Psychedelic-assisted therapy: An overview for the internist

Classic vs nonclassic psychedelics

There is debate among researchers about which drugs should be classified as psychedelics. From a phenomenological standpoint, substances with a variety of pharmacologic mechanisms produce psychedelic subjective effects. For example, the effects of LSD are produced via serotonin 2A receptor agonism; ketamine, N-methyl-D-aspartate receptor antagonism; and MDMA, serotonin release into the synaptic cleft. However, some researchers argue that only compounds that produce these effects primarily via serotonin 2A receptor agonism (eg, LSD, psilocybin, dimethyltryptamine) are psychedelics. In a compromise between these competing views, primary serotonin 2A agonists are referred to as classic psychedelics, while compounds that exert similar effects via alternate pharmacologic mechanisms are termed nonclassic psychedelics.³

Underlying mechanisms are being explored

Over the past 2 decades, numerous studies have explored multiple psychedelic compounds for their effects on various mood, anxiety, and substance use disorders, with promising findings on efficacy and favorable safety profiles in research settings.¹ How psychedelics might be able to treat such diverse conditions remains unclear, but multiple potential explanatory hypotheses are currently under investigation.⁴

Functional neuroimaging studies suggest that psychedelics can disrupt the default mode network, a group of brain regions involved in self-referential thinking and introspection.⁴ This network is often overactive in several psychiatric disorders and substance use disorders. Temporarily disrupting the default mode network may enable it to reorganize in a way that fosters more flexible thought patterns, facilitating more adaptive ways of thinking and behaviors.

Neurochemically, psychedelics seem to temporarily enhance neuroplasticity—the brain’s ability to reorganize and form new neural connections—for weeks after their immediate effects have ceased. This increased neuroplasticity may promote learning and cognitive flexibility, which patients can use to develop new perspectives and facilitate lasting behavioral changes.

Early medical use of psychedelics and subsequent regulation

Humans have used naturally occurring psychedelics such as psilocybin and mescaline for thousands of years, and knowledge from indigenous peoples’ ritualistic use informs the delivery of psychedelic-assisted therapy.⁵ Interest in therapeutic applications of psychedelics in Western medicine is not new. After Swiss chemist Albert Hoffman discovered LSD’s psychoactive effects in 1943, his employer Sandoz disseminated LSD to physicians to identify potential clinical applications. Clinical use of LSD in the 1950s and 1960s showed promising results for alcohol use disorder, cancer-related psychological distress, and other conditions.^6,7 Hoffman identified psilocybin as the primary psychoactive compound in Psilocybe mexicana mushroom samples in 1958 and first synthesized psilocybin in 1959. Sandoz subsequently also disseminated it for psychiatric research.⁸

In the mid-1960s, the FDA began requiring that drugs be subjected to monitored clinical trials to establish safety and efficacy for specific indications. Amid growing public concern about nonmedical use of psychedelics and the patent for LSD expiring in 1965, Sandoz did not pursue these trials, so clinical use of psychedelics drew to a close.⁹ In 1970, most psychedelics were designated under the Controlled Substances Act as Schedule I drugs (ie, no accepted medical use and a high potential for abuse) in the United States, erecting significant bureaucratic and cost barriers that essentially halted early research into psychedelics’ therapeutic benefits.

Although MDMA was synthesized in 1912 by Merck chemists,¹⁰ the company conducted no human testing, so it was not designated a Schedule I drug in 1970 because its psychoactive effects were still unknown. American chemist Alexander Shulgin re-synthesized MDMA and performed self-trials in 1976,¹⁰ which led to therapists using MDMA as an adjunct in psychotherapy (permissible in some states at the time). Uncontrolled case series from that period suggested MDMA held therapeutic potential for multiple psychiatric conditions.¹¹ However, in 1984, once it learned of nonmedical use of MDMA, the US Drug Enforcement Administration announced plans to make MDMA a Schedule I drug. MDMA-assisted therapists attempted to halt this action via administrative hearings,¹² and the US Drug Enforcement Administration administrative judge overseeing the case concluded MDMA should be a Schedule III drug. However, the US Drug Enforcement Administration overruled this and placed MDMA into Schedule I in 1985.

