My last psychedelic update was nearly 2 years ago and at that time there was a sense that FDA approval for psychedelics like psilocybin was inevitable. Here we are in 2021 and there’s still a lot of excitement and astounding interest in using psychedelics to treat mental health conditions. Financial entities have rushed in with at last count 38 publicly traded companies hoping to patent older drugs exclusively and make profits. All the major universities have now established psychedelic studies. Among my patients, there is an incredible hunger for new treatments due to the limitations of the current antidepressant medications. The early studies have shown benefit in conditions such as PTSD and cancer related distress but new questions without current answers have arisen in the last few years and need to be figured out before we enter this new psychedelic space. In this article, I will offer an overview of where things stand in our current research and what the major challenges are in moving forward.
Since 2000, there have been several small academic studies on psychedelics with 1000 subjects in total using the “setting approach”: a psilocybin session lasts 6-10 hours in a comfortable environment with 2 facilitators and the patient laying on a couch, wearing an eye mask and headphones with music to set the emotional tone. How can something you take for 6 hours help you feel still feel better 6 months later? The answer is we still don’t know but we believe that the psychedelic allows many parts of the brain a voice that are usually kept silent and results in profound experiences. Within a psychedelic session, there are 2 long term benefit predictors of a “sudden gain”: 1) if the subject has a mystical experience which helps her feel a sense of purpose and more connected to the world, God, and life, 2) if the subject goes through an emotionally difficult experience during the session and rather than push the feelings away, the person faces it, accepts it and feels better. When a person is depressed, there is an unwillingness to remain in contact with uncomfortable private events by escaping or avoiding these experiences—termed experiential avoidance (EA). There was a British study that showed that when after using psilocybin, people faced painful feelings (i.e. reduced their EA), they became more psychologically flexible and undepressed. The psychedelic is a pharmacologic agent when used in a psychotherapy environment allows people to have sudden gains with new insights that can have long lasting benefits for anxiety and depression. This is a bit different than how standard antidepressants work which is to help a person not experience negative feelings as painfully as negative thoughts fade out but there is a good chance a person will relapse after stopping the antidepressant.
Here’s where the story gets complicated. It may be a mistake to assume that if psychedelics produce long-term benefits after single/double dosing for some states of anxiety and depression, they will do this for all such states. For example, in the studies with psilocybin for cancer related distress or the MDMA studies for Post Traumatic Stress Disorder, subjects remained in remission even 4 years later as the psychedelic agent helped fix the acute problem the person was struggling with. However, in chronic conditions such as Major Depressive Disorder, treatment resistant depression, or generalized anxiety disorder, will a single/double dose of a psychedelic be effective long term? We don’t know and in truth there has only been one small study published to date by Imperial College (London, UK) with 20 patients with treatment resistant depression who received 2 doses of psilocybin. Half of the patients were in remission at Week 5 but the positive effects wore off over time so by 6 months only 30% were better. Interestingly, this study was made into a one hour documentary called, Magic Medicine, that you can watch for free on YouTube. This movie followed 3 of the male patients in the study, none of whom had a good outcome. A second study from Imperial College comparing 2 doses of psilocybin with Lexapro (SSRI antidepressant) was published earlier this year showed psilocybin just as effective as Lexapro after 6 weeks but larger and longer trials are still needed. For now, the take home message could be that psychedelics may be most effective with longest duration of action in single/acute problem conditions, but less effective and with shorter length of benefit for chronic conditions like treatment resistant depression. At this point, the FDA is more focused on a psychedelic indication for chronic conditions and the appropriate studies still need to be done.
Current development efforts for chronic treatments are focused on single or at most time-limited dosing strategies based on the assumption that they will have very long-term efficacy in these conditions. What if these medicines work, but don’t work “forever”? There are different ways of approaching this issue. Perhaps they could be used as “single opportunities” to be used to jump start psychotherapy. Another option would be to set a time limit on how often dosing can occur. That raises the question if there was a decision to re-dose every 6 months but the person relapsed after 3 months, do we deny the person more frequent treatment who is depressed and suicidal? Of course not. Would we be willing to re-dose an indefinite number of times upon clinical relapse? What if multiple dosing turned out ineffective compared to the initial dose? We don’t have the answer to these questions yet and we also don’t know if psychedelic agents are viable over time without the psychotherapeutic support. The other issue is the cost of delivery with the longer acting psychedelics like psilocybin and LSD that require 6-10 hour therapy sessions versus shorter acting psychedelics (like 5-Meo-DMT which is one hour); the latter would obviously be more efficient and probably be the standard of care.
As you can see, there are still quite a few things that need to be figured out. Nonetheless, psychedelic treatment may provide significant benefit for chronic, recurrent, and/or previously treatment-resistant mood, anxiety, and substance use disorders but how to optimize this benefit is currently unknown. A key question is whether treatment of these disorders with psychedelics will be best optimized by repeat dosing or provision of significant therapeutic support to cope with loss of acute effects. Psychedelics may be novel, game-changing interventions for mental health but for us to be sure of that a lot of work still needs to be done.
Finally, please keep in mind, despite underground treatment with psychedelics in the U.S, psychedelics are still illegal in the U.S.—even in Denver or Oregon. There is only one agent, ketamine, which is really a semi-psychedelic, that is legal in the U.S. However, there is a way to have legal psychedelic experiences abroad such as in Mexico, the Netherlands, and Jamaica that are reputable but very expensive. I would also keep an eye on Oregon which passed Psilocybin Measure 109 last year and will go into effect in 2023; this will allow psilocybin to be used legally but dispensed by a therapist who has special training to use the psychedelic clinically under medical supervision—this initiative may serve as a model that other states can follow in the coming years.