Winter 2023/2024

Changing Minds? Unlocking the Potential of Psychedelics in Mental Health Therapy

Fast Focus

Psychedelic drugs have in some ways shed their colorful pasts and proven across clinical trials their potential to effectively treat certain mental illnesses. In some cases, psychedelic treatments are already available, and in other cases they may soon gain FDA approval, meaning there is much to learn about the evolving psychedelic landscape.

What are Psychedelics?

Psychedelics are a class of psychoactive substances that produce changes in perception, mood, and cognitive processes. Psychedelics affect all the senses, altering a person’s thinking, sense of time, and emotions.

Psychedelic drugs include but are not limited to:

Psilocybin (the active ingredient of “magic” mushrooms)
Mescaline (the active ingredient found in peyote)

The Changing Landscape of Psychedelics

Traditionally perceived to be recreational party drugs, the science behind psychedelics’ medical benefits has come quite far in the last decade. According to recent clinical developments, the altered sense of thinking and feeling caused by psychedelics can lead to mental health breakthroughs when appropriately navigated by qualified clinicians.

Certain researchers believe psychedelics have the potential to change the mental health landscape, making it important to understand their relevance to workers’ comp.

Clinical Developments Across Psychedelics

Ketamine was approved by the FDA in 2019 for treatment-resistant depression1
Based on Phase 3 trials and cooperation from the FDA, MDMA will see a new drug application for the treatment of PTSD submitted by Q3 of 20232
Psilocybin is currently in Phase 3 clinical trials for treatment-resistant depression, having previously received Breakthrough Designation from the FDA in 20193
Johns Hopkins University established a center for psychedelic research in 2019, receiving a $4 million federal grant from the National Institutes of Health in 20214

By the end of this year a major psychedelic could receive FDA approval for the treatment for PTSD. These developments increase the potential for more drug approvals to come in the next few years. And while there are federal complications as most psychedelics are classified as Schedule I drugs, there is a growing wave of psychedelic decriminalization at a more local level.

Psychedelic Decriminalization

At the time of publication of this article, psilocybin alone has been decriminalized in:5

Washington D.C.
Port Townsend and Seattle in Washington
Denver, Colorado
Oakland, Arcata, and Santa Cruz in California
Somerville, Cambridge, and Northampton in Massachusetts
Detroit, Ann Arbor, and Hazel Park in Michigan

As clinical research continues to evolve, expect to see even more psychedelic initiatives proposed in the coming years.

How are Psychedelics Used in Medical Settings?

When used appropriately and under specialized medical supervision, psychedelics have demonstrated significant potential to treat mental illness. But what does this look like?

Though the details vary between different drugs, there is enough common ground in the administration of psychedelic therapy to provide a rough description of therapy.1, 6-7

Psychedelic treatment should only be legally available through certified clinicians in supervised therapeutic settings. Only after patients have received no benefit from first-line, traditional therapies can patients be considered for psychedelic therapy.

When deciding to pursue psychedelic therapy, patients must engage in several standard sessions of traditional therapy with a certified clinician to ensure a trusting therapeutic relationship. Patients are then prepped on what to expect from a psychedelic experience.

Once ready for the experience, a proper medical setting is established, designed to help patients focus internally and dive deeper into the mental processes that are causing them harm. This includes a comfortable room with a bed or couch, two therapists, and possibly a sleep mask and calming music to avoid overstimulation.

The patient is then given the psychedelic medication. Upon administration, the drug floods the brain with hormones and neurotransmitters that evoke feelings of trust and well-being. This promotes a “time-out” from the mind’s ordinary thought process, providing relief from negativity, enhancing a patient’s ability to engage in meaningful psychotherapy.

These intensive sessions last anywhere from three to eight hours, with two therapists guiding the patient carefully into a productive analysis of their mental processes and associations. Depending on the psychedelic, patients may only engage in one psychedelic experience, or possibly a few.

After the psychedelic experience(s), follow-up psychotherapy continues without psychedelics, where the patient processes emotions and insights brought up during the experience.

Ketamine: The Psychedelic That is Already Here

Ketamine is a powerful anesthetic that has occasionally been used as an analgesic. However, ketamine can also induce dissociation – the feeling of being disconnected from oneself and the surrounding world – and it is this psychedelic property that led the drug to be abused as a party drug known colloquially as “Special K.”