Renewed interest in therapeutic applications

Through considerable efforts of researchers and philanthropists who believed potentially useful medicines had become unnecessary casualties of the “War on Drugs,” clinical trials exploring the therapeutic potential of psilocybin and MDMA were revived in the 2000s. Due to positive findings from these trials,¹ numerous biotechnology companies hoping to develop psychedelics as medicines have recently emerged.¹³ Psychiatry has also warmed to the notion of psychedelics as medicines, with 81% of psychiatrists in a 2023 national survey agreeing they show promise in treating psychiatric conditions, and over half planning to incorporate psychedelics into their practices upon FDA approval.¹⁴

Research into therapeutic applications of psychedelics is now progressing after several decades of dormancy due to regulatory requirements and a lack of federal research funding.¹⁵ In a promising sign, the FDA has granted breakthrough therapy status to LSD, MDMA, and psilocybin because they show potential for significant improvement over existing treatments. With this designation, pharmaceutical companies developing psychedelic treatments receive intensive guidance from the FDA on their drug development programs, and the FDA review process is accelerated.

Regulatory approval efforts

The field suffered a notable setback in August 2024, when the FDA declined to approve a New Drug Application for MDMA for PTSD despite positive findings from 2 phase 3 trials and asked its sponsor, Lykos Therapeutics, to conduct another phase 3 trial.¹⁶ The FDA typically does not publicly disclose its reasoning for New Drug Application decisions, and Lykos Therapeutics has not publicly shared the complete text of the FDA’s response letter. However, Lykos Therapeutics stated that the letter’s contents “echo” critiques raised during a June 2024 meeting of an FDA Advisory Committee that recommended against approving MDMA.¹⁷ Concerns raised about Lykos Therapeutics’ trials during that meeting included ineffective blinding due to MDMA’s psychoactive effects; failure to collect electrocardiograms, liver function tests, and data on participants’ feelings of euphoria (to assess addictive potential); and risk of therapist sexual misconduct after a therapist in a phase 2 clinical trial in Canada engaged in a sexual relationship with a participant.¹⁶

Prior to this decision, it was believed by many in psychiatry that MDMA would become the first FDA-approved psychedelic. Due to the FDA’s requirement of a new phase 3 trial, it now seems more likely that psilocybin will be approved by the FDA first. After a positive phase 2 trial,¹⁸ Compass Pathways is conducting 2 phase 3 trials of psychedelic-assisted therapy for treatment-resistant depression. If these trials are successful, FDA approval could be granted in 2026.

The Usona Institute has also reported positive findings in a phase 2 trial of psilocybin for major depressive disorder¹⁹ and launched its first phase 3 trial in March 2024.

Rationale for investigation of MDMA-assisted therapy

PTSD is marked by intrusion symptoms such as nightmares or flashbacks; avoidance of trauma-related thoughts, feelings, or external reminders; negative alterations in cognition and mood; and changes in arousal and reactivity in people exposed to traumatic events. While trauma-focused therapies are considered first-line treatment, response rates are variable, dropout rates are high, and evidence quality of trials is generally poor.³² Further, only 20% to 30% of patients respond to treatment with sertraline or paroxetine, the only 2 FDA-approved medications for PTSD.³² Therefore, there is need for novel PTSD treatments.

MDMA may enhance therapeutic alliance via its prosocial effects while also facilitating a less-threatening experience of traumatic memories. It reduces activity in brain regions associated with fear and anxiety, which may allow severe emotional reactions to traumatic memories to be unlearned.^33,34 Similar to classic psychedelics, MDMA may also enhance or reopen critical periods of learning, which can facilitate behavioral change.

Functional unblinding in trials a challenge

Clinical trials of MDMA-assisted therapy for PTSD typically involve 2 or 3 treatment sessions, along with preparation and integration sessions. In randomized controlled trials, participants receive the same number of psychotherapy sessions whether they receive MDMA or placebo. Given the strong psychoactive effects of psychedelics, a common criticism of this line of research has been that most participants can easily distinguish whether they have received active drug or placebo (functional unblinding). In the most recent phase 3 trial of MDMA-assisted therapy for PTSD, 94% of participants receiving MDMA guessed they had received it, while 75% of participants in the placebo group were aware they had received placebo.³⁴

