Psychedelics for Mental Illness:
The Evidence to Date

Todd Murphy

March 12, 2020

Psychedelic drugs show real promise as treatment for psychiatric illnesses, particularly posttraumatic stress disorder (PTSD) as well as depression and anxiety, new research suggests.

A literature review showed completed clinical trials support the efficacy of 3, 4-methylenedioxymethamphetamine (MDMA), commonly known by its street name of Ecstasy, to treat chronic PTSD.

The review also confirmed that psilocybin, a compound contained in some species of mushrooms, significantly helped in the treatment of depression and cancer-related anxiety.

Other promising, though more preliminary, results suggests that the hallucinogenic drug LSD (lysergic acid diethylamide) and a plant-based brew called ayahuasca may also be effective in treating psychiatric disorders.  

Senior author William M. McDonald, chair for late-life depression and professor of psychiatry and behavioral sciences at Emory University School of Medicine, Atlanta, Georgia, said psilocybin treatments might represent a completely new treatment paradigm for some types of depression.

In the clinical trials his team reviewed, the treatments weren't just "helping patients get better but actually keeping them well," McDonald told Medscape Medical News.

"The thing that's very impressive to me is that this really has the potential to provide some new treatments using some very novel mechanisms," he added about both MDMA and psilocybin.

The findings were published online February 26 in the American Journal of Psychiatry.

MDMA for PTSD

The investigators analyzed the results of 14 well-designed clinical trials that explored the effectiveness of MDMA, psilocybin, LSD, and ayahuasca for a range of disorders. This included mood and anxiety disorders, trauma and stress-related disorders, and substance-related and addictive disorders.

Some studies also analyzed psychedelic-assisted treatment in end-of-life care.

The findings revealed especially positive results in the use of MDMA for PTSD and psilocybin for depression.

In a 2011 study of MDMA-assisted psychotherapy, 23 participants who had chronic PTSD received two sessions of psychotherapy, with either the active drug or placebo.

The study measured the participants' scores on the Clinician-Administered PTSD Scale (CAPS), a commonly used assessment of PTSD in which a score of 50 or higher indicates treatment-resistant PTSD symptoms. Baseline mean scores were 79.6 for the placebo group vs 79.2 for the MDMA group.

Three to 5 days after the first experimental psychotherapy session, CAPS scores were 74.1 for the placebo group and 37.8 for the MDMA group. Three to 5 days after the second experimental session, CAPS scores were 66.8 for the placebo group and 29.3 for the MDMA group.

A full 2 months after the second experimental session, CAPS scores decreased even further to 59.1 for the placebo group and 25.5 for the MDMA group (P = .013).

In addition, a significantly greater proportion of the MDMA group (10 of 12) than the placebo group (2 of 8) met criteria for categorical response.

The study then offered all placebo-treated participants the option of subsequently receiving the active treatment, and 7 of 8 chose this option. Results showed that all seven had a significant clinical response 4 to 6 weeks after two MDMA-assisted sessions.

Short-Term Treatment, Long-Term Effects

In 2018, the same researchers conducted a study of firefighters, police officers, and military service members and veterans diagnosed with treatment-resistant PTSD.

The study randomly assigned participants (n = 26) to receive low-dose, moderate-dose, or high-dose MDMA in two psychotherapy sessions 1 month apart.

Results revealed that the moderate- and high-dose groups had significantly greater reductions in PTSD symptoms than the low-dose group. Almost all (6 of 7) participants in the moderate-dose group and 7 of the 12 participants in the high-dose group had complete remission of their PTSD symptoms. In the low-dose group, 2 of the 7 participants had remission.

Lead author Collin Reiff, MD, clinical assistant professor of psychiatry, New York University School of Medicine and NYU Military Family Clinic, New York City, specializes in treating addiction and trauma — and treats military veterans with PTSD.

Reiff told Medscape Medical News there is a high psychotherapy dropout rate among PTSD patients and they often experience significant side effects from medications used to treat the disorder.

"Based on the data I’ve seen, it looks like MDMA might be a better [treatment option]," he said.

