Chris Aiken, MD. Editor-in-Chief of The Carlat Psychiatry Report. Assistant Professor, NYU Langone Department of Psychiatry. Practicing psychiatrist, Winston-Salem, NC.
Garrett Rossi, MD. Inpatient/Consult Attending Psychiatrist, AtlantiCare Regional Medical Center, Pomona, NJ.
The authors have no financial relationships with companies related to this material.
Psychedelic-assisted psychotherapy is moving closer to FDA approval, but some are not waiting for the green light. Patients are seeking out psychedelics on the streets, overseas, or through underground clinics, often without the psychotherapy that these drugs are supposed to assist. Drugs that were once feared by the public are increasingly viewed as benevolent panaceas. For this issue, we’ve combed through the research to figure out how to guide patients through this brave new world.
What is a psychedelic?
Psychedelics are drugs that alter consciousness and perception, and they are divided into two types. Classic psychedelics, including psilocybin, dimethyltryptamine (DMT), and lysergic acid diethylamide (LSD), activate the serotonin 5-HT2A receptor. Atypical psychedelics achieve similar psychological effects through different mechanisms. This category includes the amphetamine derivative MDMA (3,4-methylenedioxymethamphetamine) and the glutamatergic ketamines, although the relationship between the therapeutic and psychedelic effects of the ketamines is under debate.
All of these drugs produce immediate effects, and all have been used as drugs of abuse: “magic mushrooms” (psilocybin), “special K” (ketamine), “ecstasy” or “molly” (MDMA), and “fantasia” (DMT). On the other hand, psychedelics have been used in religious ceremonies for at least 9,000 years, and some lack many of the qualities that define a drug of abuse.
Over 50 trials of psychedelics are underway in depression, anxiety, substance use disorders, and cognitive impairment in schizophrenia. Most of those trials involve two psychedelics that we’ll focus on in this issue, one a classic (psilocybin) and the other an atypical (MDMA).
Psilocybin is a psychoactive compound found in certain species of mushrooms. It activates the serotonin 5-HT2A receptor, operating like a less potent version of LSD. It tends to induce a state of connection and self-transcendence, along with perceptual hallucinations that range from the wondrous to the frightening. In depression, psilocybin’s trials have matured to the final Phase III level, while trials in anorexia are just starting up.
MDMA is a synthetic amphetamine analogue that is in Phase III trials for PTSD. It affects multiple pharmacodynamic pathways, including dopamine, norepinephrine, serotonin, and oxytocin. Compared to other psychedelics, MDMA provokes a stronger emotional response, evoking intense feelings of empathy that may be related to its ability to increase oxytocin.
Both of these drugs were used to enhance psychotherapy in earlier times—psilocybin in the 1950s and MDMA in the 1970s—but that use was forced underground by regulatory changes that are detailed in the box below (“Lessons From History”). In line with their earlier use, today’s trials are testing these drugs as an adjunct to psychotherapy, but is that pairing necessary or can they work on their own?
A drug for psychotherapy
The psychotherapies that are paired with psychedelics range from general support that buffers the risk of a “bad trip” to extended sessions that help sustain the insights of the psychedelic experience. At a minimum, the drug is delivered in a controlled setting after counseling the patient to prepare them for the experience. Typically the patient will wear eyeshades and listen to relaxing music during the four- to eight-hour experience, while one or two facilitators provide psychological support. This basic setup was used in the early, uncontrolled trials of psilocybin, with good effect. Patients found long-lasting relief from treatment-resistant depression (TRD), but those trials were not controlled. In the controlled FDA registration trials, psilocybin was paired with a brief course of psychotherapy based on the acceptance and commitment therapy (ACT) model. The therapy guides patients to turn the insights gained from the psychedelic experience into meaningful changes in their lives.
Most practitioners believe that follow-up therapy sessions are an essential part of the treatment, and though controlled trials have not tested the idea, it does gather indirect support from research on ketamine. Ketamine is one of the most effective treatments for depression, but its efficacy is short-lived. Several medications have been tested to prolong ketamine’s effect, including lithium and the glutamatergics d-cycloserine and riluzole, but none have worked. In contrast, lasting benefits were achieved when ketamine sessions were followed by cognitive behavioral therapy (CBT; Wilkinson ST et al, Psychother Psychosom 2021;90(5):318–327).
