improved in the psilocybin group at the 1- and 6-month follow-ups.

A few years later, Dr. Griffiths’ group conducted a doubleblinded study involving 18 terminal cancer patients with anxiety or mood disorders who were treated with psilocybin administered in two sessions, one at high dose, the second at a negligible dose. As the team reported in a 2016 paper, at the 6-month follow-up, 78% of participants with depression were still experiencing a response (at least a 50% reduction in symptoms from baseline), as were 83% of those with anxiety. Remission was experienced, respectively, by 65% and 57% in each group 6 months following the end of the trial.

Another small but impressive preliminary trial led by Dr. Griffiths, involving 15 subjects, showed psilocybin to help people quit smoking. The 2014 paper reported remarkable rates of success, compared with conventional smoking-cessation programs.

A preliminary trial by Dr. Michael Bogenschutz and colleagues at NYU testing psilocybin combined with psychotherapy in 10 participants with alcohol dependence reported in 2015 that abstinence significantly increased after the first psilocybin session at 4 weeks and was largely sustained at 36 weeks.

Dr. McDonald and members of the APA review team, after studying results from 14 papers which they judged to be of the highest quality among several hundred involving psychedelics, concluded that while evidence published to date “is insufficient for FDA approval of any psychedelic compound for routine clinical use in psychiatric disorders at this time, continued research… is warranted.”

The APA reviewers observed that researchers often noted correlations between reductions in patient symptoms and their descriptions of their psilocybin experiences as having been “mystical” or “personally meaningful.” But they and others have noted that the psychedelic experience has a flip side. While “hallucinogens such as psilocybin are not thought to precipitate new psychotic illness, they may unmask a psychotic disorder in those who are susceptible,” the APA reviewers noted.

Concern about how psychedelics might destabilize vulnerable individuals helps explain the caution with which many commentators on recent psychedelics research approach the prospect of the “mainstreaming” of psychedelics in uncontrolled community settings. Particularly worrisome is the growing practice of “microdosing.” This involves taking psychedelics such as psilocybin, LSD and MDMA repeatedly over short periods of time in very small quantities that do not induce psychedelic experiences. No one knows whether such unsanctioned and illegal practices have any potential therapeutic benefits. One worry is that positive publicity over the encouraging results of recent psychedelic research trials may be misinterpreted by some as giving the public a green light to use the substances in non-research settings.


Concerns about patient safety and research rigor have helped guide what has emerged as standard protocol in current (and fully legal) psychedelic-assisted psychotherapy research. The protocol addresses what practitioners call the “set” and “setting” of psychedelic sessions. These seek to identify appropriate patients for these treatments, to protect their interests, and above all their safety. They also seek to optimize trust and cooperation between patient and therapist—the “therapeutic alliance”— deemed by many psychiatrists as a crucial factor in generating therapeutic insights.

Drs. Carhart-Harris and Nutt of Imperial College London, among the recent innovators in testing psychedelics in the clinical setting, describe “set and setting” in a 2020 commentary published in JAMA Psychiatry. “In depression trials, the model is becoming standardized as a 4-stage process,” they note, involving assessment, preparation, experience, and integration. They explain:

Assessment determines if the patient is suitable for psychedelic therapy, from both a mental and physical perspective.” Those with a personal or family history of psychosis or bipolar disorder are excluded, as are those with conditions such as hypertension “because psychedelics transiently increase blood pressure.” Medications that block the serotonin 2A receptors which are stimulated by “classic psychedelics” are stopped or tapered down—including SSRI antidepressants like Prozac, which reduce sensitivity of the receptor.

Preparation sessions typically take place the day before the drug administration.” The participant is “prepared” by one or two therapists, often referred to as guides. “An overview of the dynamics and nature of psychedelic experiences is explained, including how it can be challenging for many people, how such challenges can be confronted, and how the participant can get the most out of the experience.”

