After a legally mandated, decades-long global arrest of research on psychedelic drugs, investiga- tion 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.

Introduction—Why the Psychedelic Revolution in Psychiatry?

Research leading to the discovery of new pharmacological treatments for psychiat- ric disorders has been painfully slow. With a few exceptions, including the use of orexin antagonists for insomnia, current medicines are derivatives of drugs discovered in the 1950s through seren- dipity and refined through pharmacolog- ical modifications. For these reasons, most major pharmaceutical companies have retreated from researching brain targets, threatening to halt a progression in research knowledge and possibly inducing the same sort of dark age that antibiotic research has found itself in.

One way out is to revisit drugs that were once used but fell out of use because of political machinations, especially the war on drugs (Nutt, 2015). Cannabis was the first to be resurrected and the glutamate receptor antagonist anesthetic ketamine has recently been shown to have antide- pressant properties, leading to the enan- tiomer esketamine becoming licensed in the USA and Europe. Now, serotonergic psychedelics, particularly psilocybin (the active compound in ‘‘magic mushrooms’’) are being resurrected as potential treat- ments for a range of different psychiatric disorders (Rucker et al., 2018). These drugs include LSD, ayahuasca (a drink that contains dimethyltryptamine [DMT] and a monoamine oxidase inhibitor that prevents its breakdown in the gut), as well as 5-MeO-DMT (from the Sonora toad) and mescaline (from the peyote cactus). In the 1950s and 1960s, LSD was widely researched and was consid- ered to achieve major breakthrough treat- ments by many psychiatrists. At the same time, psilocybin was an experimental medicine supplied by Sandoz as ‘‘Indocy- bin’’. However, once LSD became used recreationally by young people, it was banned and most other psychedelics were sucked into the legislation; research on their potential therapeutic efficacy ground to a halt. In the past decade, research on these compounds has been re-established by a few groups around the world, culminating in new centers for psychedelic research at Imperial College London and Johns Hopkins University.

Because psilocybin is a Schedule 1 controlled drug, meaning that it has been defined as having high potential for abuse with limited therapeutic utility, it took several years of battling with regulators and ethics committees to gain permission to do clinical research with it, but the strug- gle was worth it. Its effects on patients suffering from depression were remark- able—e.g., two experiences with psilocy- bin improved depression scores for weeks, and in some people, years (Car- hart-Harris et al., 2018), positioning it as one of the most powerful therapeutics for treatment-resistant depression. There have also been three placebo-controlled trials of psilocybin for anxiety and depres- sion related to end-of-life diagnoses (re- viewed in Rucker et al., 2018). Based on this body of positive findings, at least two companies have been set up to take psilo- cybin to the clinic, funding multi-center dose-finding studies of psilocybin in depression (U.S. National Library of Medi- cine, 2020a; 2020b). In parallel, we will soon be completing a double-blind trial of psilocybin versus the selective seroto- nin reuptake inhibitor (SSRI) escitalopram in depression (U.S. National Library of Medicine, 2020c). There have also been studies showing efficacy in alcoholism and tobacco dependence (Rucker et al., 2018), and similar studies in anorexia, obsessive-compulsive disorder (OCD), chronic pain, and opioid use disorder are being developed.

This might seem a strange and dispa- rate set of disorders for a single medicine to work in, and this speaks to the innova- tive nature of psychedelic therapy. In most studies, the psychedelic is given just once (though in a few studies, twice or three times over a period of weeks) as part of an ongoing psychotherapy course, in complete contrast to currently available medications, which are given at least daily, often with little therapeutic support. We suggest one way of looking at the dif- ference between them is that current medicines suppress symptoms in a similar way that insulin suppresses hyper- glycemia in diabetes. Standard antide- pressants protect against the stressors that lead to and perpetuate depression, but don’t directly access and remedy un- derlying biopsychosocial causes. In contrast, psychedelic therapy harnesses a therapeutic window opened up by the brain via the effects of the drugs to facili- tate insight and emotional release and, with psychotherapeutic support, a subse- quent healthy revision of outlook and life- style (Carhart-Harris and Nutt, 2017).

Arguably all of the conditions in which psychedelics have been shown to work share the common feature of being inter- nalizing disorders. In depression, patients continually ruminate about their failings, reiterate thoughts of guilt, and engage in self-critical inner narratives.

