Introduction
Over the past few decades, the life sciences industry has seen renewed interest in the potential ability of psychedelic therapies to provide fast-acting, sustained benefit for mental health conditions such as depression, anxiety, and post-traumatic stress disorder (PTSD).
The medicinal and spiritual use of plant-based psychedelics, such as psilocybin, dates back many centuries. Relatively modern interest and research of their ability to aid psychotherapy for mood disorders and alcohol dependence began in the 1950s and lasted until the early 1970s when popular hallucinogens such as lysergide D-tartrate (LSD) and psilocybin (or “magic mushrooms”) were placed in Schedule I of the 1970 Controlled Substances Act (drugs with no currently accepted medical use and a high potential for abuse) in the U.S. This decision stemmed from the use of unorthodox research methods by some leading researchers of the time and increasing recreational use that was considered dangerous, despite the therapeutic promise demonstrated by many studies.
The result of the criminalization of psychedelic substances, including MDMA in 1985, on research was profound. Reduced federal funding, professional consequences, and stigma related to their use effectively ended the research in this area for decades. However, bolstered by the documented benefit during that early research, neuroimaging, psychology, and psychopharmacology studies of psychedelic compounds picked up again globally in the early to mid-1990s and helped lay the foundation for the more robust interventional studies that began in the early 2000s, especially after the publication in 2006 of what many consider to be the milestone study reviving psilocybin research.
We’ve come a long way since then, with more than 270 active studies of psychedelics on clinicaltrials.gov as of this writing, including some by biotech companies such as MindMed, Cybin Inc, Compass Pathways plc, and Transcend Therapeutics; FDA breakthrough designation granted to an LSD therapy for generalized anxiety disorder (GAD) in March 2024 based on positive phase 2 results; and a new drug application (NDA) submission to the FDA for MDMA to treat PTSD.
In this blog post, I’ll take a closer look at some of the evidence that’s been generated for depression, anxiety, and PTSD and briefly discuss where we go from here.
Types of psychedelics for therapeutic use
First, let’s review which drugs I’ll be discussing. Psychedelics typically produce an altered state of consciousness and do this via a few mechanisms of action. Regarding the drugs in this post, LSD, psilocybin, and dimethyltryptamine (DMT) belong to a class of 5-HT2A or 5-HT1A serotonin receptor agonists, affecting the pathways and often resulting in a “trip” involving vivid visual hallucinations and an altered sense of time, space, and reality. MDMA is of a class that stimulates the production of serotonin, dopamine, and norepinephrine, which can increase a sense of connection and empathy. Ketamine inhibits the N-methyl-D-aspartate (NMDA) receptors of glutamate, which strengthens the neural connections affected in depression. These drugs are of particular interest because of their potential to address the underlying causes of mental health disorders, rather than only providing symptomatic relief.
Of note, psilocybin, LSD, and MDMA remain Schedule I drugs in the United States, while ketamine can be used legally under medical supervision. However, researchers in this space have recommended that psilocybin be reclassified from a Schedule I drug to a Schedule IV drug (low potential for abuse and a currently accepted medical use) based on its potential as a mental health treatment, but with greater oversight once it clears phase 3 trials for a condition.
Benefits of psychedelics for depression and anxiety
Depression is a highly complex condition that can be challenging to treat, and the heterogeneity of treatment response often means that an individual tries multiple therapeutic options before potentially finding one that works. It can take several weeks for many traditional medications such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SRNIs) to show a benefit, and for some, the side effects (e.g., sexual, mood, weight, cognitive effects) are not tolerable. As a result, trial and error to find the best-fit medication can take weeks or months.
In addition, approximately one-third of individuals with diagnosed major depressive disorder (MDD) experience treatment-resistant depression, in which they fail to respond adequately to any of the commonly used prescription medications.
Psychedelics, especially when combined with psychotherapy, have the potential to address this treatment gap. Ketamine has the distinction of being available for use today, under supervision. It was first approved as an anesthetic and is increasingly being used at low doses and in short dosing sessions for treatment-resistant depression. It’s available in both nasal spray form and as an intravenous infusion, with multiple doses typically needed to prevent relapse of depression.
In a small study of major depression, two doses of psilocybin, paired with psychotherapy, rapidly produced large reductions in depressive symptoms for the majority of participants, with half of them achieving remission at four weeks. It has also shown promise for treatment-resistant depression, and a recent randomized controlled trial of MDD found that one dose of psilocybin (vs niacin) plus psychotherapy resulted in a rapid, sustained antidepressant effect, with significantly greater reductions in Montgomery-Asberg Depression Rating Scale (MADRS) and Sheehan Disability Scale (SDS) scores in the intervention group than the control group at 43 days.