A related question is whether the altered state of consciousness is integral to the treatment. This is difficult to unravel and depends on what we mean by “altered state.” Ketamine’s antidepressant effects are unrelated to its dissociative effects, but they are associated with its ability to quiet depressive rumination and reduce activity in the default mode network, the area of the brain that is responsible for this negative spiral of ruminative thought (Wade BSC et al, Psychol Med 2022;52(12):2376–2386).
Psilocybin also reduces the chatter in the default mode network, but it is not yet clear which of its many actions are responsible for its antidepressant effect. After a dose of psilocybin, people tend to be more extroverted, open, spiritual, connected to nature, and altruistic. They are also less likely to endorse authoritarian political views. The psilocybin experience has a “noetic” quality, which means the person has a sense of profound truth that is difficult to put into words.
One study suggests that psilocybin’s hallucinatory effects are not integral to the treatment. In an animal model, psilocybin still alleviated depressive behaviors even when the serotonin 5-HT2A receptor responsible for its hallucinogenic actions was blocked (Hesselgrave N et al, Proc Natl Acad Sci U S A 2021;118(17):e2022489118).
Psilocybin in clinical trials
Psilocybin first proved useful not for mental illness but for the profound anxiety that comes with awareness of impending death. The drug was tested in 68 patients with terminal cancer in three small, randomized, crossover trials, the first in 2011. Two of those were positive, with approximately 70% showing large responses after a single dose. Six months later, those benefits were maintained (Dodd S et al, CNS Spectr 2022;11:1–11).
In depression, psilocybin has positive results from two randomized controlled trials that tested the drug in the context of a supportive psychotherapy. The first compared psilocybin to escitalopram 20 mg/day in 59 patients with long-standing major depressive disorder (mean duration 22 years). Psilocybin passed, but did not live up to its hype. The psychedelic worked no better than the SSRI (Carhart-Harris R et al, N Engl J Med 2021;384(15):1402–1411). One in three participants had tried psilocybin in the past, raising the possibility of a recruitment biased in favor of those who had positive past experiences with the drug.
The second trial tested psilocybin in a treatment-resistant population who had failed two to four antidepressant trials. This large trial compared two doses of psilocybin (25 mg vs 10 mg) to placebo. The results were positive, but not without disappointment. Psilocybin separated from placebo on the primary outcome measure at three weeks, but not at 12 weeks, and only the high dose (25 mg) was effective. This dose was also associated with a high rate of side effects, with 84% reporting headache, nausea, or dizziness (Goodwin GM et al, N Engl J Med 2022;387(18):1637–1648).
One problem with psychedelic research is that the immediate psychological effects of the drug might unmask the blind, alerting subjects that they did not receive the placebo. To get around this, both psilocybin trials used microdoses of psilocybin in the placebo arm (1–3 mg instead of 25 mg).
MDMA in clinical trials
MDMA is an amphetamine analogue that also increases transmission of serotonin and secretion of oxytocin. MDMA has small studies supporting its benefits in anxiety in autism, social anxiety disorder, and terminal illness, but it is in trials of PTSD that it has made the most progress. Like psilocybin, MDMA is used as an adjunct to psychotherapy, only here the therapy is longer, involving monthly MDMA dosing over three months, with each dose followed by three weekly 90-minute therapy sessions.
The first test of this approach came from six very small randomized controlled trials involving 105 patients with a mix of military and civilian traumas. When pooled together, those trials registered a large effect size that grew larger after the therapy was completed. When followed up at least a year later, remission rates increased from 56% to 67% (Jerome L et al, Psychopharmacology (Berl) 2020;237(8):2485–2497).
Those results were confirmed by a Phase III randomized trial that was larger but still on the small side. Of the 89 patients enrolled, 67% reached full remission from PTSD, and there were improvements on secondary outcomes of alcohol use and eating disorder symptoms as well (Mitchell JM et al, Nat Med 2021;27(6):1025–1033).
Most of the MDMA studies enrolled patients with severe PTSD who had not responded to SSRIs or evidence-based psychotherapies like eye movement desensitization and reprocessing and CBT. The main limitation of this research is that it was all funded by the same company and conducted by the same group.
