Published on March 29, 2025.

A look at the potential of MDMA, ketamine, and psilocybin to help people with treatment-resistant mental health conditions

When researchers recruit participants for studies involving psychedelic drugs, they are often looking for people who continue to suffer from mental health conditions even after trying current treatments—and there are many people who fall into that category.

An estimated 40%–60% of people with posttraumatic stress disorder (PTSD) do not respond to the selective serotonin reuptake inhibitors (SSRIs) that are first-line medications for the condition, and many do not respond to trauma-focused psychotherapies (Brady, K., et al., JAMA, Vol. 283, No. 14, 2000; Steenkamp, M. M., et al., JAMA, Vol. 314, No. 5, 2015). About a third of people diagnosed with major depressive disorder experience treatment-resistant depression (Zhdanava, M., et al., Journal of Clinical Psychiatry, Vol. 82, No. 2, 2021).

While small studies in recent years started to show promising results, regulatory agencies required larger randomized, multisite clinical trials to evaluate the safety and therapeutic efficacy of psychedelic drugs. Now the results are in on the largest studies to date of psilocybin (the compound in “magic” mushrooms) and MDMA (3,4-methylenedioxymethamphetamine, also called Ecstasy or Molly). In response to an application from Lykos Therapeutics, the U.S. Food and Drug Administration (FDA) targeted August 2024 to decide whether MDMA in combination with therapy to treat PTSD would be the first type of psychedelic-assisted therapy approved in the United States.

On Aug. 10, the FDA ruled to reject MDMA for assisted psychotherapy for PTSD, citing insufficient evidence and the need for more research. The ruling is consistent with a letter APA sent the FDA earlier this year that stated that a review of the literature on MDMA-assisted psychotherapy by a multidisciplinary panel of experts determined that there is insufficient evidence to be able to recommend MDMA-assisted psychotherapy for patients with PTSD.

The APA Services Inc. comments to the FDA drew on the expertise and recommendations of the experts who are currently updating APA’s 2017 Clinical Practice Guideline for the Treatment of PTSD in Adults. The comments also pointed out that more high-quality research is needed on MDMA-assisted psychotherapy to clarify the balance of potential benefits versus potential harms.

Larger studies have also supported the benefits of psilocybin for treatment-resistant depression, and researchers suspect this drug could be the next in line for FDA approval. Evidence is also mounting that psychedelics, which typically produce an altered state of consciousness, could help people suffering from substance use disorders, racial trauma, obsessive-compulsive disorder, and other conditions.

“If we rely on antidepressants for treatment, it can take several weeks before people experience amelioration of symptoms, if at all,” said Nora Volkow, MD, director of the National Institute on Drug Abuse. “Psychedelics may offer the opportunity to get a very fast and lasting response, and with some conditions, this could be lifesaving.” The latest research findings are also uncovering the potential neurobiological mechanisms that might make it possible for these controlled substances to produce mental health benefits.

While the latest evidence is encouraging, scientists are concerned that the hype in the public is ahead of the evidence. Recent data suggest that the number of people using magic mushrooms recreationally is increasing: Law enforcement seizures of the substance tripled from 2017 to 2022, and calls to U.S. poison control centers related to psilocybin use for adolescents tripled between 2018 and 2022 (Palamar, J. J., et al., Drug and Alcohol Dependence, 2024, in press; Farah, R., et al., Journal of Adolescent Health, 2024, in press). “I worry that people think they can self-medicate with these drugs,” said Joshua Gordon, MD, PhD, director of the National Institute of Mental Health (NIMH). “Existing studies have been conducted with guided psychotherapy along with the treatment, though more research is needed to understand how crucial therapy is in the process.”

In one survey of more than 2,300 people who used psilocybin in real-world settings for self-exploration, 11% of the respondents reported persisting negative effects, such as mood fluctuations and depressive symptoms, weeks or sometimes months after using the drug (Nayak, S. M., et al., Frontiers in Psychiatry, Vol. 14, 2023). Psychedelics are also not recommended for people who have a predisposition to or family history of psychotic disorders or bipolar mood. The drugs, which can increase heart rate and blood pressure, are also contraindicated for people with cardiovascular conditions.

