Psychedelic-Assisted Therapy as Treatment for Mental Disorders

Meg Seymour, PhD

The term “psychedelic” refers to a type of drug that affects mood, thought, and perception.1 People who take these substances often do so because they are hoping for “mystical” experiences, feelings of insight, or even hallucinations.1,2 What is known and not known about the risks and benefits of these drugs?

Researchers in the mid 20th century began testing the psychological effects of these consciousness-altering drugs, but that research was stopped for various reasons, particularly legal restrictions.3 More recently, since the mid 2000s, researchers have begun studying these drugs again, in order to test whether they could be used as psychiatric treatments.3 Because of how psychedelic drugs change chemical processes in the brain and because of their psychological effects, researchers have been testing whether they can safely help treat mental disorders. The research and the results are very preliminary, and studies need to be better designed to determine the risks and benefits of these drugs.

What are called “classic” psychedelics, such as psilocybin, LSD, and DMT (each described below) affect a particular serotonin receptor in the brain.1 Serotonin is involved in mental disorders such as depression,4 so researchers have been testing whether these drugs can safely help people suffering from depression. 

This article will describe some of the key research on the therapeutic properties of psychedelic drugs when used in a medical setting and their potential risks and benefits for specific mental disorders. When reading about these studies, it is important to remember that the studies were done in carefully controlled clinical settings where patients were screened to reduce the chance of negative or harmful side effects. This article is intended to describe the research on these drugs, and the results are likely to be different than they would be if these drugs were used outside of a controlled and supervised clinical setting.  

Psilocybin

What is Psilocybin?

Psilocybin is the psychedelic chemical in “magic mushrooms.” Clinical research has shown that people who take psilocybin report experiences such as a positive mood, visual effects, insight, feelings of awe, meaningfulness, and mystical experiences, although there can also be feelings of fear or anxiety and an increase in blood pressure or nausea.5,6  One clinical study found that a year afterwards, participants who took psilocybin (compared to another, non-psychedelic substance) reported that the mystical experience they had from the drug was one of the most meaningful and spiritually significant experiences of their lives.7        

As mentioned above, psilocybin affects a particular type of serotonin receptor in the brain.1 Because serotonin is involved in depression, scientists decided to test whether psilocybin could act as an antidepressant.8 

What Does the Research Show? 

The U.S. Food and Drug Administration (FDA) has expedited the review of psilocybin for Major Depressive Disorder and for treatment-resistant depression, which is depression that has not responded to antidepressant medications.9 The studies that have been done so far are small. For example, a 2020 clinical trial studied 24 patients with Major Depressive Disorder.10 Patients received at least 18 psychotherapy appointments, including 2 where they were given psilocybin before engaging in the therapy. Patients were provided with therapy before, during, and after their treatment with psilocybin. There were no serious adverse events in response to the drug, although some participants reported headaches and other side effects, and many reported feeling like crying. Most patients in the study had a clinically significant reduction in their depression when measured at a follow-up 4 weeks after their psilocybin-assisted therapy sessions. There was no control group of people who had psychotherapy without psilocybin; instead, the researchers randomly assigned the patients to receive the psilocybin-assisted therapy at different times (half of the participants began their psychotherapy 8 weeks after the others did) in order to determine any improvement in depression symptoms that occurred 1 and 4 weeks after completing the psilocybin-assisted therapy.

In even smaller, less rigorous studies, psilocybin has also been tested as a treatment for alcohol addiction, as well as for Obsessive Compulsive Disorder (OCD).11

If psilocybin-assisted psychotherapy is effective, what is the most likely explanation? In addition to the connection with serotonin (mentioned above), psilocybin affects how people think, which might help them process their emotions and troubling thoughts. For example, psilocybin may help people become accepting of their emotions and become open to new ways of thinking.12

Researchers have cautioned people to not draw conclusions based on these small studies because they were not well designed to determine the impact of the psilocybin itself. For example, since the patients had therapy sessions before, during, and after they took psilocybin, it is not possible to entirely separate the effects of the psilocybin from the effects of the therapy sessions. Moreover, depression is a disorder that can get better or worse over time regardless of treatment.12 Larger, better designed clinical trials are needed to help determine the specific effects of the psilocybin treatment.