For individuals with treatment-resistant depression, the results of an inhalable DMT-containing product recently showed its ability to significantly improve depression and anxiety scores, result in less severe depression and anxiety, and enhance quality of life, with substantial differences from placebo. More than two-thirds of the participants who received one to four treatments over a six-month period were in remission at the end of that period.
In addition, LSD-assisted psychotherapy helped significantly reduce terminal illness-related anxiety, with the effect lasting up to one year. A recent placebo-controlled study of a single dose of LSD for generalized anxiety disorder (GAD) showed rapid, clinically meaningful, and statistically significant improvements on the Hamilton Anxiety Rating Scale (HAM-A) as early as study day 2 and that were sustained for 12 weeks.
Benefits of psychedelics for PTSD
PTSD is another area with significant unmet treatment needs. Up to one-half to two-thirds of people with PTSD do not respond to first-line SSRIs, and trauma-focused psychotherapies also lack efficacy for many. This is one reason for the interest in therapies like MDMA, which has been shown to be effective for PTSD in some trials.
In a recent phase 3 trial of moderate-to-severe PTSD, MDMA-assisted therapy resulted in significantly greater decreases in Clinician-Administered PTSD Scale Clinician-Administered PTSD Scale (CAPS-5) and SDS functional impairment scores than placebo plus therapy.
Individuals with chronic treatment-resistant PTSD (mean illness duration of 19 years) benefited from MDMA-assisted psychotherapy in another pilot study, even more so than with currently available pharmaco- and psychotherapies. Of the 12 participants who received MDMA, ten clinically responded (83%) based on a 30% reduction in symptom severity on the CAPS versus only two of eight participants (25%) in the placebo group. In addition, some of the participants receiving MDMA no longer met the DSM-IV criteria for PTSD. At a 3.5-year follow-up, 74% of individuals treated with MDMA-assisted psychotherapy still had a meaningful reduction in their CAPS scores.
Additional evidence for safety and efficacy required according to regulators
Given their benefit, why do we not see more approvals of psychedelics? One of the concerns from regulators is the small study sizes, with most trials since the early 1990s considered only pilot or “safety and tolerability” studies with fewer than 25 people. However, the most recent trials of psilocybin for MDD, DMT for treatment-resistant depression, LSD for GAD, and MDMA for PTSD have involved 80-105 participants and used more robust study designs. Moreover, all the studies to date have reported no serious adverse events and tolerable side effects.
However, the FDA recently denied approval for MDMA+psychotherapy for PTSD, which would have been a landmark decision, based on the need for more evidence from another phase 3 trial and have recommended larger, randomized, multisite clinical trials for all psychedelic drugs.
Psycheledic use has been associated with persistent negative effects, such as mood fluctuations or depressive symptoms, in a small percentage of individuals using it outside of the clinical trial setting, and in uncontrolled situations, they can intensify negative emotional experiences, resulting in erratic or potentially dangerous behaviors. In addition, they are not recommended for individuals with a family history of bipolar disorder or psychotic disorders as well as those with cardiovascular conditions. So, it’s understandable that regulators believe that more data are needed to ensure that psychedelics can be implemented safely within a clinical setting.
Future directions
However, I’m excited about the potential of these compounds to offer relief and improve quality of life for individuals with mental health conditions who have not yet found a suitable, effective treatment. As we gain a better understanding of how psychedelics work in the brain and collect more evidence in studies such as those we’re conducting at Headlands Research, we move closer to achieving that first approval. Open questions that we’re working to answer include the effect of chronic antidepressant medication strategies on psychedelics’ anti-depressant effects (and how to safely discontinue existing medication), the most effective administration methods (e.g., rapid relief via inhalation), optimal dosing, and the translation of controlled care in clinical trials to real-world practice.
From there, we have the possibility to extend the benefit to individuals with substance use, racial trauma, and other conditions that tend to be comorbid with depression, anxiety, and PTSD — all in one setting—which would be a game changer for so many people.
I’ll be attending the American Society of Clinical Psychopharmacology (ASCP) Annual Meeting in Scottsdale, AZ, May 27-30, 2025. If you’re also attending, I’d love to hear what you think about the progression in psychedelic treatment clinical research and their potential future applications. Feel free to contact me in advance of the meeting, and we can set up a time to chat.