The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report: Serotonergic Psychedelic Treatments for Major Depressive Disorder

Serotonergic psychedelics include psilocybin, LSD, DMT and mescaline, all with tryptamine structures similar to serotonin.^18–20 5HT2A receptor agonist effects have been demonstrated to induce the hallucinogenic experiences that distinguish psychedelics.²¹ There is also evidence that pre-medicating with 5HT2A receptor antagonists, such as ketanserin, prevents the psychoactive effects of psychedelics.^21,22 5HT2A receptors are highly expressed in brain regions involved in perception, emotional processing, memory, executive function and self-awareness, including the prefrontal cortex, anterior cingulate and amygdala.^21,23 There is evidence that effective treatments for depression such as antidepressant medications and electroconvulsive therapy down-regulate brain 5HT2A receptors.^24–26 However, the potential role of 5HT2A receptor downregulation following psychedelic treatment has yet to be determined. Furthermore, these burst 5HT2A effects stimulate a downstream cascade that triggers increased production and release of brain-derived neurotrophic factor (BDNF), ultimately increasing neuroplasticity, a common pathway for mechanistically distinct antidepressant treatments.^27,28 Immunomodulatory and anti-oxidant effects of psychedelics have also been implicated in their potential antidepressant effects.^18,28,29

On a network level, preliminary imaging and electrophysiological studies have implicated the modulation of several key brain regions. Modulation of connectivity patterns and the default mode network (DMN) has been a major focus of neuroimaging studies to date.³⁰ Activity and connectivity of brain regions crucial to self-referential thinking in the DMN are most strongly impacted by psychedelics.^31–33 Notably, however, the DMN theory of psychedelics has been criticized, with some studies suggesting that the observed changes in the DMN are not specific to classic psychedelics, but may be a non-specific change observed with other mind-altering substances.³⁴

Beyond material changes observable through molecular, electrophysiological and neuroimaging studies, significant theories have been advanced to determine the psychological mechanisms underlying the antidepressant effects of psychedelic-assisted psychotherapy.^7,9 The belief that psychedelics may act as a catalyst to achieve greater insight and have emotional breakthroughs in therapy has been a central theory for the mechanism of action of psychedelics.^23,35,36 Another theme is the possibility that psychedelics address rigid, inflexible and maladaptive thoughts and ruminations patterns, providing the opportunity for accessing and shifting these negative core beliefs. This theory is supplemented by the entropy hypothesis that posits that concrete, rigid negative thought patterns underlie depression. A robust acute increase in entropic brain activity, or randomness, during a psychedelic experience, may allow these ruminative and rigid thought patterns to be released and potentially replaced with more adaptive core beliefs and psychological flexibility.^31,37 Additionally, spiritual or mystical experiences have been shown to predict sustained psychological benefits, suggesting that they may play a key psychological role in facilitating the antidepressant effects of psychedelics.^38,39

Lastly, it has also been suggested that the large antidepressant effect sizes associated with psychedelics may be primarily driven by placebo or expectancy effects.^40–43 The positive effects of placebo have been demonstrated for both mental and physical diagnoses.^44–47 Given the dramatic experiential effects and propensity for functional unblinding with psychedelics, the neurobiological mechanisms of the placebo effect (as summarized in recent reviews^44,48,49) may play an important role.

Notably, the negative connotations of placebo effects have been questioned in recent years, and are considered legitimate neurobiological effects that should not be avoided, but robustly evaluated and optimized to improve patient outcomes.⁴⁴ Moreover, patient improvements in clinical practice secondary to placebo effects are still beneficial, regardless of the underlying neurobiological mechanism at play (e.g., placebo vs. non-placebo mechanisms). As such, an agnostic approach may be advantageous; considering placebo and expectancy effects as a single contributing factor to psychedelics’ central mechanism of action, rather than just a troublesome and unavoidable confounder. Nevertheless, placebo effects may still be problematic for researchers attempting to design rigorous, blinded, clinical trials evaluating psychedelics with comparable scientific standards as clinical trials evaluating standard antidepressant medications. Notably, however, challenges with blinding are not unique to psychedelics as functional unblinding frequently occurs with disparate pharmacological and non-pharmacological interventions. For example, psychotherapy trials comparing cognitive behavioural therapy to non-directive therapy or wait-list controls would similarly have high rates of functional unblinding given how dramatically different these interventions are subjectively experienced by trial participants.