Psychologists have played a critical role in clinical studies on psychedelics through their work as clinicians who prepare participants for the “trip,” or the experience with the drug, which often lasts many hours, and “integration,” or incorporating the key insights gained during the experience into their lives in the weeks and months after the trip. To equip licensed professionals to responsibly incorporate psychedelic medicine into the clinical setting, psychologists are developing education programs focused on the latest research and evidence-based practices. For now, these clinical settings are restricted to research studies, but that could change soon if the FDA approves MDMA-assisted therapy.

“Psychedelics have been illegal for years, and in the next several years there will likely be a significant shift because some of these drugs will be classified as medicine,” said Albert Garcia-Romeu, PhD, the associate director of the Center for Psychedelic and Consciousness Research at Johns Hopkins University. “Thousands of doctors, nurses, and psychologists will be lining up to practice with these drugs who have not been trained to use them, and the health care system needs to prepare for this unprecedented change.”

The brain science of psychedelics

Although psychedelics typically lead to an altered state of consciousness, the experience during the trip can vary based on what drug is used. MDMA, an empathogen, can increase the sense of connection and empathy toward oneself and others, and patients often want to interact with a clinician during parts of the 8-hour dosing session, said Joseph Zamaria, PsyD, an associate clinical professor at the University of California, San Francisco (UCSF) School of Medicine and a faculty member of the Berkeley Center for the Science of Psychedelics. Psilocybin is usually an internal experience with less interaction between the patient and clinician during the trip, which may include vivid visual hallucinations and an altered sense of time, space, and reality. LSD (lysergic acid diethylamide) is a well-known psychedelic, but most of the research on the drug was done in the 1950s–70s. More recently, though, scientists have started studying its therapeutic potential again. In March 2024, the FDA granted breakthrough designation to a form of LSD to treat generalized anxiety disorder based on data from a clinical trial.

One of the recent breakthroughs in psychedelic research is a better understanding of how these compounds work in the brain. Chronic stress, PTSD, and depression can damage brain circuits, particularly in the prefrontal cortex. “This part of the brain talks to other regions that regulate mood, motivation, fear, and reward, and we hypothesized that psychedelics could quickly regrow lost synapses,” said David Olson, PhD, director of the Institute for Psychedelics and Neurotherapeutics at the University of California, Davis. The results in rodents indicated that these compounds stimulated serotonin 2A receptors to promote neuron growth in the prefrontal cortex (Vargas, M. V., et al., Science, Vol. 379, No. 6633, 2023).

“These drugs are not rewiring the brain, but instead repairing damaged circuitry,” said Olson. “SSRIs can grow the same neurons, but it takes weeks or months to show therapeutic efficacy and a lot of patients do not respond at all.” In other words, psychedelics and SSRIs both promote structural neuroplasticity, but research suggests that psychedelics may act faster.

Ketamine

Ketamine, a legal anesthetic that is increasingly used in lower doses for treatment-resistant depression, also promotes synaptic changes that help neurons communicate with one another, but serotonin receptors are not involved. Instead, the drug inhibits N-methyl-D-aspartate (NMDA) receptors of glutamate, and this strengthens the neural connections weakened during depression. Ketamine can lead to feelings of being outside of one’s body and having different types of altered consciousness, but unlike classic psychedelics, the dosing sessions are much shorter. The FDA requires health care providers to monitor patients for 2 hours after administering the nasal spray form of an isomer of ketamine, Spravato. People can also receive ketamine intravenously, and studies have shown that patients usually need multiple doses to prevent relapse of depression. Treatments may initially be more frequent. “The goal is to find the sweet spot for frequency that prevents relapse,” said Carlos Zarate, MD, chief of the Experimental Therapeutics and Pathophysiology Branch at NIMH. “Over time, some people may need boosters every month or two.”

