Psychedelic Psychiatry’s Brave New World

This popular commentary article (2020) describes the current resurrection of research into psychedelics (both neuroscience and therapeutic applications). It describes the evidence for the serotonin receptor (5-HT2a) agonism (psychedelics binding to that receptor) and the possible mechanisms through which long-lasting therapeutic effects can be found.

Abstract

“After a legally mandated, decades-long global arrest of research on psychedelic drugs, investigation of psychedelics in the context of psychiatric disorders is yielding exciting results. Outcomes of neuroscience and clinical research into 5-Hydroxytryptamine 2A (5-HT2A) receptor agonists, such as psilocybin, show promise for addressing a range of serious disorders, including depression and addiction.”

Authors: David J. Nutt, David Erritzoe & Robin L. Carhart-Harris

Summary

Introduction—Why the Psychedelic Revolution in Psychiatry?

Research leading to the discovery of new drugs for psychiatric disorders has been painfully slow. Most major pharmaceutical companies have retreated from researching brain targets.

Psychedelic drugs were once used but fell out of use because of political machinations, especially the war on drugs. However, in the past decade, research on these compounds has been re-established by a few groups around the world.

Psilocybin is a Schedule 1 controlled drug that took several years to gain permission to do clinical research. It has shown remarkable effects on patients suffering from depression, and there are currently two companies funding multi-center dose-finding studies of psilocybin in depression.

Psychedelic therapy works in a wide range of disorders, and is given just once as part of an ongoing psychotherapy course. This contrasts with currently available medications, which are given at least daily, often with little therapeutic support.

Psychedelics have been shown to work in a range of disorders that share the common feature of being internalizing disorders. They likely work by dysregulating activity in systems and circuits that encode these habits of thought and behavior.

Is 5-HT2A Stimulation the

Classic serotonergic psychedelics act by agonizing the 5-HT2A receptor, which is maximally expressed in the cerebral cortex. These receptors are found on the cell bodies and apical dendrites of large pyramidal neurons concentrated in layer V of the cortex.

Activation of 5-HT2A receptors increases the excitability of the host neuron, causing a spike to wave decoherence and dysregulation of spontaneous activity in cortical populations. This dysregulation is reflected in increased entropy and decreased alpha oscillations, as well as changes in the integrity of intrinsic networks.

Would Shorter-Acting Psychedelic Drugs Work?

Different psychedelics have different durations of action, but the oral route is generally considered the most appealing for therapeutic work because it allows the patient to enter into the psychedelic state with plenty of time to explore personal material and potentially experience therapeutic breakthrough.

Are the Psychedelic Effects Necessary?

Microdosing psychedelics to putatively improve wellbeing and creativity raises the question of whether a full psychedelic experience is needed. There have been no trials of microdosing for any psychiatric disorder, but growing evidence suggests the best outcomes are from patients experiencing the most powerful psychedelic effects.

Psilocybin can produce clinical remission in some people, and this effect persists for years. The key might be how psychedelics relax limiting beliefs and promote insight and emotional release, which can motivate the revision of these beliefs.

How Much Is ‘‘Just Pharmacology’’?

Psilocybin therapy for psychiatric disorders is given within a structured psychotherapeutic setting with a considerable therapist input. However, the question is whether there can be an action on the brain and long-term therapeutic effect, without a noticeable mediating subjective experience.

Although ethically challenging to implement, giving people a psychedelic under anesthesia and assessing their subsequent effect on a mental-health-relevant outcome might help resolve debate about the importance of the psychological components of psychedelic therapy.

Remedy Psychiatry Disorders?

There is great current interest in understanding how psychedelics remedy psychiatry disorders, particularly depression, because half of patients relapse within 6 months. This suggests that depression might become a persistent, intractable problem that influences thinking processes forever.

The 5-HT2A receptor is likely the key molecular mediator of cases of major psychological change. It is also likely to be activated in states of extreme stress to provide solutions to the crisis and help lay down new, more adaptive behavioral and cognitive patterns.

In recent years, psilocybin has been shown to suppress the amygdala response to threat cues in healthy volunteers, but the opposite effect was seen in treatment-resistant patients 1 day after psilocybin therapy. This suggests a complex, non-linear process of change.

Protecting Research

Major hurdles facing research with psychedelics include the Schedule 1 status, associated costs, and damaging stigma, which likely deterred governmental agencies, other reputable funding bodies, and companies from backing the relevant research.

COMPASS Pathways and Usona are making psilocybin at scale, and magic mushrooms are becoming legal in some South American countries. The Dutch have a fast-growing industry in magic truffle retreats, and we have set-up an online platform for collecting data on psychedelics.

It is possible to make new 5-HT2A receptor agonists that would be outside national or UN Conventions, but the risk of them becoming restricted is very high.

The best way forward to foster research and therapeutic application of psychedelics is to reschedule them, especially psilocybin, which was made Schedule 1 on the shirt-tails of politically motivated banning of LSD.

Summary

Research into the neuroscience and therapeutic application of psychedelics has resurfaced in the past ten years, providing remarkable insights into brain function and instigating an exciting new approach to the treatment of a range of psychiatric disorders.