Thirty years ago, the National Institute of Mental Health announced the “decade of the brain.”1 The institute promised that we would find the biological underpinnings of every mental illness and from that knowledge, medications would be created to address these illnesses. As a result, psychiatry began to drift away from psychotherapy and toward biology.2 While we certainly have more pharmacologic arrows in our quiver today, these treatments are only modestly effective3 and we are still far from a definitive understanding of the biological underpinnings of psychiatric illness. Yet, our society is impacted as much, if not more so, by mental illness today than it was three decades prior.

PTSD, for instance, is endemic not only in Veteran populations but in society at large, and despite the proliferation of antidepressants, depression has surpassed cardiovascular disease as the largest cause of global disability.4

Against this backdrop, a dedicated group of bootstrapped researchers has revived psychedelic-assisted therapy, begun in the 1950s but shuttered in 1970 by the Controlled Substances Act, into one of the most promising therapies of the 21st century. The FDA granted breakthrough designation to psilocybin (the active agent in so-called “magic mushrooms” which acts primarily as a 5HT2A agonist with lesser activity at other receptors) as a treatment for major depressive disorder in 2019, and the substance is now being advanced by two sponsors in Phase 2 and 3 trials.

In addition, MDMA (historically sold as an adulterated drug known as “ecstasy” or “molly”) assisted therapy for PTSD is part-way through Phase 3 clinical trials. MDMA also received breakthrough designation from the FDA in 2017.5 Full disclosure: I am involved with both of these studies in the role of a therapist and have had the opportunity to deliver this therapy and see its impact first-hand.

Could 21st-century psychiatry be a brave new world of psychedelic-assisted therapy? Many clinicians are curious about this new modality; others are apprehensive. For the unfamiliar, below is a short primer about how these therapies are similar (and distinct) from the technologies we currently rely on in the field.

A Quick Primer on Psychedelic-Assisted Therapy

The Medications

The drugs used in psychedelic-assisted therapy, namely MDMA and psilocybin, target key barriers in the treatment of the disease state. With PTSD, for example, barriers may include excessive fear and avoidance; in depression, barriers may include rumination and difficulty in shifting out of the depressed state.

Psychedelic-assisted therapy uses a drug as a catalyst for psychotherapy. Unlike typical psychopharmacology, it is not delivered without therapy as described below.

The Approach

In the current split model of care, a prescribing clinician (usually a physician or PMHNP) prescribes medication and provides brief, supportive therapy while another clinician (usually a therapist) provides psychotherapy. There may be a nonspecific promotion of the therapy via the medication but the drug is not chosen to specifically enhance psychotherapy.

The reason for this dual approach is that the therapeutic relationship – and not just the drug(s) – appears to be critical for the success of psychedelic-based treatment. Completed studies have delivered the treatment within the context of a therapeutic relationship that is established before administration of the drug and exists for integration psychotherapy in the days and weeks following the treatment.6 This relationship allows for the physical and psychological safety of the patient and enables the deepening of trust – an essential component of any psychotherapeutic relationship. It is not a “one and done” treatment.

Safety Considerations

There has been understandable concern about the potential for diversion and misuse of psychedelic drugs, which do have a history of unsupervised use. Should psychedelic therapies achieve FDA approval in the future, they are bound to be subject to a REMS program requiring that they be given only to trained clinicians for use in controlled settings, much like esketamine is delivered now. Psychedelics will likely never be available as a prescribed or take-home medication.

The Evidence for Psychedelic-Assisted Therapy to Date: MDMA and Psilocybin


MDMA assisted therapy for PTSD was shown to be more than twice as effective in Phase 2 trials compared to placebo, leading the FDA to grant “breakthrough therapy” status in 2017.5

MDMA is 3,4 methylenedioxymethamphetamine is a substituted phenylethylamine which appears to cause a significant release of presynaptic serotonin, prolactin, and oxytocin.7 This release leads to decreased activity of the amygdala and increased activity of the prefrontal cortex. The patient experiences these changes as a calm state in which traumatic memories that would ordinarily be intolerable to process, can be examined and even re-organized into a less-distressing, more manageable state.

In Phase 2/3 studies, the drug was given on three occasions, with preparatory and integration therapy woven between the drug-therapy sessions. Side effects included mild pressor effects, loss of appetite, insomnia, and transient anxiety, all of which were able to be managed without hospitalization or rescue medication. Findings demonstrated that 54% of subjects treated with MDMA no longer could be diagnosed with PTSD as compared to 23% of placebo-treated subjects.8 The study sponsor, the Multidisciplinary Association for Psychedelic Studies, is working on an interim analysis of the Phase 3 data and plans to apply for FDA approval in 2022–2023 if the results are favorable.