First, the good news. Psilocybin’s lethal dose is approximately 1,000 times its therapeutic dose. The most common side effects are anxiety, headaches, nausea, confusion, vomiting, and increases in blood pressure and pulse. These side effects are usually transient and mild, and there are no reports of psychiatric or medical reactions that required intervention in the clinical trials (Johnson MW et al, Neuropharmacology 2018;142:143–166). The subjects in those trials, however, were a carefully selected few. They numbered less than 500 and lacked the complex comorbidities that are the norm in practice. People who had bad trips in the past were unlikely to enroll in these trials. In fact, the enrollment was biased toward those with past positive experiences on the drug.
Negative feelings accompany the majority of psilocybin trips, but most people report that the good eventually outweighs the bad. In an online survey of 1,993 people who reported psychological difficulties after taking psilocybin, 39% said the experience was among the most challenging events of their life, but most of them (84%) felt they benefited from the challenge. Anxiety, depression, and paranoia were common and lasted more than a week for one in four respondents, and more than a year for one in 10. A total of 7.6% sought professional help for these adverse effects. More concerning were the 11% who put themselves or others in physical danger after taking the drug (Carbonaro TM et al, J Psychopharmacol 2016;30(12):1268–1278).
Hallucinations and illusions are common reactions to a psilocybin dose, but none of these persisted in the clinical trials. That possibility is, however, enshrined in the DSM-5 diagnosis of hallucinogen persisting perceptual disorder (HPPD). People with HPPD have persistent illusions of flashes of color, trails of moving images (palinopsia), halos around objects, and shrinking or enlarging of objects (micropsia and macropsia). Up to half of recreational psilocybin users develop HPPD, although the doses they take tend to be higher than those in the clinical trials.
As an amphetamine, MDMA carries medical risks that are not known with psilocybin. In particular, there are reports of death from hyperthermia, cardiotoxicity, and seizures among recreational users. Psychiatric side effects include worsened mood, suicidality, and worsened psychosis or mania. At high doses, MDMA also has neurotoxic effects, but it is unknown whether these occur in the clinical dose range (Costa G and Gołembiowska K, Exp Neurol 2022;347:113894).
Psychosis and mania
Most psychedelics have been linked to mania and psychosis, including new-onset schizophrenia. However, it is not clear if the drugs caused these syndromes or hastened their onset in vulnerable people.
Psilocybin, MDMA, and other psychedelics are Schedule I drugs, which means they have a high risk of abuse and no accepted medical use in the eyes of the DEA. However, these drugs do not hijack the reward center like opioids, sedatives, cocaine, and cannabis can. In human and animal studies, psychedelics show only mild or no reinforcing effects. In those experiments, euphoria and pleasure were rare. More often, people reported aversive effects like dysphoria, anxiety, and altered sensations after taking the psychedelic (Johnson et al, 2018).
Repeated use of psilocybin does not lead to physiologic dependence or withdrawal, but tolerance to its beneficial effects can develop over time, and there is cross-tolerance between psilocybin and LSD. In the clinical trials, psilocybin was only dosed once or twice. For most subjects, the benefits continued over the long term, but not for all. In one trial of psilocybin in TRD, 25% of subjects sought additional doses when the benefits wore off six months later (Carhart-Harris RL et al, Psychopharmacology (Berl) 2018;235(2):399–408). Even if clinical guidelines limit repeated dosing, patients will not find it hard to obtain psychedelics on their own. Psilocybin is decriminalized in nine US cities and readily available in nonmedical settings in Oregon.
Another side effect is societal. As psychedelics gain acceptance in psychiatry, we may see more use in the general public. Based on research carried out in New York City nightclubs, about one in five adults are more likely to use MDMA or ketamine after seeing positive media coverage about their therapeutic benefits (Palamar JJ and Le A, Addict Res Theory 2022;30(2):96–103).
One serious risk that is unlikely to show up in clinical trials is boundary violations. Psychedelics put patients in a more suggestible, vulnerable state. They are less aware of dangers and less restrained by the boundaries between self and others.
Many unregulated practitioners believe that physical touch enhances the therapy, and that it works better when both patient and practitioner are under the influence. Research trials, in contrast, employ two therapists and a chaperone to monitor the results, but those safeguards may not survive the cost constraints of clinical practice.
