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Hello. I’m Dr. Sydney LeFay, a consultation-liaison psychiatrist. Today, we will discuss one of the most compelling topics in psychiatric practice: The therapeutic use of psychedelic compounds. The recent surge of interest in psychedelics can be overwhelming, and often, fundamental questions are overlooked. What benefits do psychedelics offer, and how do they work? What implications does research on psychedelic compounds have for the future of psychopharmacology?
Psychedelics have been used for millennia for various purposes, but they carry stigma as illicit substances in contemporary times. Many people hold strong beliefs and biases about psychedelics, leading to confusion. The American Journal of Psychiatry published a review providing fundamental insights into psychedelic compounds, their mechanisms of action, and their potential role in developing novel therapeutics. It is crucial to understand what constitutes a psychedelic. This paper defines a psychedelic compound as one that induces an LSD-like state in humans and acts as an agonist at the 5HT2A receptor. It’s noteworthy that dissociative anesthetics, like ketamine or phencyclidine, as well as entactogens, like MDMA, do not fit the definition of a psychedelic compound despite being psychoactive. Even with this precise definition, psychedelics encompass a broad array of substances, including psilocybin, ibogaine, mescaline, and DMT, to name a few.
This paper does not delve into every compound and its potential therapeutic uses; indeed, it doesn’t aim to. The only conditions explored in detail are anxiety and depression, yet numerous trials are underway for trauma-related disorders, obsessive-compulsive disorder, and substance use disorders. This represents a significant but understandable limitation. However, by grouping these compounds and broadly describing their common mechanisms, the paper provides a valuable framework for understanding how they function.
The paper focuses on the mechanism of action at the 5HT2A receptor, a key target in psychopharmacology. Our atypical antipsychotics block this receptor. Research shows that blocking 5HT2A receptors inhibits psychedelic effects. This has been demonstrated with both LSD and psilocybin. Psychedelic drugs bind to 5HT2A receptors, activating G proteins and leading to changes in genetic transcription. Evidence also suggests that psychedelics promote neuroplasticity through the TrkB receptor, the receptor for brain-derived neurotrophic factor (BDNF), and Kalirin-7 signaling. This might explain their effect on depression. Enhancement of neuroplasticity through BDNF is also a proposed mechanism for the benefits of ECT. The primary therapeutic role of the 5HT2A receptor in psychedelics remains a subject of debate. Trials with selective 5HT2A antagonists like pimavanserin may offer further insights. Recent work with 5HT2A agonist compounds in mice shows antidepressant effects without psychedelic experiences. However, human studies on this are yet to be conducted.
Recent phase 2 placebo-controlled trials in humans of psilocybin and LSD, combined with psychotherapy, have shown promising rapid reductions in symptoms of anxiety and depression. It’s intriguing to see many 5HT2A agonists improving depression while existing drugs like mirtazapine, tricyclic antidepressants, and antipsychotics like brexpiprazole, potent 5HT2A antagonists, have different effects. Chronic antidepressant treatment has been found to downregulate 5HT2A receptors. More discussion on reconciling the antidepressant effects of 5HT2A agonists with the widespread use of 5HT2A antagonist therapies would have been beneficial.
The authors also discuss the off-target effects of psychedelics. Psychedelics activate multiple neurotransmitters and receptors, including dopamine, serotonin, and noradrenergic receptors, particularly D1 and D2 receptors. The paper references these receptors but does not address specific risks for patients with a history of psychosis or those taking dopamine-blocking agents. It highlights lesser-known concerns about psychedelic activation of 5HT2B receptors, implicated in the development of valvular heart disease with compounds like MDMA and ergot derivatives. Though direct studies on psychedelics and these risks are lacking, it’s crucial to consider these potential effects in patients chronically microdosing psychedelic compounds. There is insufficient data to recommend microdosing, and safety concerns warrant caution.
In summary, this review clarifies that psychedelics are psychoactive compounds that induce an LSD-like state and act as agonists at the 5HT2A receptor. This action leads to a cascade of molecular effects, including promoting neuroplasticity via the TrkB receptor and Kalirin-7 signaling.
We are still in the early stages of understanding the therapeutic mechanisms of psychedelics and their relation to psychiatric diagnoses and existing therapeutics. Psychedelics offer an exciting template for future therapeutics, but current data do not support chronic use, such as through microdosing, due to potential valvular cardiac risks. In my practice, I advise patients, especially those with cardiovascular risk factors, against chronic microdosing. I eagerly anticipate future research on 5HT2A agonist therapies, which may provide a safe way to harness the efficacy of psychedelic therapeutics.
Abstract
Psychedelics as Transformative Therapeutics
Bryan L Roth, Ryan H Gumpper
Over the past decade, psychedelic compounds have emerged as potentially transformative therapeutics for a variety of intractable neuropsychiatric conditions. However, historically most of the basic science has utilized these compounds as probes to interrogate various endogenous neurotransmitter systems-mainly the serotonin 5-HT2A receptor. With the renewed interest in utilizing these compounds as therapeutics and the explosion in clinical trials, psychedelics have been purported to treat many neuropsychiatric disorders, including depression, cluster headaches, migraines, anxiety, and obsessive-compulsive disorder. It is therefore imperative to understand the biology and pharmacology behind their therapeutic mechanisms as well as expose any potential pitfalls in their widespread use as treatments. This review covers the latest advances in understanding the biological mechanisms, the newest efforts in drug discovery, and potential pitfalls when it comes to utilizing this class of compounds as emerging therapeutics.
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Reference
Roth, B. L., & Gumpper, R. H. (2023). Psychedelics as transformative therapeutics. The American Journal of Psychiatry, 180(5), 340–347.