Although the FDA does not require therapy as part of ketamine treatment, the drug appears to improve the capacity to respond to future interventions, such as therapy or neuromodulation, said Todd Gould, MD, a professor in the departments of psychiatry, pharmacology, and neurobiology at the University of Maryland School of Medicine. “The brain is more prepared to adapt following ketamine, so combining ketamine with CBT [cognitive behavioral therapy] or other types of therapy could improve outcomes,” he said (Molecular Psychiatry, advanced online publication, 2024).

MDMA

Unlike ketamine, talk therapy will likely be required as part of MDMA treatment if MDMA is approved for patients with PTSD. The most recent Phase 3 clinical trial led by researchers at UCSF included three 90-minute preparatory talk therapy sessions before the first dosing and a 90-minute therapy session after each dosing. The participants received MDMA once a month for 3 months, and more than 90% had comorbid major depressive disorder.

“It was remarkable to see how the PTSD and depression scores plummeted after the treatment,” said Jennifer Mitchell, PhD, lead author of the study and a professor in the departments of neurology and psychiatry and behavioral services at UCSF. More than 71% no longer met the criteria for PTSD diagnosis, compared with 48% for the placebo group. The MDMA-assisted therapy also significantly decreased symptoms of depression (Nature Medicine, Vol. 29, No. 10, 2023).

About a third of people with PTSD also suffer alcohol use disorder (AUD), and researchers are also exploring whether MDMA-assisted therapy could help this dual diagnosis population. “This patient group seems to be more severe, with high rates of self-harm, suicide, and other crises,” said Christy Capone, PhD, a clinical psychologist at Brown University who is involved in a new MDMA study for these co-occurring conditions. “I’ve also worked with a lot of veterans who are disillusioned with the prescribed medications and stopped taking them.”

There are currently no FDA-approved medications to treat PTSD and AUD concurrently, so patients are prescribed different drugs that treat each disorder. Clinical trials for substance use disorder treatments often exclude participants who have comorbidities because the dual diagnosis can be a confounding factor, said Carolina Haass-Koffler, PharmD, PhD, one of the lead researchers for the new study and an associate professor of psychiatry and human behavior at Brown University. The investigators, including clinical psychologist Erica Eaton, PhD, of Brown University, will study how MDMA-assisted therapy affects AUD and PTSD as well as neuroinflammation, white matter integrity, and functional connectivity between the prefrontal cortex and amygdala.

Psilocybin

Though MDMA is further along in the FDA review process, there has also been an explosion of research on psilocybin in the last several years. The largest Phase 2 trial to date suggested a 25-mg dose of psilocybin with psychotherapy before and after the dosing was associated with a rapid and sustained antidepressant effect, measured by a change in depressive symptom scores (Raison, C. L., et al., JAMA, Vol. 330, No. 9, 2023).

“We need this as an option for patients because the current pharmacological treatments don’t work for everyone and are not well tolerated by many people,” said Alan Davis, PhD, director of the Center for Psychedelic Drug Research and Education at The Ohio State University. The current medications for depression can include sexual, mood, weight, cognitive, and other side effects, and it often takes weeks or months of trial and error with different medications to find something that may or may not be effective. Psilocybin has a much more favorable side effect profile: transient headache, which can be treated with over-the-counter medications, and mild to moderate transient anxiety.

Davis has also found that psilocybin can reduce symptoms of racial trauma, such as depression and anxiety, in diverse populations. People of color who participated in a recent study reported reductions in racial trauma symptoms as well as reductions in alcohol and drug use after psychedelic experiences (Haeny, A. M., et al., Journal of Substance Use and Addiction Treatment, Vol. 149, 2023).

Psilocybin also has the potential to help people quit smoking. In a recent study at Johns Hopkins, participants who received one dose of psilocybin followed by CBT showed higher rates of smoking abstinence than those who received a nicotine patch and CBT. “Oftentimes people feel more energetic and optimistic for a week or two after the dosing, and this is a crucial period that allows them to reset and stop smoking,” Garcia-Romeu said. “People sometimes have experiences that are terrifying, like a sense that they are dying or going crazy, but this can also be important fodder for productive conversations in a therapeutic relationship.”