But in the last several years, clinical research has found ketamine’s dissociative properties to have strong antidepressant effects when properly administered. A systematic review of 83 published reports provide support for robust, rapid and transient antidepressant and anti-suicidal effects of ketamine.8

In 2019, the FDA approved intranasal esketamine spray for use in treatment-resistant depression, in conjunction with an oral antidepressant, making ketamine the only psychedelic drug legally available to mental health providers in the U.S. This drug is only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS).1

This approval was based on a series of short-term clinical trials and a longer-term maintenance-of-effect trial. In one short-term trial, patients received esketamine or a placebo nasal spray, in conjunction with a new oral antidepressant at the time of randomization. Esketamine demonstrated statistically significant effect compared to placebo on the severity of depression.1

In the longer trial, patients in stable remission from depression who continued treatment with esketamine plus an oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than placebo patients.1

Additional data has also encouraged further research into the efficacy of ketamine-assisted psychotherapy for a variety of psychiatric diagnoses including depression, anxiety, and PTSD.9

Potential Concerns

Like any drug, ketamine comes with precautions, contraindications, and the potential for adverse events. However, considering how new psychedelic therapy is, there is much uncharted territory as to what conditions, comorbidities, patient-specific factors, medications, and other matters may make psychedelic therapy unfeasible.

What is known is that ketamine may lose potency when interacting with benzodiazepines, a drug class commonly found in workers’ comp. Additionally, common side effects seen in ketamine assisted therapy include nausea, vomiting, and agitation.

However, it is crucial to remember that psychedelic therapy must be properly administered, wherein lies a new concern. Like all FDA-approved medications, ketamine can be prescribed off-label for other indications that providers deem appropriate. This has led to the proliferation of ketamine clinics across the country. Enough have popped up that the Department of Veteran Affairs now covers treatment in certain ketamine clinics.10

From 2015-2018, the number of ketamine clinics in the country rose from 60 to 300, but since the 2019 approval, there are estimated to be hundreds to thousands of clinics specializing in ketamine therapy.11

According to the Multidisciplinary Association of Psychedelic Studies (MAPS) – the research institution that has led the way on psychedelic research– a majority of ketamine clinics do not provide adjunct psychotherapy with ketamine treatment. It has also been reported that certain ketamine clinics engage in aggressive marketing and offer deliveries of ketamine – a noteworthy concern as psychedelics should be administered in medically supervised settings.10

As the utilization of ketamine therapy evolves, the need to ensure proper oversight may grow.

MDMA: Just Over the Horizon for PTSD

Methylenedioxymethamphetamine (MDMA) – known by the street names ecstasy and molly – is both a stimulant and psychedelic that produces an energizing effect that distorts time and perception and causes intense euphoria.

While illegal recreational use has been popular for decades due to MDMA’s euphoric effects, those very same effects have proven to have therapeutic value when administered in an appropriate clinical context, particularly for the treatment of PTSD.

In 2017, the FDA granted breakthrough therapy designation to MDMA-assisted therapy for the treatment of PTSD in response to positive results from Phase 2 clinical trials, agreeing that this treatment may have a meaningful advantage over available medications for PTSD.12

In one Phase 2 trial, 56% of patients treated with MDMA no longer qualified as having PTSD at the two-month mark; that percentage grew to 68% within 12 months.12

An analysis of six double-blind controlled clinical trials found MDMA-assisted psychotherapy to be efficacious and well-tolerated in a large sample of adults with PTSD.13 An additional Phase 2, double-blind, dose-response trial found MDMA-assisted therapy to be effective and well-tolerated in reducing PTSD symptoms in veterans and first responders.14

First Responders a Prime Population for MDMA-Assisted Therapy?

Due to the nature of their work, first responders such as firefighters and police officers are regularly exposed to potentially traumatic events, such as witnessing horrific injuries and deaths, making them far more likely than the average person to develop PTSD.

Presumptions for PTSD without an accompanying physical injury have sprouted across the nation, meaning workers’ comp coverage for PTSD treatment is now relatively common. Should MDMA receive FDA approval as game-changing treatment for PTSD, this unique patient population could see significant utilization.

At this time, two Phase 3, double-blind, placebo-controlled trials have been completed and are serving as the basis for a new drug application (NDA) that is expected to be submitted to the FDA at some point in Q3 of 2023.2

In both Phase 3 trials, patients who received MDMA-assisted therapy saw significant positive changes from baseline in Clinician-Administered PTSD Scale for DSM-5, as well as reduced disability scores, and a lack of adverse effects.2,15

While MDMA may require some back and forth between researchers and the FDA for additional data, as is often the case with NDAs, it is highly likely that MDMA will very soon be approved, considering the significant cooperation the FDA has had with researchers.

In fact, the FDA allowed select patients early access to MDMA-assisted therapy for PTSD in 2020, recognizing it a potentially beneficial investigational therapy for people facing a serious or life-threatening PTSD, for who current options have not worked, and who were unable to participate in Phase 3 clinical trials.16

Down the Road: MDMA as a Treatment for Schizophrenia?