“During the psychedelic experience [i.e., drug administration], the participant is placed in a room with comfortable seating and low lighting; “is offered eyeshades, and earphones to listen to a music compilation that has been prepared [by the patient] in advance.” Oral psilocybin sessions typically last 4 to 6 hours. “Verbal engagement with the therapists is not expected, and most patients go deep into their own visions, thoughts, and memories and do not want to be disturbed. But the guides are present, and, with permission, they can hold the patient’s hand to reassure that he or she is being looked after.”

“The next day is the integration session, during which the same guides talk through the experiences and help the patient make sense of it.” While this portion of treatment will vary according to the practitioner, Drs. Carhart-Harris and Nutt suggest a “small number of standard talk-based psychotherapy sessions” be made available to deal with issues that emerged during the psychedelic experience and need to be processed. Treatment studies conducted to date, they note, have typically been limited to one or two psychedelic administrations, weeks or months apart, with psychotherapy varying to include, for instance, a standard 10- to 20-week abstinence-based program in treatments for addiction.

Drs. Carhart-Harris and Nutt take up the question of why psychedelic-assisted therapy might work in a wide range of disorders—depression, anxiety, addiction, PTSD—which presumably have distinct underlying biological causes. “We suggest this may be because these conditions are all internalizing disorders. In depression, patients continually ruminate about their failings, reiterate thoughts of guilt, and engage in self-critical inner narratives. In addiction, drug craving drives behavior that is specific, narrow, and rigid: individuals ruminate on the drug—where to get it, how to pay for it, etc. In OCD and anorexia, there is excessive rumination about threats to the person, from contamination or the effects of eating and overeating, respectively.”

Drs. Carhart-Harris and Nutt propose: “The psychedelic experience opens a therapeutic window that disrupts entrenched thinking and allows insight, which with psychotherapeutic support can lead to a recalibration of one’s spectrum of [mental] associations.” But Dr. McDonald and the APA reviewers note in their APA review paper that “it is unclear whether it is the psychedelic drug itself, the psychedelic-assisted psychotherapy experience, or drug-facilitated enhancements in the therapeutic alliance that promote change” in patients.


How safe—or dangerous—are psychedelic drugs? “Hallucinogens are not associated with drug-seeking behavior,” note the APA review authors. “Animals [such as mice] cannot be trained to self-administer” them, in contrast to addictive substances such as nicotine, alcohol, and cocaine. This is not to say, however, that psychedelics are safe. MDMA, an amphetamine, is one psychedelic thought to have potentially addictive properties. And while psychedelics are cleared from the system in a matter of hours, everyone involved in studying them stresses that responses to the actual experience of the psychedelic “trip” can vary widely. While “these drugs on a relative basis are considered quite safe and don’t have classic addiction potential,” notes Dr. Griffiths of Johns Hopkins, “that doesn’t mean they’re safe for everybody and under all circumstances. People who have vulnerability to psychotic illnesses may get exposed and end up with a diagnosis of schizophrenia, and that would be awful. We also know it is almost certain that some people who take these substances under unconstrained conditions are going to become frightened and engage in behaviors that put themselves or others at risk.”

Drs. Carhart-Harris and Nutt, in their 2020 JAMA Psychiatry commentary, note that “patient demand [for psychedelics] is growing, as is interest in the general population, with the possibility that expectations are outpacing the current data on what outcomes can be confidently foreseen.” They caution: “Psychedelics are neither a cure for mental disorders nor a quick fix for an unfulfilled life and should not be portrayed as a panacea.”

With respect to specific results obtained in preliminary studies of psychedelics, Alan Schatzberg, M.D., of Stanford University, a BBRF Scientific Council member and 2005 BBRF Falcone Prize winner, in a 2020 commentary in the American Journal of Psychiatry asks whether or not, for example, therapeutic benefits experienced by advanced-stage cancer patients after psilocybin-assisted psychotherapy more broadly “tells us something [useful] regarding the use of psilocybin in refractory major depression.” He asks: will psilocybinassisted therapy help patients with anxious depression? Milder depression? “It is possible that clinical trials now under way may be targeting the wrong population or the wrong outcome.”