Psilocybin continues to be investigated as a treatment for major depression following promising results in small studies of patients with depression.9-12 Positive results were also demonstrated in studies attempting to treat anxiety and despair experienced by people with life-threatening illnesses.

The first contemporary paper on psilocybin was published by researchers at Johns Hopkins University in 2006 demonstrating that psilocybin could be safely delivered within a therapeutic context.13 Later studies at Hopkins and New York University examined the use of psilocybin-assisted psychotherapy for persons facing emotional distress related to life-threatening illness, demonstrated dramatic and enduring benefits for most subjects.11,12 Similar to MDMA, side effects were transient and included hypertension, tachycardia, and transient anxiety/paranoia that could be managed with reassurance from the study therapists. Also similar to MDMA, psilocybin was delivered after the establishment of a therapeutic relationship where there had been preparatory therapy sessions followed by integration therapy after the drug was delivered.

With the exception of one open-label trial in the United Kingdom, depression was not a primary outcome measure of these studies. However, significant improvements in secondary outcome measures of depression led to two sponsors (the Usona Institute in the US, and Compass Pathways in the UK) obtaining FDA “breakthrough status” and the pursuit of Phase 2/3 trials for major depressive disorder and treatment-resistant depression, respectively, with a goal of obtaining FDA approval in the next 5 years.

Editor’s Note: In early November 2020, JAMA published a study showing improvement in depression severity in subjects who received immediate psilocybin-assisted therapy compared with delayed treatment.

Clinical Considerations

The Default Mode Network

Psychedelic therapies may disrupt rigid thought and behavior patterns, allowing for change in the post-psychedelic state in areas that had been previously resistant to change.

While it is important to understand that MDMA and psilocybin have significantly different pharmacologic mechanisms of action, they may both act to disrupt overly stable functional neural networks.7 In depression, for example, the default mode network (DMN) – which is active when we are introspective – predominates the outward-directed task-positive network. This role may account for the phenomenon of rumination, often seen in patients with depression, and the functional impairment caused by a person with depression who is unable to focus on external tasks.

Psilocybin appears to disrupt this network, albeit temporarily, but importantly. Following the clearance of the drug, the DMN and the task-positive network are more able to shift predominance to match the demands of the environment. The brain becomes less rigid and more flexible.14 Phenomenologically, this may take the form of a patient “changing their story” about their life circumstances and developing a more adaptive narrative about previous adversity, their relationship with others, and their own capacity to overcome challenges attendant to mental illness.15 This healthier psyche is more flexible and similar to the model proposed in Acceptance and Commitment Therapy which is also being adapted to work with psychedelic therapies.16

Ketamine as a Model

The growth of ketamine as a treatment for depression creates a possible template for future psychedelic therapies. Thought to be a fringe idea a decade ago, the rapid adoption of ketamine within mainstream psychiatry provides both a glimpse of a post-MDMA or psilocybin approval landscape and provides some caution.

While a handful of providers have adapted the psychedelic therapy model to work with low-medium doses of ketamine, many clinics use this drug simply as a biologic agent, with little in the way of psychological support. In doing so, they may overlook much of the drug’s potential and subject their patients to psychological harm if the patient becomes emotionally distressed during ketamine administration without adequate emotional support. It is crucial that we do not allow this to occur with future psychedelic drugs.

Professional Takeaways

Clinicians should be aware that psychedelic therapy is labor-intensive, with most protocols calling for two therapists who spend between 24 to 50 hours with each patient. This time commitment is likely to create tensions with insurers who may balk at the upfront costs, despite the well-known long-term costs of partially treated or untreated PTSD and depression.

Additionally, there will need to be more clinicians trained in how to use this modality. It is important to understand that, if approved, psychedelics will not just be a new drug on the market. Their use will represent a true sea-change in the way we practice psychiatry, and those who provide it will need to be appropriately trained to maximize potential benefits and prevent possible harm.

However, the benefits can be life-changing. In my work with psychedelic research, it has been deeply satisfying to see patients who have felt stuck in their psychiatric symptoms for decades, to be able to shift their stories to one where they have agency, perspective, and compassion for themselves and their own experiences. I have been able to witness real healing – not just symptom amelioration. To play a small part in this kind of deep healing was what drew me to psychiatry in the first place, and it is profoundly inspiring.

More on Psychedelic-Assisted Therapy

Psycom Pro continues to cover the emergence of psilocybin, MDMA, and psychedelics in mental health care

Psilocybin Training Program for CliniciansPsilocybin & Depression

See also, Andrew Penn’s tip about imagining the future and more Practice Essentials from your peers and how to respond when clients ask to try psychedelics.

Last Updated: Jun 3, 2021