Selective serotonin-reuptake inhibitors (SSRIs) are first-line treatments for major depressive disorders and post-traumatic stress disorder (PTSD), but SSRIs and related therapeutics take weeks to produce therapeutic effects, if at all, and treatment resistance is not uncommon. Psychedelics and entactogens may represent the next revolution in the treatment of severe mood disorders, as they appear to be both fast- and long-acting. (Entactogens, also known as empathogens, are a class of psychoactive drugs that produce experiences of emotional communion, oneness, relatedness, emotional openness, MDMA being one typical example. These experiences are different from those produced by Psychedelics).
Currently, around 150 clinical trials are registered with Clinicaltrials.gov, using ‘classic’ psychedelics, e.g. lysergic acid diethylamide (LSD), psilocybin (magic mushrooms), ayahuasca, DMT (N,N-DiMethylTryptamine), and the entactogen 3,4-MethyleneDioxyMethAmphetamine (MDMA). Phase 2 and early phase 3 clinical studies support psychedelics/MDMA to represent a new class of rapid- and long-acting treatments for severe anxiety, treatment-resistant depression (TRD) and PTSD respectively, and possibly bipolar, substance use and eating disorders.
Psilocybin and other psychedelics, as well as MDMA, are expected to produce transformational outcomes in TRD, PTSD and beyond, for which current treatments are not satisfactory. Psilocybin has received priority status for treatment of TRD by the U.S. Food and Drug Administration (FDA), as has MDMA for PTSD. Several American states have decriminalised the use of mushrooms and psychedelics, whereas ketamine clinics are being set up by various commercial operators/clinics that will charge $4,000-6,000 per session. Sessions need to be repeated monthly to treat depression durably, meaning that money is an issue. How did all that happen?
LSD was synthesised by Albert Hoffman at Sandoz in Basel and its psychedelic effects were discovered in 1943. Subsequently, Hoffman synthesised mescaline, psilocybin and other mushroom/plant-based psychedelics. This was part of the ergolines and related compounds chemistry efforts at Sandoz, with several drugs registered to treat endocrine, mental health and other disorders.
LSD was registered in Europe/US (as Delysid) to treat mental illnesses in combination with psychotherapy between the late 1950s and the 1970s, when the US government had LSD withdrawn from the market. Events such as protests against the Vietnam war, Woodstock and the hippy movement and the May ‘68 revolution across campuses and globally, were all unacceptable to the Nixon government, which enforced a worldwide ban on psychedelics use and research.
However, LSD research never stopped, since LSD-related ergolines opened investigations into serotonin (5-HT, which was discovered in the mid 1950s) and its many receptors. Fast forward to today, LSD, psilocybin and various psychedelics are reported to act as rapid acting antidepressants in TRD, whereas MDMA shows promising effects in treating PTSD, when administered in tightly controlled clinical settings, with trained nurses, psychologists and/or psychiatrists in attendance.
LSD, psilocybin, ayahuasca and other psychedelics, modulate the Default Mode Network (DMN), a range of interconnected brain regions (the medial prefrontal and posterior cingulate cortex, the precuneus and angular gyrus), which at rest, show a pattern of increased temporal coherence. The DMN appears to be dysfunctional in various neuropsychiatric disorders such as depression, anxiety, PTSD, attention deficit and hyperactivity disorder, schizophrenia, and obsessive-compulsive disorder. The main molecular target of LSD, psilocybin/psilocyn, ayahuasca, DMT, and others, is the 5-HT2A receptor. An issue with 5-HT2A receptor agonists is selectivity, since 5-HT2A, 5-HT2B and 5-HT2C receptors share very similar 5-HT binding pockets. On the positive side, 5-HT2C agonists have antiaddictive, antidepressant and anti-obesity potential. On the negative side, 5-HT2B agonists are toxic and when used chronically, fenfluramine, benfluorex, pergolide, and MDMA (at higher doses), all cause valvulopathies and death. Hence, all registered 5-HT2B agonists were withdrawn from the market in the 1990s. However, the currently used doses in TRD are very low (LSD 100-125 micrograms) and patients will only get two active doses in a strictly controlled hospital environment a couple of weeks apart, since the psychedelics effects are very long lasting. In addition, there is both a pre- and post-trial session to ensure that patients get used to the setting, and to wrap up and evaluate the impact of treatment (typically a session lasts eight hours in hospital, in the presence of a trained nurse/psychologist/psychiatrist).
In a phase 2B trial, psilocybin 25 mg, but not 10 or 1 mg (combined with integrative psychological support sessions), alleviated symptoms of depression in TRD patients, three weeks after a single dose. 30% of the 25 mg group was considered in remission after three weeks, but not 12 weeks. A phase 3 trial is underway.
Carhart-Harris et al, in another phase 2 study with TRD patients, compared the effects of two doses of psilocybin (25 mg combined to psychological support sessions) with escitalopram (10 mg) administered during six weeks. The two doses of psilocybin outperformed chronic escitalopram in depression severity and wellbeing scales at six weeks.
In therapy-resistant PTSD patients, three doses of MDMA (80-180 mg) combined with nine integrative psychological support sessions improved PTSD symptoms over 18 weeks, when compared to placebo combined with psychological support sessions in a phase 3a study. A 2nd phase 3 study has been completed with apparently similar results, but has not been published yet.
Such trials, if replicated in large phase 3 settings, will open the way to registration in TRD and PTSD, and have the potential for approval in further indications. However, one must keep in mind that psychedelics and the likes can only be prescribed/used in a medical environment with trained healthcare professionals in attendance. The idea that psychedelics could be used freely and chronically in low doses (microdosing) is not supported by any clinical data. For that matter, there are no currently accepted toxicology/safety studies to support chronic microdosing. Once established, valvulopathies are irreversible, and bad trips can happen, hence the need for therapists to be in attendance.
This requirement, however, may change once we have new drug candidates that do not produce the classical psychedelic trip. Such psychoplastogens (like psychedelics, they stimulate brain plasticity and neuronal growth), are in early stages of discovery/development. In pre-clinical models, psychoplastogens produce long lasting antidepressant-like effects, without inducing the head twitch response, a typical behaviour produced by LSD and other psychedelics. This would solve one of the issues that may result from an FDA approval of MDMA or any psychedelic, since the FDA does not regulate the treatment aspects; by contrast, psychoplastogens may not need assisted psychological support, since they would not induce the LSD-like trip. However, the effectiveness of psychoplastogens will only be established in adequate clinical trials: animal models of depression (or PTSD) do often not translate into clinical effectiveness, as seen again recently, when the FDA rejected a neurosteroid as a rapid acting antidepressant to treat major depression disorder, although the same drug was recently approved by the FDA for the treatment of past partum depression.
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