Importantly, functional unblinding can occur due to a drug’s psychoactive effects or side effects as well as its efficacy. This challenge is not unique to psychedelics; high rates are reported in trials of many commonly used psychiatric medications, including stimulants, benzodiazepines, antidepressants (primarily older ones due to more prominent side effects),³⁵ and antipsychotics.³⁶ Early MDMA trials used low-dose MDMA as an active placebo to reduce functional unblinding, but later studies switched to inactive placebo after low-dose MDMA was found to worsen PTSD symptoms for some participants. Low-dose MDMA also led to increased anxiety and re-experiencing of trauma during therapy without the emotional breakthrough necessary for processing conferred by high-dose MDMA, with some participants requiring benzodiazepine rescue treatments.³⁷

Promising efficacy results

In a 2022 systematic review and meta-analysis,³⁰ all 5 eligible randomized controlled trials of MDMA-assisted therapy from 2011 to 2021 used the Clinician-Administered PTSD Scale (CAPS) to evaluate treatment effects (score range 0–80, with higher scores indicating more severe PTSD symptoms; CAPS score ≥ 50 signifies severe PTSD).³⁸ These trials involved 175 participants with baseline CAPS scores ranging from 44.0 ± 6.0 to 94.4 ± 20.2. Assessment of the primary end point occurred from 3 weeks to 2 months after the last MDMA session, with a 22-point greater reduction in baseline CAPS score occurring in participants receiving MDMA-assisted therapy than in controls (mean difference −22.03; 95% confidence interval [CI] −38.53 to −5.52).³⁰

In a recent confirmatory randomized, placebo-controlled phase 3 trial of MDMA-assisted therapy for moderate or severe PTSD, after 3 treatment sessions, response rates at 18 weeks after baseline (6–8 weeks after MDMA session 3) were 86.5% and 69.0% for MDMA and placebo, respectively, while remission rates were 46.2% and 21.4%.³⁴ This translated to an effect size of 0.70 for MDMA vs placebo. (Effect size is a statistical measure used to quantify the magnitude of a difference between 2 groups’ means, which provides a measure of the practical significance of study results. It is calculated as the difference between the 2 means divided by the pooled standard deviation, and is generally interpreted as follows: 0.2 small effect, 0.5 medium effect, and 0.8 or higher large effect.)

While no clinical trials have directly compared MDMA-assisted therapy with sertraline or paroxetine, at the primary end point of phase 3 trials for those medications, the effect sizes were smaller (0.45–0.56 for paroxetine and 0.31–0.37 for sertraline) than the effect size of MDMA in phase 2 trials (0.90) or the 2 phase 3 trials (0.91 and 0.70).^34,39 There have been no trials directly comparing MDMA-assisted therapy with traditional trauma-focused therapies. However, meta-analysis of randomized trials of trauma-focused therapies that included a control condition, rather than waitlist or treatment as usual, showed an effect size of 0.96 after 14 to 27 weeks of treatment.⁴⁰

A dropout rate of 6.8% was observed among participants who received MDMA in phase 2 trials.³⁹ In contrast, in a recent randomized trial that evaluated 2 trauma-focused therapies for PTSD—prolonged exposure and cognitive processing therapy—dropout rates were 56% and 47%, respectively.⁴¹ It is also notable that phase 2 trials for MDMA-assisted therapy included only participants who had previously been intolerant of or unresponsive to available treatments.³⁹ Therefore, MDMA-assisted therapy might offer the most public health benefit for PTSD in its potential for patients not helped by existing PTSD treatments. Only head-to-head trials can provide an accurate assessment of comparative efficacy due to differences in study designs and study populations. Caution is warranted in any comparison of outcomes without head-to-head trials.

Low risk in clinical trial settings

MDMA has been well tolerated in clinical trials. Although adverse events are common, they have been primarily mild to moderate in severity. Serious adverse events have been rare. One clinical trial participant with a history of premature ventricular contractions experienced worsening contractions after receiving MDMA and was hospitalized, with full resolution and without long-term sequalae.⁴²

Given that antidepressants can rarely worsen or induce suicidality, suicidal ideation and suicidal behaviors are important safety outcomes for psychedelic clinical trials. There have been no suicide attempts or completed suicides in clinical trials of MDMA. One trial participant with a history of suicide attempts was hospitalized for suicidal ideation 13 days after their second MDMA session and went on to complete the study.^30,42 In the most recent phase 3 trial of MDMA for PTSD, 2 participants in both the MDMA and placebo groups reported treatment-emergent suicidal ideation, and 1 participant in each group engaged in posttreatment nonsuicidal self-injuring behavior.³⁴

MDMA appears to be physiologically safer in controlled settings than in recreational settings. While nonmedical MDMA use has caused rare deaths from hyperthermia or hyponatremia-related seizures, these are typically associated with multiple drug toxicity and dancing in high-temperature environments with likely overhydration.