LSD

What is LSD?

LSD is the common name for the laboratory-synthesized chemical “Lysergic acid diethylamide.” The chemical is another “classical” psychedelic, meaning that it affects a particular serotonin receptor in the brain.13

There have been some clinical studies into psychiatric uses for LSD, such as LSD-assisted psychotherapy for people with anxiety due to having a life-threatening disease. The participants in those studies reported feeling a distorted sense of time, a distorted sense of the size and shape of objects, visual hallucinations, seeing their problems from a new angle, and a loss of a sense of “self.” These sensations can cause be positive or negative, resulting in positive feelings of euphoria or make people feel anxious or distressed.13,14 

What Does the Research Show? 

A 2015 study compared the long-term effects of LSD compared to a placebo on anxiety for people with life-threatening diseases, such as cancer.14 All 10 patients received 6-8 sessions of talk therapy over the course of 3 months, and some received LSD during 2 different sessions, whereas others received a placebo. Like with the psilocybin research described above, patients received therapy before, during, and after their treatment with the drug (or placebo). Most patients who received LSD showed a reduction in their anxiety following treatment, and this reduction in anxiety was still present when the researchers followed up with the patients a year later. The patients also reported positive feelings, such as increased openness and a deeper sense of “awareness.” There were no serious adverse events reported,13 however, some people who take LSD report a slight increase in blood pressure and heart rate, so it is recommended that people with cardiovascular disease do not participate in these studies or consider taking LSD.14

It is very important to note that these clinical studies were done in a very controlled setting, and there may be considerably more negative side effects in other settings.13 

Other small, randomized, controlled clinical trials have suggested that LSD might be helpful for the treatment of other mental health problems, such as alcoholism.13 However, larger clinical trials with a greater range of patients are required to fully understand if LSD has therapeutic potential.  

Ayahuasca

What is Ayahuasca?

Ayahuasca is a brew made of plants, including the classical psychedelic chemical dimethyltryptamine (DMT), as well as a monoamine oxidase inhibitor (MAOI), which is a type of chemical that is in some older FDA-approved antidepressant medications. As a classical psychedelic, DMT affects certain serotonin receptors. This means that drinking ayahuasca affects various brain chemicals implicated in depression. Research has shown that ayahuasca affects blood flow in regions of the brain responsible for regulating moods and emotions.15 That is why ayahuasca has been tested as a potential antidepressant treatment. 

What Does the Research Show?

A small 2019 study found that ayahuasca has fast-acting antidepressant effects.16 Researchers randomly assigned 29 patients with treatment resistant depression to receive either ayahuasca or a placebo drink (designed to look and taste like ayahuasca but not containing any psychedelic chemicals). The patients’ depression was measured 1, 2, and 7 days later. Those given ayahuasca showed significantly less severe depression than those given the placebo the day after treatment, and over half of the patients given ayahuasca were still significantly less depressed when measured 7 days later. Although this study suggests that ayahuasca may produce an antidepressant effect quickly, more research is needed in order to see how long-lasting the effect is. 

However, although the patients given ayahuasca showed more improvement in their overall depression than those given the placebo, there was no significant difference between the 2 groups with respect to suicidal feelings.17 Also, although no serious adverse events were reported in the study, most of the patients given ayahuasca reported nausea, and over half of them vomited. 

As with the other drugs discussed in this article, it is important to note that the study described was done under carefully controlled clinical settings. The MAOI chemical in ayahuasca can interact with some medications, so patients are screened before studies, and researchers decide whether or not it is potentially safe to include them in a study. Overall, there has been little clinical research done on the therapeutic effects of ayahuasca, which is why larger studies are needed to further explore its impact on depression and the extent they outweigh the very unpleasant side effects, as well as any other potential therapeutic uses.  