In addition to ongoing research for the treatment of PTSD, MDMA will soon begin Phase 2 clinical trials for the treatment of schizophrenia.17

These trials will specifically seek to treat the asociality – impaired social motivation – symptom of schizophrenia, in the hopes of causing significant functional improvement. Though many antipsychotic medications can treat schizophrenia, deficits exist in the treatment of asociality.

Potential Concerns

While there was little-to-no report of adverse events, MDMA does come with side effects like any other drug. MDMA transiently increases heart rate, blood pressure, and body temperature in a dose-dependent manner. However, serious adverse events involving administration of MDMA in clinical trials have been uncommon and non-life threatening.12

But outside of a controlled environment, MDMA is followed by a period of neurochemical recovery, when low serotonin levels are often accompanied by lethargy and depression. Regular usage can also lead to serotonergic neurotoxicity, memory problems, sleep disturbances, lack of appetite, concentration difficulties, depression, heart disease, and impulsivity.

Additionally, outside of a clinical environment, MDMA has been linked with increased mortality when mixed with benzodiazepines, anesthetics, amphetamines and stimulants, ethanol, opioids, certain antidepressants, and other drugs.18

Psilocybin: In a Few Years for Depression?

The active ingredient found in hallucinogenic “magic mushrooms,” psilocybin is a naturally occurring psychoactive substance with mind-altering effects that include changes in perception, a distorted sense of time, perceived spiritual experiences, hallucinations, and euphoria.

While historical evidence has found that psilocybin has been used for at least 6,000 years,19 modern research has found psilocybin to have potential mental health applications when administered in an appropriate clinical setting.

In 2018, the FDA granted psilocybin-assisted therapy Breakthrough Designation for treatment-resistant depression (TRD), later granting the same designation for the treatment of major depressive disorder (MDD) in 2019, noting that psilocybin-assisted therapy may have a meaningful advantage over available medications for these indications.20-21

A Phase 2 double-blind clinical trial found that psilocybin reduced depression scores significantly in patients with TRD, with 29.1% of psilocybin participants in remission after three weeks – a higher response rate seen across equivalent lines of treatment for TRD.22

Positive results such as this have led to the launch of Phase 3, double-blind, randomized, placebo-controlled clinical trials for psilocybin-assisted therapy for the treatment of TRD.3

If psilocybin therapy continues to demonstrate significant improvements in mental health, it is possible psilocybin could see a new drug approval within a few years.

Studies so far have also shown promise for MDD. A Phase 2 randomized clinical trial found that psilocybin-assisted therapy was efficacious in producing large, rapid, and sustained antidepressant effects in patients with MDD, with a follow-up studying noting that such effects may be durable for at least 12 months in certain patients.23-24

In addition to TRD and MDD, more studies are underway to test pisolcybin’s impact on other indications, such as:25-27

Smoking cessation
Problematic alcohol use
Opioid addiction
Alzheimer’s disease
Psilocybin for Smoking Cessation

An open-label pilot study saw 12 out of 15 participants (smokers averaging 31 years of use) exhibit seven-day point prevalence abstinence at 6-month follow-up after undergoing psilocybin therapy. This exceeds smoking cessation rates commonly reported for other behavioral and/or pharmacological therapies (typically <35%).25

Current research has proven so promising that Johns Hopkins University received a $4 million federal grant from the National Institute of Health (NIH) to continue researching psilocybin’s potential to assist in smoking cessation.4

Potential Concerns

Like any drug, psilocybin comes with side effects and the possibility of adverse events. Common side effects include confusion, fear, hallucinations, headache, dizziness, fatigue, high blood pressure, nausea, and paranoia.

And with the potential for side effects such as this, comorbidities and drug-drug interactions must be considered to avoid any potential harm to patients. However, when administered in clinically appropriate settings, the potential for adverse events can be mitigated.

An evaluation by Neuropharmacology found that the abuse potential and potential harms of medical psilocybin to be low when administered according to a medical model that addresses these concerns.26 Additionally, human studies have indicated no physical dependence potential.26

In fact, Johns Hopkins University researchers recommend psilocybin be rescheduled from Schedule I to Schedule IV, once the drug clears Phase 3 clinical trials.27

How Do Psychedelics Impact Overall Care?

If psychedelics research evolves to the point of drug approvals, these medications will work their way into mainstream healthcare, and workers’ comp could see some of that activity due to its applications in behavioral health, and especially within populations that qualify for mental health presumptions.

Avoiding drug-drug and drug-disease interactions are just the start. As more research unveils the ins and outs of psychedelic therapy, the workers’ comp industry must work to keep pace with these new drug trends. Understanding how these drugs could impact an injured worker’s overall health, their injury, and the other components of their care will be important.