Figure 1. The Three Levels of Activity of Psilocybin

Psilocybin, along with other serotoninergic psychedelics, acts to stimulate 5-HT2A receptors in the cortex, particularly layer 5 pyramidal cells. This leads to massive depolarization and thence rapid repeated firing of these neurons (lower inset). Because these neurons are responsible for organizing cross-cortical integration, this activity results in a profound alteration of cortical signaling. Both magnetoencephalography and electroencephalography measures reveal a major loss of typical rhythmical activity, resulting in a state of extreme desynchronization or enhanced entropy (middle inset). Also, these layer 5 neurons mediate the ‘‘top down’’ perceptual and cognitive predictions (so called ‘‘priors’’), which form the basis of normal brain processing. Thus, under psychedelics the brain ‘‘escapes’’ from its usual tightly constrained and predictable ways of working; this leads to a global increase in connectivity (top inset) that allows new insights into past behavior, memories, actions, feelings, and beliefs. These in turn can lead to therapeutic changes in conditions such as depression and addiction, which are driven by dysfunctional brain processing. Average density map for 5-HT2A receptor adapted from Beliveau et al. (2017).

In addictions, the object of addictions takes on the role of negative thinking in depression, driving behavior that is specific, narrow, and rigid; addicts ruminate on relief afforded by the object, how to get it, how to pay for it, etc. The rationale for using psychedelics in OCD and anorexia is consistent given that there is rumination on intrusive thoughts, e.g., about contamination or cal- orie mismanagement. Psychedelics likely work by dysregulating activity in systems and circuits that encode these habits of thought and behavior (Carhart-Harris and Friston, 2019), allowing them to recalibrate as the acute effects of the drugs subside. Despite this potential for efficacy across a range of disorders and the initial prom- ising results, many questions remain.

Is 5-HT2A Stimulation the Therapeutic Mechanism of Action ?

The defining action of classic serotonergic psychedelics is mediated primarily through agonism of the 5-Hydroxytryptamine 2A (5-HT2A) receptor (Figure 1). This is exem- plified by recent positron emission tomography research, showing that the psyche- delic effects of psilocybin in humans are predicted by the degree of occupancy of the 5-HT2A receptor revealed by displace- ment of the agonist tracer [11C]Cimbi-36 (Madsen et al., 2019). Moreover, 5-HT2A receptor antagonists such as ketanserin block psychedelic effects (Preller et al., 2017). The 5-HT2A receptor is maximally expressed in the cerebral cortex, and because humans have considerably more cortex than other species, they logically have the highest expression. These recep- tors show some regional heterogeneity in the cortex, being relatively sparse in the sensorimotor cortex, and especially dense in visual and association cortices—with high expression also noted in the claus- trum in vitro.

5-HT2A receptors are localized on the cell bodies and apical dendrites of large pyramidal neurons concentrated in layer V of the cortex. There are also found, albeit to a lesser degree, on GABAergic interneurons that regulate pyramidal cell firing (Andrade, 2011). Activation of 5-HT2A receptors appears to increase the excitability of the host neuron, causing a spike to wave decoherence and associ- ated dysregulation of spontaneous activ- ity in cortical populations. This dysregula- tion reliably manifests as increased entropy in on-going activity recorded via local field or scalp potentials, as well as related changes in the power spectrum, e.g., marked decreases in alpha oscilla- tions. A number of aspects of cortical functioning associated with predictive processing appear to be dysregulated un- der psychedelics, including the following: functioning of layer V pyramidal neurons; the strength of alpha oscillations; the strength of backward traveling waves; and the integrity, segregation, and hierar- chical organization of intrinsic networks. This is consistent with our current hypoth- esis that the main functional effect of psy- chedelics is to relax the precision weight- ing of the predictive models encoded in the brain (Carhart-Harris and Friston, 2019). An earlier model takes a different view: that psychedelics disrupt the normal gating of sensory inputs via the thalamus (Vollenweider and Geyer, 2001), and this leads to altered perceptions. However, given a low density of 5-HT2A receptors in the thalamus, it might be that thalamic effects are driven by psychedelics dis- rupting cortical activity that projects to the thalamus, so the two theories might not be so different.

The therapeutic benefit we theorize is also mediated via this receptor, but as yet, this has not been established in hu- mans—because to do this would require a trial in which a 5-HT2A receptor antago- nist is given before the psychedelic to see whether this blocks its therapeutic effects.

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