MDMA

What is MDMA?

MDMA, often called “ecstasy” or “molly,” is not a classic psychedelic drug like the ones described above. However, it is occasionally referred to as a psychedelic because it is a mind-altering substance.18

MDMA causes the brain to release the chemicals serotonin, dopamine, and norepinephrine.19 The drug can cause feelings of euphoria, openness, feelings of being connected to others, and it causes attention to shift to positive things and decreases negative feelings. However, it can also cause negative side effects such as muscle cramps and teeth clenching.20 Because MDMA decreases the effect of negative feelings and increases feelings of openness, MDMA-assisted therapy has been tested as a treatment for PTSD. The idea is that the effects of MDMA will make it easier for patients to process the negative and traumatic memories that they would otherwise avoid or feel overwhelmed by.

What Does the Research Show?

A 2019 study combined the results of six randomized, double-binded, controlled clinical trials examining the effects of MDMA-assisted therapy for PTSD patients.21 One hundred and five patients received 3 90-minute talk therapy sessions, followed by 2 or 3 8-hour therapy sessions where they were randomly assigned to receive an active dose of MDMA or a “control” of either a placebo or a low dose of MDMA. All patients also received 3 or 4 additional 90-minute talk therapy sessions following those 2 or 3 treatment sessions. This means that all patients received therapy sessions before, during, and after their 2 or 3 treatments with MDMA (or the control). 

Patients who received active-doses of MDMA showed a statistically significantly greater reduction in PTSD severity, compared with those in the control groups. At a follow-up 1 to 2 months following treatment, 54% of the patients who received an active-dose of MDMA no longer met the criteria for a diagnosis of PTSD, more than twice the percentage of those in the control groups. In a 2020 follow-up study, the patients who had been in the control group in the original study were also given MDMA-assisted psychotherapy.22 Then, the follow-up study examined patients who had all received MDMA, comparing their outcomes from soon after treatment to approximately 12 months after their treatment. At the end of treatment, 56 of 100 participants no longer met the criteria for PTSD diagnosis. The researchers were able to follow up with 91 of those patients after 12 months, and 61 of 91 of patients no longer met the criteria for diagnosis. That means 67% patients studied no longer were diagnosed with PTSD after 12 months, compared with 56% soon after completion of treatment.

Double blind clinical trials are considered the most scientifically solid, but in this case blinding could have potentially been compromised because adverse events were more common in those receiving the active dose of MDMA. Those adverse events included symptoms such as anxiety, dizziness, headaches, and nausea. One patient who had a history of suicidal feelings was admitted to the hospital for suicidal feelings 13 days after treatment. The feelings could have been caused by the drug, or could have been caused by the patient processing traumatic memories during the therapy. No patient reported any long-term serious harms.21 The patients in the studies who received active-doses of MDMA only received 2 doses of the drug, but research has shown that heavy use of the drug may lead to depression, memory problems, and impaired impulse control.19 It is therefore important to determine if MDMA has long-term benefits that do not require more than 2 doses.

The FDA has used an expedited review pathway to consider MDMA-assisted therapy for the treatment of PTSD. Phase 3 clinical trials of MDMA-assisted therapy for PTSD are currently underway and are expected to be completed by late 2021, and reviewed by the FDA in 2022.23 The studies involve patients undergoing MDMA-assisted therapy at special clinics administered by trained clinicians, so if the treatment is approved, patients would only be able to access MDMA-assisted therapy under those same conditions.

For more information about treatments for PTSD, you can read this article.

A Word of Caution

All of the drugs in the studies described above were administered by trained clinicians and most of the studies have been conducted in the context of psychotherapy. For example, the researchers who study MDMA-assisted therapy believe the drug is helpful because it is taken alongside talk therapy, where the psychological effects of the drug, such as increased openness, can help enhance the process of psychotherapy.24 The drugs themselves could have very different effects if taken in a different setting and should not be seen as a sort of panacea or “magic cure.”25

All of the drugs described in this article have been studied in controlled, clinical trials, and these drugs are expected to have more risks and would likely have fewer psychological benefits if taken at home as a sort of “DIY therapy.” Moreover, in most cities in the United States, these drugs are illegal to possess outside of a medical setting. Additionally, the drugs given during the clinical trials were “pure” versions of the drugs, whereas many illegally purchased drugs contain impurities and additives that can make them dangerous. 

