Is the psychedelic experience an essential aspect of the therapeutic effect of serotonergic psychedelics? Conceptual, discovery, development and implementation implications for psilocybin and related agents

KEYWORDS:

• Psychedelic
• psilocybin
• lysergic acid diethylamide
• mood disorders
• antidepressants
• discovery
• pharmacology
• FDA

1.

The moniker ‘psychedelic’ was coined in 1956 by the British psychiatrist, Humphrey Osmond, referring to ‘mind manifesting.’ Clinically, mind manifesting referred to a subjective phenomenon that included hallucinogenic experiences and alteration in consciousness. Pharmacodynamically, psychedelics are polysemous but historically have been synonymous with serotonergic psychedelics. Serotonergic psychedelics can be categorized into three subcategories: tryptamines [e.g. psilocybin, N,N-dimethyltryptamine (DMT)], ergolines [e.g. lysergic acid diethylamide (LSD)] and phenylalkylamines which are further subcategorized as phenethylamines (e.g. mescaline) and phenylisopropylamines [e.g. 2,5-dimethoxy-4-methylamphetamine (DOM)] [1].

The tryptamines and ergolines are nonselective across serotonergic (i.e. 5HT) receptors, while phenylalkylamines are more selective at 5-HT2_A,B,C receptors [1]. The effect of psychedelics in persons who administer these agents is a profound change in consciousness, perception, mood, and other human experiences which is often described in testimonials as life-changing.

During the past several decades, the pharmacodynamic definition of psychedelic has broadened to include a quantity of mechanistically dissimilar pharmacologic classes and agents with distinct in vitro binding profiles that are also associated with psychedelic experiences. For example, entactogens (e.g. 3,4-Methylenedioxymethamphetamine; MDMA) which are monoamine reuptake and vesicular monoamine transporter 2 (VMAT2) inhibitors as well as dissociative agents (e.g. ketamine, nitrous oxide) that are antagonists of the glutamatergic N-methyl-D-aspartate (NMDA) receptor are also referred to as psychedelics [2]. The imprecise and multiple definitions of psychedelic to a large extent belies the research, clinical, and regulatory utility of the moniker, and like most psychiatric drugs, a more precise pharmacodynamic nomenclature is needed.

A prevailing view is that the ‘psychedelic experience’ or ‘trip’ is a critical feature of a psychedelic agent. This view may be in part a consequence of the namesake moniker insofar as a psychedelic agent should induce a psychedelic experience. This latter aspect has been considerably embraced in the implementation of psychedelics in specialty clinics as well as by research protocols that are evaluating the safety, tolerability and efficacy of psychedelics for mental disorders. Moreover, the psychedelic experience is thought to be a critical element facilitating psychedelic-assisted psychotherapy [3]. In addition, the robust psychedelic experience is described as so unique and powerful that therapist self-administration of psychedelics has been encouraged by some groups to facilitate empathic connection with participants [4].

An overarching question, however, is whether the psychedelic experience is in fact required for the efficacy of psychedelics and/or the benefit of accompanying psychotherapies that are contemporaneously administered. A non-mutually exclusive hypothesis is that the psychedelic experience is not required but instead is an epiphenomenon that is dissociable from the therapeutic effect and/or may be a treatment-emergent adverse event (TEAE).

The necessity of the psychedelic experience has extraordinary implications from the point of view of conceptualizing putative mechanisms of action of psychedelics, the discovery and development of psychedelic agents, implementation requirements and safety monitoring at point-of-care, as well as access, availability, and reimbursement policies. There are also significant safety concerns that are introduced as some individuals receiving psychedelic agents may be at risk of Hallucinogen Persisting Perception Disorder (HPPD) [5]. Moreover, the centrality of the psychedelic experience has resulted in the exclusion of some persons being enrolled in psychedelic studies (e.g. persons with family history of bipolar disorder or schizophrenia) out of rational concern that they may be at greater risk of psychotomimetic experiences [6]. Although the rationale for excluding populations is apt, if the psychedelic experience is unnecessary, excluding participants will have unfortunately excluded a population who may potentially benefit from these treatments.