MDMA’s misuse potential is low compared with other commonly used psychoactive drug classes, but somewhat higher than that of classic psychedelics.⁴³ The existence of addiction to MDMA has been questioned.⁴⁴ Elements of addiction, including tolerance, cravings, and psychological dependence, have been reported with MDMA, but physical withdrawal symptoms such as dysphoria appear minor. Questions have been raised about whether these symptoms more accurately reflect subacute “comedown” effects rather than withdrawal. Clinical trials thus far have not yielded evidence of MDMA misuse among participants. While neuroimaging studies of nonmedical users of MDMA have raised concerns about serotonergic neurotoxicity, participants have typically been unusually heavy MDMA users. These studies have also suffered from likely confounding by use of multiple drugs and questions of purity, and have had only limited replicability.⁴⁵ Further investigation is necessary, but it is currently thought unlikely that exposure to a small number of MDMA-assisted psychotherapy sessions should cause appreciable risk in this regard.

Rationale for investigation of psilocybin-assisted therapy

Depression involves decreased mood; anhedonia; loss of motivation; disruptions in appetite, sleep, and functionality; and sometimes suicidal ideation or suicide. While antidepressants and psychotherapy are effective for many patients with depression, they are unhelpful or only partially helpful for a substantial minority, and symptomatic improvement is slow. Further, antidepressants can cause problematic adverse effects, including sexual dysfunction and emotional blunting. Treatment-resistant depression, most commonly defined as 2 failed antidepressant treatments, affects approximately one-third of patients with depression.⁴⁹ Modalities such as electroconvulsive therapy, transcranial magnetic stimulation, and ketamine or esketamine can be effective for patients with treatment-resistant depression, but there are multiple barriers to their use. Novel rapid-acting agents that produce durable antidepressant effects after only a few administrations would provide considerable improvement in comparison.

Significant efficacy findings

A meta-analysis of 9 clinical trials of psilocybin-assisted therapy for depression (1 or 2 treatment sessions) included 596 participants and evaluated antidepressant efficacy using multiple instruments, including the Hamilton Depression Rating Scale and the Montgomery-Asberg Depression Rating Scale.⁵⁰ The standardized mean difference in depression outcomes between experimental and control arms was –0.78 (95% CI −1.06 to −0.51, P < .00001), signifying a large effect of psilocybin. The pooled response rate at primary end point (which, across included trials, ranged from 1 to 7 weeks after psilocybin administration) was 57% for psilocybin vs 22% for control. Remission was also higher in the psilocybin group compared with the control group (45% vs 14%). Large, statistically significant effect sizes for psilocybin were also observed in 2 open-label trials that had 6- and 12-month follow-ups (1.4 and 2.4, respectively).

Reassuring safety results

Adverse events are frequently reported in participants receiving psilocybin, though they are usually mild to moderate in severity. Serious adverse events have been rare in clinical trials. One participant sought psychiatric hospitalization for worsening depression after psilocybin treatment.⁵⁰ While recent research suggests psilocybin-assisted therapy reduces suicidality,⁵¹ treatment-emergent suicidality remains an important area of interest.

The largest study of patients with treatment-resistant depression to date is a double-blind, randomized controlled phase 2 trial of a single psilocybin-assisted therapy session with 25 mg, 10 mg, and 1 mg (placebo dose) involving 233 participants.¹⁸ From day 2 (first day after psilocybin) to week 3, incidence of suicidal ideation for the 25-mg, 10-mg, and 1-mg groups was 6%, 5%, and 3%, respectively. Incidence of nonsuicidal intentional self-injury during that period was 3%, 1%, and 0%, respectively. From week 3 to week 12, suicidal behavior was reported by 4% of participants in the 25-mg group (all had a history of suicidal behavior or nonsuicidal self-injury), compared with none in the other groups. The incidence of nonsuicidal intentional self-injury during that period for the 25-mg, 10-mg, and 1-mg groups was 0%, 1%, and 1%, respectively. Although not statistically significant, these differences warrant continued investigation into the potential for psilocybin-induced suicidality.

Psilocybin misuse has not been reported in clinical trials.