After seeing the growing evidence that psilocybin may help people with a variety of mental health disorders, Christopher Pittenger, MD, PhD, director of the Yale Program for Psychedelic Science, was curious if people with obsessive-compulsive disorder (OCD) could benefit from the compound. He and his colleague, Benjamin Kelmendi, MD, launched a controlled long-term study of a single dose of psilocybin for treatment-resistant OCD. The participants received psychological support before, during, and after the dosing session. Preliminary results suggested that half of the patients experienced benefits. “The people who improve typically tell us that while the obsessions are still there, they do not bother them as much,” said Pittenger. Kelmendi presented the preliminary findings at the annual American College of Neuropsychopharmacology conference in 2023.

“Psilocybin seems to universally have a beneficial effect for a variety of mental health conditions,” Davis said. “In the next 5 years, it may be possible that a clinic providing psychedelic-assisted therapy could help people with substance use, depression, PTSD, and other conditions all in one setting.”

Though psilocybin is showing promise for a growing list of conditions, one researcher recently discovered a surprising factor that affected outcomes when the substance was used in an experiment that tested fear memories, which are relevant to understanding PTSD. In the study, adult male and female rats were trained to associate a tone with an electric foot shock. The next day, some of the rats received psilocybin and others received a control substance, and then the rats learned that the tone no longer resulted in a foot shock. In male rats, psilocybin increased the rate of fear extinction compared with the control group, but the opposite was true for the female rats. “We were surprised that in females, the drug slowed the rate of fear extinction and led to greater fear compared to controls,” said Phillip Zoladz, PhD, a psychology professor at Ohio Northern University. He presented the findings in November 2023 at the annual meeting for the Society of Neuroscience. “Nobody has been looking at the sex differences in psilocybin, and we need to take that into consideration in clinical trials of the drug.”

The role of therapy

While the results are encouraging, Mitchell said it is important for the public to recognize that the partnership between the patient and a savvy care team was a critical aspect of the experience in the clinical trial.

“Psychedelics have a tendency to stir the pot emotionally and cognitively, and therapists can help people process what they are feeling,” said Mitchell. “If patients are confronted with something dark about themselves, they need trained providers to create an environment of love and protection.” Rape victims or war veterans, for example, may have memories that are patchy, and when they revisit the memories while taking MDMA, they may feel shame, blame, or embarrassment. “The therapist can help patients reprocess the memories and encode them differently,” Mitchell said.

Mitchell’s team also worked to create a participant pool that was diverse, with more than 24% participants who were Hispanic or Latino. “We do not want this to be a drug [exclusively] for the White upper-middle class,” she said. If the FDA approves MDMA-assisted therapy, she hopes health insurance providers will explore ways to cover the cost. In her most recent Phase 3 study, the cost was $12,000 per participant, which did not include the cost of training the health care providers.

It is also critical for clinicians to allow people to find their own meaning from a psychedelic experience by asking questions rather than interpreting for them. “These sessions can be one of the most meaningful experiences people have in their lives, and I cannot overstate the importance of staying metaphysically neutral,” said Matthew Johnson, PhD, senior researcher at the Center for Excellence for Psilocybin Research and Treatment at Sheppard Pratt, a psychiatric hospital in Baltimore, Maryland. “We should not push any particular religious beliefs or fall into the trap of being seen as a guru revered by the client.”

Though Johnson is adamant about the need for caution, he is eager to increase awareness about the potential benefits of psychedelics for people who are suffering from a variety of conditions. He remembers one participant in a study who could not quit smoking, and she would sit on an air conditioner in the backyard to hide from her family when she smoked. During a psilocybin session, she imagined herself as a vine growing into the sky—a life force that chose to grow and flourish.

“She came to an understanding that smoking was not intrinsic to who she was,” he said. “She was far more special, and the behavior was not core to someone who chooses to live and be healthy.” She also received CBT as part of the treatment to help her build on the realizations she had during the trip, and she quit smoking. “I have seen how psychedelics can transform the internal narrative and motivational level,” he said. “It is powerful to work with people who are astonished that they can actually make changes that seemed impossible.”

Original article: https://www.apa.org/monitor/2024/06/psychedelics-as-medicine

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