Rationale proffered to support the view that the psychedelic experience is sine qua non derives from several sources. For example, case reports have provided compelling testimonials that the subjective experience while receiving psychedelics was inextricably linked to the reported benefit on ratings of distress, psychopathology, quality of life and function [7]. A separate line of research is the notion that hallucinogenic experiences provide access to manifest psychological and emotional phenomenon which can be then accessed, edited, and reconsolidated with psychotherapy [8,9].

The requirement for psychotherapy has been justified for multiple reasons. Not only is it hypothesized by some to be the ‘active ingredient’ of psychedelic-assisted psychotherapy, it is also required for patient support and general safety. Moreover, in light of the considerable patient vulnerability and risk for boundary violation, multiple psychotherapists are recommended for the duration of the psychedelic trip [10]. In light of the extraordinary costs that would be required for prolonged psychological support, questions with respect to implementation, equity, and access are immediately raised as many persons would be unlikely to have sufficient resources for these services [6].

Notwithstanding the opinion that the psychedelic experience is requisite, there is no compelling evidence to support the assertion and instead it remains a testable hypothesis. A methodological aspect that complicates the interpretation of study results with psychoactive substances with significant and immediate psychoactive effects is functional unblinding. Despite efforts to reduce the impact of functional unblinding (e.g. low-dose vs. high-dose psychedelic designs) it remains unclear if this approach adequately mitigates or abrogates functional unblinding [11]. The high likelihood of functional unblinding does not necessarily imply that the totality of the effect with psychedelics is nonspecific and based on expectancy.

Moreover, preliminary evidence from phase II studies suggests that the acute, rapid benefit of psychedelics is sustained in many participants, which would not be expected in a difficult-to-treat population receiving placebo and/or via expectancy alone [12]. Furthermore, ketamine and esketamine have also demonstrated benefits in difficult-to-treat populations; an effect that is difficult to explain entirely by functional unblinding [13].

The answer to the question as to whether the psychedelic experience is required, or not, can be addressed by evaluating neurobiological mechanisms that are hypothesized to mediate efficacy of the agent and whether those mechanisms overlap with mechanisms that mediate the psychedelic experience. A separate approach is to identify whether hallucinogenic and other psychological experiences with psychedelics correlate with, covary, and/or predict symptom alleviating effects in mental disorders. The latter approach is especially challenging in light of functional unblinding, expectancy, and confirmation bias.

During the past five years, extraordinary public, media, clinical, academic, and commercial interest has been given to psychedelics and their possible role in the treatment of diagnosable mental disorders (e.g. major depressive disorders, post-traumatic stress disorder) as well as alleviating human suffering in select subpopulations (e.g. palliative care) [14,15]. A confluence of factors has ignited and amplified the interest in psychedelics. First, there is international recognition of the extraordinary and rising burden of mental health-related problems affecting humanity across high-, high-middle-, middle-, and low-income countries [16]. Secondly, despite the availability of evidence-based pharmacologic, neurostimulatory and psychosocial interventions for common and severe mental disorders, the majority of affected persons with access to high-quality integrated care do not experience acute and sustained recovery with existing treatments [17,18].

Moreover, there is no central nervous system (CNS) therapeutic that is curative or considered disease-modifying for mental disorders. In addition, reimbursement and formulary policies that reimburse innovative treatments over the existing pharmacopoeia provide incentive to develop and/or repurpose innovative and breakthrough treatments that are more likely to be reimbursed.

Aspects that are more specific and provide impetus to develop psychedelics as a category of agents include the historic and current use of psychedelics in indigenous cultures where extraordinary benefits have been described with respect to well-being, emotional communion, and social connectedness [19]. In addition, an accumulating evidentiary base suggests that some psychedelic treatments may provide benefit for persons living with mood, trauma, and substance-related disorders, as well as alleviate end-of-life suffering in persons receiving palliative care [7,20]. Further evidence promoting this category of agents derives from compelling testimonials from persons with mental disorders who have administered psychedelics who describe not only rapid and sustained alleviation of distress but also life-changing mystical, spiritual, and metapsychological experiences which are described as growth promoting [21].