The Bottom Line

None of the drugs discussed in the article are currently FDA-approved for use as psychiatric treatments. Someone who is interested in trying psychedelic-assisted therapy would need to register for a clinical trial.

More research on a larger number of patients is needed to determine which of these psychedelic drugs are more effective than placebo when combined with psychotherapy. The “classic” psychedelics discussed (psilocybin, LSD, and DMT/ayahuasca) can cause very unpleasant side effects but are not considered life-threatening or addictive.1 However, the studies described did not include patients with psychotic disorders, such as schizophrenia, or a family history of psychosis, because there is a potential risk that the drugs could lead to a psychotic episode in someone with those risks.26 In contrast to the other drugs described in this article, MDMA is chemically different, and there is more of a potential for abuse.26

Researchers do not know for certain why psychedelic-assisted therapy seems to have a therapeutic effect for some patients. The exact psychological and neurobiological mechanisms are still unknown.27 One hypothesis is that the drugs, when combined with psychotherapy, can help people become more accepting of their feelings and experiences. It is important to note that there is no evidence that these drugs are cures for mental disorders. Keep in mind that these drugs have been studied as treatments in clinical settings only, and taking these drugs outside of a clinical setting is not a medical treatment, nor is it advised, either scientifically or legally.

Psychedelic-assisted therapy is an emerging, experimental field of research. Although this article is based on the latest and most quality research, this information may be subject to change when phase 3 clinical trials are completed and new data are released. 

All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff.

The National Center for Health Research is a nonprofit, nonpartisan research, education and advocacy organization that analyzes and explains the latest medical research and speaks out on policies and programs. We do not accept funding from pharmaceutical companies or medical device manufacturers. Find out how you can support us here.