FDA Publishes Draft
Guidance on Clinical Trials for Psychedelics
The FDA psychedelic conversation will likely continue for some time as the FDA is working on guidance for psychedelic trial conduct, data collection, subject safety, and new drug application requirements.28


  1. FDA approves new nasal spray medication for treatment-resistant depression; only available at a certified doctor’s office or clinic. FDA. March 5, 2019.
  2. MAPS PBC announces positive results from confirmatory phase 3 “MAPP2” trial of MDMA-assisted therapy for treatment of PTSD. CISION PR Newswire. Jan 5, 2023.
  3. COMPASS pathways announces phase 3 pivotal program design for COMP360 in treatment resistant depression at capital markets day. COMPASS Pathways. Oct 12, 2022.
  4. Johns Hopkins Medicine receives first federal grant for psychedelic treatment research in 50 years. Johns Hopkins Medicine. Oct 18, 2021.
  5. Levenson MS. Where are psychadelics legal or decriminalized in the US? Leafly. Sept 2, 2022.
  6. Phillips D. Ecstasy as a remedy for PTSD? You probably have some questions. The New York Times. May 1, 2018.
  7. About psilocybin therapy. COMPASS Pathways. Accessed June 26, 2023.
  8. Walsh Z, Mollaahmetoglu OM, Rootman J, et al. Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review. BJ Psych Open. Dec 23, 2021.
  9. Doblin RE, Christiansen M, Jerome L, et al. The past and future of psychedelic science: an introduction to this issue. J Psychoactive Drugs. May 27, 2019.
  10. M. Ketamine clinics have emerged across the US. They’re already going bust. The Guardian. April 11, 2023.
  11. Bricken H. The ketamine clinic craze: legalities and possibilities. Lexology. June 20. 2022.
  12. FDA grants breakthrough therapy designation for MDMA-assisted therapy for PTSD, agrees on special protocol assessment for phase 3 trials. Multidisciplinary Association for Psychedelic Studies. Aug 26, 2017.
  13. Mithoefer MC, Feduccia AA, Jerome L, et al. 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. May 7, 2019.
  14. Mithoefer MC, Mithoefer AT, Feduccia AA. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. The Lancet Psychiatry. June 2018.
  15. Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine. May 10, 2021.
  16. FDA agree to expanded access program for MDMA-assisted therapy for PTSD. Multidisciplinary Association for Psychedelic Studies. Jan 17, 2020.
  17. Tolerability of MDMA in schizophrenia (TMS). U.S. National Libraries of Medicine. 2023.
  18. Cohen IV, Makunts T, Abagyan R, et al. Concomitant drugs associated with increased mortality for MDMA users reported in a drug safety surveillance database. Sci Rep. 11, 5997 (2021).
  19. Akers BP, Ruiz JF, Piper A, et al. A Prehistoric Mural in Spain Depicting Neurotropic Psilocybe Mushrooms? Economic Botany. (2011). 65 (2): 121–128. doi:10.1007/s12231-011-9152-5. S2CID 3955222
  20. Duffy S. Psilocybin gets breakthrough Tx designation for treatment-resistant depression. EMPR. Oct 24, 2018.
  21. Ernst D. Psilocybin designated breakthrough Tx for major depressive disorder. EMPR. Nov 25, 2019.
  22. COMPASS Pathways announces publication of phase 2b study of COMP360 psilocybin therapy for treatment-resistant depression in The New England Journal of Medicine. COMPASS Pathways. Nov 3, 2022.
  23. Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2021;78(5):481-489. doi:10.1001/jamapsychiatry.2020.3285
  24. Gukasyan N, Davis AK, Griffiths RR, et al. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: prospective 12-month follow-up. Journal of Psychopharmacology. Feb 15, 2022.
  25. Johnson MW, Garcia-Romeu A, Cosimano MP, et al. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol. 2014 Nov;28(11):983-92. doi: 10.1177/0269881114548296. Epub 2014 Sep 11. PMID: 25213996; PMCID: PMC4286320.
  26. Jones H. Johns Hopkins launches center for psychedelic research. Johns Hopkins University HUB. Sept 4, 2019.
  27. Johnson MW, Griffiths RR, Hendricks PS, et al. The abuse potential of medical psilocybin according to the 8 factors of the controlled substances act. Neuropharmacology. Nov 2018.
  28. FDA issues first draft guidance on clinical trials with psychedelic drugs. FDA. June 23, 2023.



Since 2010, the semi-annual RxInformer clinical journal has been a trusted source of timely information and guidance for workers’ comp payers on how best to manage the care of injured worker claimants and plan for the challenges that lay ahead. The publication is an important part of Healthesystems’ proactive approach to advocating for quality care of injured workers while managing the costs associated with treatment.