Although insights extracted from in silico, in vitro and in vivo studies have illuminated the pharmacodynamic effects of CNS-acting psychotropic agents, the mechanistic steps that mediate symptom alleviation in mental disorders is unclear. The lack of clarity with respect to the mechanism of action of psychotropic drugs is a consequence of the incomplete understanding of the pathogenesis of mental disorders. Notwithstanding, a concatenation of study findings indicates that multimodal therapeutics for mental disorders [e.g. pharmacologic, protocolized psychotherapies, neurostimulation (e.g. electroconvulsive therapy)] converge on molecular mechanisms implicated in neurogenesis, dendritogenesis, spinogenesis, and neuroplasticity [22,23].

The foregoing molecular and cellular effects are hypothesized to be the biological substrates which subsequently affect neural circuit and network connectivity in select brain regions. It is also hypothesized that established and investigational pharmacologic agents for mental disorders alleviate symptoms by engaging ‘druggable targets’ (e.g. monoaminergic, glutamatergic, GABAergic) that set in motion a molecular cascade that eventually resets circuitry and brain topology.

In keeping with this conceptual framework, classic psychedelics (e.g. psilocybin and its active moiety psilocin, LSD) have molecular, cellular, and circuit/network connectivity effects that are similar to those observed with therapeutic modalities [12,24]. The observed effects with classic psychedelics are immediate and sustained and do not necessarily require multi-dose administration.

It is hypothesized that psychedelics exert their therapeutic effects primarily through 5-HT2_a agonism. It is also known that psychedelics have a combination of effects across monoaminergic, glutamatergic, GABAergic, and other systems which may also be relevant to the mechanism of action. The co-administration of a 5-HT2_a antagonist with psychedelics and the observed mitigation of efficacy and/or molecular and cellular outputs is a compelling methodological approach to instantiate the relevance of the 5-HT2_a receptor. It is also noted that agonism of the 5-HT2_a receptor mediates the psychedelic experience with reversal of the psychedelic effect observed with 5-HT2_a antagonism [25,26]. This observation has informed protocols of psychedelic development wherein co-administration of 5-HT2_a antagonists is discouraged in combination with psychedelics.

Evidence however is accumulating that there are discrete mechanisms mediating molecular and cellular effects subserving efficacy and those related to the psychedelic experience. For example, both psilocin and LSD exert antidepressant-like behavior and neuroplasticity independent of 5-HT2_a agonism. It is reported that head-twitch, a rodent behavioral proxy of hallucinations induced by 5-HT2_a agonists, is blocked by the 5-HT2_a/5-HT2_c antagonist, ketanserin [1,27]. It is also reported that after a single exposure, LSD and psilocybin bind to similar sites of the transmembrane domain of the brain-derived neurotrophic factor (BDNF) receptor, tropomyosin receptor kinase B (TrkB). It is noted, however, that other investigators have reported on the critical role of 5-HT2_a agonism in mediating neuroplasticity enhancing effects of psychedelics.

Through positive allosteric modulation, both LSD and psilocybin augment BDNF signaling in part by increasing cell surface retention of the TrkB dimers. The binding of LSD and psilocybin to TrkB is approximately 1000 times greater than fluoxetine or ketamine [28]. These molecular findings that effectors implicated in psychedelic experiences dissociate from neurotrophic and neuroplasticity effects are observed in other investigational, non-hallucinogenic psychedelics (i.e. 5-HT2 agonists without hallucinatory effects) [29].

Notwithstanding the foregoing molecular and cellular evidence militating against the notion that the psychedelic experience is warranted, some evidence from brain imaging studies suggests psychedelic experiences may serve as a proxy of efficacy and/or target engagement of the psychedelic. Specifically, replicated findings indicate that serotonergic psychedelics alter brain activity with a reduction in the control energy to transition between states with a greater dynamic profile and entropy, notably in self-referential circuits [i.e. in the Default Mode Network (DMN)] [30,31]. Also brain circuits affected by serotonergic psychedelics are those circuits known to be affected by 5-HT2 receptor expression [32].

