Psychedelics: An Overdue Clinical Priority

Written by: Andy Cronin 

A Promising Future

Mental health conditions and neurodegenerative disorders increasingly stand out as areas of slow progress in developing effective therapeutic treatments. The last decade has seen a boom in cell and gene therapies and rapid advances in vaccine technology. Still, corresponding attempts to make progress in treating CNS disorders have been slow, subject to frequent setbacks and generating a long list of failed drug candidates. Mental illnesses and substance abuse disorders are among the most common ailments among Americans and severely affect our ability to function both socially and economically. During the COVID-19 pandemic, they only became more prevalent. 

Within this context, it is encouraging to see the slow beginnings of a revolution in treatment. Some of the nation’s leading centers for medical research have recently begun investigating the possible benefits of psychedelic compounds, including psilocybin, 3,4-Methyl enedioxy methamphetamine (MDMA), N, N-dimethyltryptamine (DMT), and lysergic acid diethylamide (LSD), among other plant-derived and synthetic drugs. When combined with suitable psychotherapies and administered in clinical contexts, these psychedelics show real promise as breakthrough therapies for a wide range of conditions. For example, just last year, the Multidisciplinary Association for Psychedelic Studies (MAPS) completed a Phase III clinical trial of MDMA-assisted psychotherapy for severe, chronic PTSD. Post-treatment, 67% of subjects no longer met diagnostic criteria – more than double the recoveries recorded in the control group. 

This is not an isolated incident. Because of their complex mechanisms of action, transformative effects on both brain function and conscious experience, and possible history of co-evolution with Homo sapiens, psychedelics offer real promise for confronting the most treatment-resistant psychiatric conditions. 

A Complicated History

Research into therapeutic applications for psychedelics began in earnest in the late 1940s, with both European and American labs beginning to publish work on LSD under the brand name Delysid. Over the 1950s and 1960s, the drug quickly attracted substantial attention from notable behavioral scientists and pharmacological researchers. Attitudes toward it echoed those beginning to become common today: it was understood to be safe, potent, consistently effective, and likely suitable for treating anxiety, depression, schizophrenia, wartime stress reactions, alcoholism and other substance use disorders. Interest grew in related compounds, including psilocybin and mescaline. The National Institute of Mental Health (NIMH) began funding research, as did several US intelligence agencies – leading, in many cases, to severe governmental abuse of marginalized communities. 

In 1970, however, the Nixon administration categorized LSD as a Schedule I narcotic and many other psychoactive and psychedelic drugs. In part, individual states rapidly followed suit due to the drugs’ association with the counter-culture and progressive activism. 

The result was severe repression of almost total cessation of research for close to 30 years. A slow resurgence of interest during the 1990s led to a more mainstream interest in the 2000s and onward, with the first significant imaging studies of LSD published in 2016. The current wave of interest resembles nothing so much as a rediscovery of relevant clinical considerations that were, for decades, obscured by politicized messaging. The results have been highly damaging; we are decades behind in exploring the most promising drug candidates for CNS disorders that we are presently aware of.

Recent Progress and Areas of Focus

At present, several major pharmaceutical and biotech firms are making rapid progress with both “classic” psychedelics and new drug candidates with similar formulations and targets. In addition to the treatment of PTSD, already mentioned above, another major area of focus is anxiety (including end-of-life anxiety) – an interest-driven in part by the pandemic. These new therapies remain heavily stigmatized in many circles, and regulatory progress has been justifiably slow, given the intensity of the experiences they elicit and the complexity of their effects. 

Two other areas of progress must be highlighted. The first is treatment-resistant depression, characterized by the increased risk of self-harm and severity and duration of anhedonia and other symptoms even when patients are administered high doses of multiple common antidepressants. LSD, psilocybin, MDMA, and DMT have all shown the potential for transformative and long-term effects in these cases. The details remain unclear, but this efficacy is likely related to the breadth of their neuromodulatory activity, as they affect serotonergic (5-HT), dopaminergic (DA), and glutamatergic systems. 

Another area of rapid progress is in the use of psychedelics for substance abuse disorders. Here, classic psychedelics are hypothesized to reorganize disordered elements of the default mode network and to “rewire” critical reward circuitry in the mesolimbic system. Unlike treatment with more traditional therapeutics such as SSRIs, these effects have been observed with just one or two doses of LSD or psilocybin. Given that the economic toll of substance abuse is estimated to be trillions of dollars, it isn’t easy to overstate the public health value represented by these treatments. 

However, the regulatory landscape, market outlook, and state of clinical progress are complex. We will begin to examine these aspects of the current state of play in future articles.

To discuss this topic further, we invite you to reach out to Andy Cronin.