References

  1.     Nichols DE. Psychedelics. Pharmacological Reviews. 2016; 68(2):264-355.
  2.     Davis AK, Barrett FS, Griffiths RR. Psychological flexibility mediates the relations between acute psychedelic effects and subjective decreases in depression and anxiety. Journal of Contextual Behavioral Science. 2020 Jan 1;15:39-45.
  3.     Yaden DB, Yaden ME, Griffiths RR. Psychedelics in Psychiatry—Keeping the Renaissance From Going Off the Rails. JAMA Psychiatry. 2020 Dec 2.
  4.     Something on serotonin’s role in depression 
  5.     Carbonaro TM, Johnson MW, Griffiths RR. Subjective features of the psilocybin experience that may account for its self-administration by humans: a double-blind comparison of psilocybin and dextromethorphan. Psychopharmacology. 2020; 5:1-2.
  6. Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology. 2006 Aug;187(3):268-83.
  7.     Griffiths RR, Richards WA, Johnson MW, McCann UD, Jesse R. Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. Journal of Psychopharmacology. 2008; 22(6):621-32.
  8.     Mahapatra A, Gupta R. Role of psilocybin in the treatment of depression. Therapeutic Advances in Psychopharmacology. 2017; 7(1):54-6.
  9.     Carhart-Harris RL, Roseman L, Bolstridge M, Demetriou L, Pannekoek JN, Wall MB, Tanner M, Kaelen M, McGonigle J, Murphy K, Leech R. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific Reports. 2017; 7(1):1-1.
  10. Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, Finan PH, Griffiths RR. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2020 Nov 4.
  11. United States Food and Drug Administration. Breakthrough Therapy. Fda.gov. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy. Updated January 4, 2018. 
  12. Agin-Liebes GI, Malone T, Yalch MM, Mennenga SE, Ponté KL, Guss J, Bossis AP, Grigsby J, Fischer S, Ross S. Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. Journal of Psychopharmacology. 2020; 34(2):155-66.
  13. Fuentes JJ, Fonseca F, Elices M, Farré M, Torrens M. Therapeutic use of LSD in psychiatry: a systematic review of randomized-controlled clinical trials. Frontiers in Psychiatry. 2020; 21;10:943.
  14. Gasser P, Kirchner K, Passie T. LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects. Journal of Psychopharmacology. 2015; 29(1):57-68.
  15. Riba J, Romero S, Grasa E, Mena E, Carrió I, Barbanoj MJ. Increased frontal and paralimbic activation following ayahuasca, the pan-Amazonian inebriant. Psychopharmacology. 2006 May;186(1):93-8.
  16. Palhano-Fontes F, Barreto D, Onias H, Andrade KC, Novaes MM, Pessoa JA, Mota-Rolim SA, Osório FL, Sanches R, Dos Santos RG, Tófoli LF. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychological Medicine. 2019; 49(4):655-63.
  17. Zeifman RJ, Palhano-Fontes F, Hallak J, Arcoverde E, Maia-Oliveira JP, Araujo DB. The impact of ayahuasca on suicidality: Results from a randomized controlled trial. Frontiers in Pharmacology. 2019; 10:1325.
  18. Johns Hopkins Medicine. Psychedelic Drug MDMA May Reawaken ‘Critical Period’ in Brain to Help Treat PTSD. Hopkinsmedicine.org. https://www.hopkinsmedicine.org/news/newsroom/news-releases/psychedelic-drug-mdma-may-reawaken-critical-period-in-brain-to-help-treat-ptsd. April 4, 2019. 
  19. T, B. The Effects of Ecstasy or MDMA on the Brain. Verywellmind.com. https://www.verywellmind.com/what-does-mdma-do-to-the-brain-63096. Updated July 13, 2020. 
  20. T, B. What to Know About Ecstasy Use. Verywellmind.com.. https://www.verywellmind.com/what-are-the-effects-of-ecstasy-mdma-63095. Updated March 23, 2020. 
  21. Mithoefer MC, Feduccia AA, Jerome L, Mithoefer A, Wagner M, Walsh Z, Hamilton S, Yazar-Klosinski B, Emerson A, Doblin R. MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacology. 2019; 236(9):2735-45.
  22. Jerome L, Feduccia AA, Wang JB, Hamilton S, Yazar-Klosinski B, Emerson A, Mithoefer MC, Doblin R. Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials. Psychopharmacology. 2020 Aug;237:2485-97.
  23. Multidisciplinary Association for Psychedelic Studies. PRESS RELEASE: MDMA-Assisted Psychotherapy May Have Lasting Benefits for PTSD, Results Published in Psychopharmacology. Maps.org. https://maps.org/news/media/8190-press-release-mdma-assisted-psychotherapy-may-have-lasting-benefits-for-ptsd,-results-published-in-psychopharmacology. June 10, 2020. 
  24. Ot’alora G M, Grigsby J, Poulter B, Van Derveer III JW, Giron SG, Jerome L, Feduccia AA, Hamilton S, Yazar-Klosinski B, Emerson A, Mithoefer MC. 3, 4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: a randomized phase 2 controlled trial. Journal of Psychopharmacology. 2018 Dec;32(12):1295-307.
  25. Yaden DB, Yaden ME, Griffiths RR. Psychedelics in Psychiatry—Keeping the Renaissance From Going Off the Rails. JAMA Psychiatry. Published online December 02, 2020. doi:10.1001/jamapsychiatry.2020.3672
  26. Tullis P. How ecstasy and psilocybin are shaking up psychiatry. Nature. 2021; 589(7843):506-9.
  27. Zeifman RJ, Wagner AC, Watts R, Kettner H, Mertens LJ, Carhart-Harris RL. Post-psychedelic reductions in experiential avoidance are associated with decreases in depression severity and suicidal ideation. Frontiers in Psychiatry. 2020; 11:782.