There is precedent in psychiatric drug discovery and development and clinical implementation wherein a subjective experience by the participant is a critical component of its therapeutic effect was erroneously embraced. For example, it was originally understood that dissociation while administering sub-anesthetic doses of ketamine is essential for ketamine to be effective for the treatment of a mental disorder (e.g. treatment-resistant depressive disorder). This observation was derived from the understanding that the molecular mechanisms mediating ketamine’s effect overlap with mechanisms mediating the psychological experience of dissociation.

Some practitioners who administer ketamine for adults with mood and related disorders dose ketamine to achieve dissociation derived from an understanding that this serves as a phenotypic marker of ‘target engagement.’ Moreover, aligned with a conceptual framework of the mechanism of ketamine, some practitioners have a belief system that dissociation while administering ketamine is critical for ‘mind manifesting’ to enable the therapeutic effect of psychotherapy. As ketamine is frequently used off-label, there is no regulatory guidance on the use of racemic ketamine in psychiatry. It is known that a large quantity of private clinics administer ketamine, of which some adhere to protocols wherein the drug is dosed to dissociation in participants raising serious questions pertaining to scientific merit and ethics [13,33,34].

Separately, the introduction of antipsychotics decades ago was soon followed by opinion that the therapeutic dose of antipsychotic treatment was the dose that resulted in extrapyramidal effects (EPS; e.g. akathisia). The prevailing view informed by the conceptual framework was that postsynaptic D2 receptor blockade was not only the principal mode of action, but also the mediator of EPS, albeit in different brain regions [35]. It was common practice to titrate antipsychotic dosing to the patient’s self-report of akathisia and/or the observation of drug-induced movement disorders [35].

It is now well established that EPS is not required for antipsychotic efficacy. It is accepted that the targets involved in antipsychotic efficacy overlap with, but are different, with respect to brain region, receptor action, and post-receptor activity compared to the EPS effect. Moreover, more recent therapies approved for the treatment of psychotic disorders (e.g. lumateperone) and investigational agents (i.e. ulotaront, xanomeline) have placebo-level rates of EPS [36,37].

The foregoing examples are cautionary reminders to the history of prematurely embracing mechanistic models of pharmacologic activity before it is empirically established. Taken together, it is unknown whether the psychedelic experience is required for the efficacy of investigational psychedelics in psychiatry. At this point, the hypothesis that a psychedelic trip is required for efficacy cannot be fully accepted or refuted. Mechanistic and clinical research will need to empirically address this issue as its implications from a safety, clinical, regulatory, and treatment discovery and development perspective are immense.

Co-administering investigational psychedelics with 5-HT2_a antagonism and/or inverse agonism would be interesting in both preclinical and clinical assays [38,39]. For example, pimavanserin, which is an inverse agonist with a high affinity for 5-HT2a receptors and negligible affinity for dopamine, histamine, cholinergic and adrenergic systems, would be interesting to evaluate in combination with classic serotonergic psychedelics. Administering psychedelics to evaluate therapeutic effects and disambiguate them from expectancy created by functional unblinding could be evaluated in persons receiving general anesthesia. However, limitations of this approach, which has been reported with ketamine, is the extraordinary placebo response, the confound of anesthesia, as well as the duration of action of many serotonergic psychedelics [40].

In the interim, academic studies and commercial investigation of psychedelics should remain open-minded that psychedelic experiences may be a proxy of efficacy but these notions should be viewed as a testable hypothesis. Psychedelics have seen a resurgence of interest in psychiatry more than five decades after their original claims of efficacy and implementation procedures were described. Rigorous and adequate well-controlled trials are needed to sufficiently inform the testing of the hypothesis that the psychedelic experience is intrinisc to the efficacy of psychedelics.

Declaration of interests

R McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Atai Life Sciences. R McIntyre is a CEO of Braxia Scientific Corp. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.