Psychedelic risks: The bottom line
When used outside of therapy, psychedelics cause dangerous behaviors or adverse psychological effects in up to 20% of users. High doses can be neurotoxic, particularly with MDMA, and repeated dosing can lead to tolerance. On the other hand, psychedelics lack the rewarding qualities that are common to most substances of abuse.
Lessons From History
The first recorded use of psychedelics is in a cave in the Sahara Desert of North Africa. The 9,000-year-old painting depicts a spiritual experience induced by a local psilocybin mushroom. Psychedelics crossed into Western medicine in 1947, when Sandoz-Novartis released LSD as Delysid. The company marketed the drug, and later psilocybin, for a use that resembles the proposed indication for psychedelics today: to enhance psychotherapy (the product labeling claimed it would “elicit release of repressed material”).
Over 40,000 patients took psychedelics in the 1950s, including Alcoholics Anonymous cofounder Bill Wilson, who credited LSD with helping him fight addiction. The practice was brought to an end when the drugs slipped into recreational use, prompted by Timothy Leary and Richard Alpert. These Harvard psychologists set out to conduct sober experiments of LSD and psilocybin, but shifted toward zealous enthusiasm after trying the drugs on themselves. Leary and Alpert began distributing psychedelics to students, resulting in their dismissal from Harvard in 1963. Sandoz responded to the controversy by withdrawing LSD and psilocybin in 1965, and the Nixon administration restricted them further in the Controlled Substances Act of 1970.
With LSD and psilocybin tightly locked away, MDMA entered the scene. This amphetamine derivative was first synthesized by Merck in 1912 but went unused until chemist Alexander Shulgin rediscovered it in the 1970s. Shulgin was impressed with the clarity of thought and depth of empathy he experienced after taking MDMA, and he shared it with his wife, a psychotherapist. The Shulgins distributed it to other therapists, who found its empathogenic effects useful in couples counseling.
MDMA also became popular in music concerts (“raves”) and as a street drug, prompting the Reagan administration to criminalize it in 1985. A year later, a group of therapists established the Multidisciplinary Association for Psychedelic Studies (MAPS) to study the therapeutic potential of the drug. In 2001, MAPS was cleared by the FDA to study MDMA-assisted psychotherapy for PTSD. The seven clinical trials that resulted from this effort are described earlier in this article.
Meanwhile, psilocybin and LSD were still barred from clinical research, but the screws were beginning to loosen. In 1993, Congress legalized the use of psychedelic drugs in religious ceremonies. This emboldened Roland Griffiths and colleagues at Johns Hopkins to test the spiritual effects of psilocybin, comparing the drug to methylphenidate in a controlled trial of normal subjects. Psilocybin, but not methylphenidate, induced a transcendent state in 60% of subjects that persisted for at least a year. The psychedelic did not cause drug-seeking behavior, but 17% developed mild, transient paranoia on psilocybin that did not require intervention (Griffiths RR et al, Psychopharmacology 2006;187(3):268–283).
Griffiths’ work opened the door for further research on this taboo drug, starting with trials in anxiety related to terminal cancer and later moving to trials in major depression. In 2018, the FDA gave psilocybin breakthrough status to fast-track research on the drug in TRD. Similar designations followed for other psychedelics, most of which are in the early stages of Phase I trials. Psilocybin is the furthest along in the pack, but events in Oregon may change its trajectory.
In 2020, Oregon voters passed a ballot initiative to allow supervised use of psilocybin outside of the medical setting. The plan, which rolled out on January 1, 2023, allows trained facilitators to deliver psilocybin for psychiatric disorders as well as personal growth. Anyone with a high school education can become a facilitator after completing a certified course. Facilitators are expected to understand pharmacology, provide psychological support, and manage psychosis, suicidality, medical emergencies, informed consent, and boundary violations. All this is done without medical supervision and after just 120 hours of education, less than what is required for a yoga instructor.
Psychedelic research is growing fast but still in its infancy. If psychedelics do earn FDA approval, it will likely be based on small studies in select populations. With limitations like those, they are best reserved for treatment-resistant cases with significant symptoms.
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