One distinct advantage is that MDMA appears to produce improvement with very limited treatments, he added. "You don’t have to take a drug for months or years, or for life," Reiff said.

Psilocybin for Anxiety, Addiction

The review also showed positive results for the use of psilocybin for depression.

A 2016 study evaluated the effectiveness of one high dose of psilocybin plus psychotherapy in patients who had cancer-related anxiety and depression. Two thirds of the study participants (n = 29) had advanced (stage 2-4) cancer.

After treatment, the patients who received psilocybin had significant reduction (greater than 50%) in commonly used depression and anxiety scores.

Patients who received placebo had no sustained symptom reduction. However, they experienced significant improvement after crossing over and receiving psilocybin.

At approximately 6 months following treatment, 60% to 80% of participants still had a sustained reduction in depression and anxiety scores that were at least 50% lower before receiving the therapy.

"This idea of doing psychedelics-assisted psychotherapy sessions and having patients remain well for weeks to months is really enticing," McDonald said.

The researchers also found evidence from clinical trials indicating psilocybin may help with smoking cessation and substance use disorders.

The results also suggest promise for LSD in patients with anxiety related to physical disease and for ayahuasca in patients with depression.

Novel Mechanisms of Action

Some of the studies used functional magnetic resonance imaging (fMRI) to assess how the brains of participants respond to psychedelics. McDonald noted that those responses and other measurements showing how the drugs might work are especially interesting.

"These compounds have very novel mechanisms of action," he said. "They are very different mechanisms from some of the antidepressants presently used. This offers a whole new area of research."

The US Food and Drug Administration (FDA) has already taken note of the compelling results in use of MDMA and psilocybin in certain disorders.

It designated MDMA as a "breakthrough therapy" for PTSD in 2017 and designated psilocybin as a breakthrough therapy for treatment-resistant depression in 2018. Those designations give the drugs priority in the FDA regulatory process.

McDonald and Reiff said the review shows real promise for the use of psychedelics to treat some conditions. However, more research is needed before any of these drugs are made available for clinical use, they added.

"There’s a lot more research that needs to be done. We really don’t understand the abuse potential of these drugs," McDonald cautioned.

"At the same time, with the research we’ve reviewed...there’s real potential here. There really needs to be an effort to accelerate understanding these compounds and understanding their potential," he said.

"Exciting" Research

Commenting on the findings for Medscape Medical News, Matthew Johnson, PhD, associate professor of psychiatry and associate director of the Center for Psychedelics and Consciousness Research at Johns Hopkins University, Baltimore, Maryland, said the review effectively encapsulates the "promising lines of research" in psychedelics and certain psychiatric disorders.

Johnson added that the size and duration of the effects in the clinical trials summarized by the paper are exciting.

"It really is quite astonishing that you can administer a substance one or a few times under close supervision...but then see lasting large effects and clinical improvements 6 months, even a year later," he said.

However, he emphasized that ongoing exploration of psychedelics should only be conducted in research settings.

"These are very powerful compounds. They're powerful tools," he said. "Whether it's going to cause a benefit or harm is very much dependent on the context. We do know that these compounds sometimes lead to harms."

Johnson also noted that researchers must work to include a broader cross-section of the population in future studies. Minorities and lower-income individuals are underrepresented in many of the studies to date.

If more advanced research continues to show efficacy, and shows the drugs are safe if administered appropriately, Johnson said he believes they may be available for some psychiatric clinical use in the next 5 years or so.

"It’s really exciting. If results hold up, it has a potential to be paradigm-shifting in mental health treatment," he said.

McDonald has received research support from Cervel Neurotherapeutics, the National Institute of Neurological Disease and Stroke, the National Institute on Aging, NeoSync, Neuronetics, NIMH, Soterix, and the Stanley Foundation; has served as a consultant for Signant Health; receives royalties from Oxford University Press; and receives funding from the JB Fuqua Foundation. Financial relationships for the other study authors are fully listed in the original article. Johnson was an investigator for a smoking cessation study that was among those assessed in this new review.

Am J Psychiatry. Published online February 26, 2020. Abstract

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