Dr. Schatzberg also notes that some of the promising results obtained in psychedelics-assisted psychotherapy have occurred in “open-label” trials, in which patients know they are receiving the treatment under study (i.e., there is no placebo). This relates to a problem that he says is inherent in trials with psychedelic drugs: it is very difficult to find credible placebos against which to compare them. People who take psychedelics know that they have done so—the experience is vivid, and perhaps impossible to mimic convincingly with non-hallucinogens. And, says Dr. Schatzberg, “without an appropriate placebo, what are we to conclude?”

While generally supportive of the APA review paper’s recommendation for continued research, Dr. Schatzberg, who was not part of the review team, stresses that “we need to be sure we are asking the right questions: In which types of patients? How severely ill?” The research process, he says, must seek “rational conclusions,” and not be swept up in a wave of enthusiasm.

This view is consistent with that expressed by Robert Malenka, M.D., Ph.D., a BBRF Scientific Council member, also of Stanford, whose commentary about psychedelics research appeared in JAMA Psychiatry in 2019. With co-author Boris Heifets, M.D., Ph.D., Dr. Malenka stresses the importance of “learning whether these drugs’ benefits are specific to specific constellations of symptoms.” For this reason, he and Dr. Heifets urge a “circuits-first approach.” By using modern neuroscience tools to “define the [brain-]circuit adaptations that contribute to a drug’s behavioral and therapeutic effects, studies can be conducted which could reveal new molecular targets in brain cells or circuits” which can be used as a basis for developing novel drugs that are more effective and cause fewer side effects than psychedelics.

Dr. Jeffrey Lieberman, in his New England Journal of Medicine editorial, similarly notes the “fundamental question [as to] whether the putative therapeutic effects of psychedelics require a patient to have a mystical experience or would occur in its absence through the pharmacologic effects on the serotonin system or remodeling of neural circuitry. To answer this question, compounds are being engineered that have the pharmacologic properties of psychedelics but that do not cause mind-altering effects.” More generally, Dr. Lieberman, writes, “given the controversial history, unique properties, and ambitious claims surrounding psychedelic drugs, their development must be guided by the most enlightened science and with the utmost methodologic rigor.”

Drs. Malenka and Heifets, like Dr. Schatzberg, stress the need for developing effective placebo controls for psychedelics. They further ask, with reference to psilocybin trial data “suggesting that the mystical aspect of the acute drug experience scales with the therapeutic benefit”: “Are all patients capable of generating this kind of subjective state?”

In the much-publicized 2020 psilocybin trial in patients with major depression led by Drs. Griffiths and Davis, reference was made to participants’ “experiences of sadness, crying, grief, loneliness, despair, and imagining of their own deaths while under the influence of psilocybin,” notes Charles Reynolds III, M.D., winner of the 2016 BBRF Pardes Humanitarian Prize in Mental Health, in a 2020 American Journal of Psychiatry commentary. This leads Dr. Reynolds to compare the psychedelic trip with psychotherapy for prolonged grief disorder. In the latter, “the therapist encourages patients to revisit the circumstances of the death and to repeatedly confront the painful affects associated with reminders of the deceased…. Such grief work, exquisitely painful and emotionally arousing, becomes a pathway to accepting and coming to terms with the finality of the loss and enabling the bereaved to find new meaning in life.”

Psychedelics-assisted psychotherapy may work in an analogous way, Dr. Reynolds suggests. But before it can be adopted outside of the research context, he cautions, “it is important scientifically and clinically to highlight the questions and caveats.” Among other things, a way must be found, he says, to compare psilocybin-assisted therapy with similar therapy using a credible placebo, in order to determine whether it is the psychotherapy component or the drug that generates the greater part of the therapeutic benefit.

Written By Peter Tarr, Ph.D.

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