Psychedelics show significant variability in their pharmacokinetics, specifically in terms of the overall duration of their hallucinogenic effects. While there is some variability and dose dependence, the overall duration of effects with moderate to high doses following oral administration is shortest for ayahuasca (∼4 h), moderate with psilocybin (∼6 h) and longest with mescaline and LSD (8–12 h).^9,50,51 Notably, oral DMT is rapidly metabolized by monoamine oxidases in the gastrointestinal tract and liver and thus has a negligible bioavailability in the absence of a monoamine oxidase inhibitor (MAOI, such as harmine, which is present in ayahuasca).^9,50,52 Conversely, intravenous and inhaled DMT may have brief bioavailability with strong psychoactive effects over 5–15 min.⁵³ Details of onset of clinical effects, half-lives, timing of peak psychedelic effects and time to complete resolution of the psychedelic experience are summarized in Table 3.

Our systematic literature search of studies published from 1 January 1990 to 31 July 2021 identified eight (k = 8) prospective clinical trials evaluating antidepressant effects of psychedelics in depressed patients (summarized in Table 4). Three trials evaluated psilocybin for MDD (two RCTs and one open-label trial) with three additional RCTs evaluating psilocybin in cancer-related depression and anxiety. Two trials (one open label and one RCT) evaluated ayahuasca for treatment-resistant unipolar depression (TRD). We identified no contemporary trials evaluating LSD, mescaline, pure DMT or 5-MeO-DMT for depression. Of note, trials with LSD and DMT for depression have been registered, however, did not have published results at the time of our literature search. Registered trials (including ongoing and unpublished studies) have been recently reviewed elsewhere.⁶⁵

All published trials of psilocybin include psychotherapy as an integral part of the intervention. Psychotherapeutic support has been associated with a greater likelihood of occasioning mystical-like experience and has been generally accepted as an essential part of psychedelic treatments.^50,81 The therapy includes preparatory session(s), non-directive dosing session monitoring by two individuals (referred to as guides, monitors or therapists) followed by integration sessions to support individuals in processing their psychedelic experience. However, only brief descriptions of the psychotherapy itself are provided in published studies. Nevertheless, a systematic review of common components of psychedelic therapy, identified the following elements.⁸² In preparation sessions, there is a focus on building therapeutic alliance and trust, understanding the patient narrative, setting intentions and providing psychoeducation on what to expect from the treatment session. Dosing sessions include two providers who are non-directive, with an emphasis on the patient focusing inwards, rather than actively engaging with external therapists during the actual dosing session. This role is primarily described as safety and support, rather than playing an active or directive role in the patient's psychedelic experience.¹² A pre-selected music playlist was also included in all trials, most commonly consisting of classical music with minimal lyrics. The use of music is described as an essential aspect of dosing sessions; however, superiority with specific types of music has not been demonstrated.^83,84 Integration sessions are described as helping the patient retell their experience and connect the experience with the initial intentions set out in preparatory sessions.⁸²

In contrast to psilocybin trials, the three ayahuasca studies had fewer psychotherapeutic components described. However, based on the inpatient milieu used in all three trials, a certain degree of preparation and support may be assumed.^33,77,79 Although some form of psychological support may be necessary for the safety and antidepressant efficacy of psychedelic treatments, it is undetermined whether psychedelics would be as safe and effective in the absence of psychotherapy.

Despite the generally accepted importance of psychotherapy, there has been minimal research to determine optimal therapy protocols or approaches. Therapy protocols and manuals have been largely developed based on expert opinion rather than empirical evidence supporting any specific component. Even basic parameters, such as the minimum amount of psychotherapy (e.g., hours or sessions) needed to adequately prepare for and integrate a psychedelic experience have yet to be evaluated, relying on expert opinion exclusively. Optimal setting (e.g., physical space, music selection, etc.) is also of great interest with potential impacts on safety and efficacy. The role of manualized therapies known to be effective for MDD, such as cognitive behavioural therapy, remains unknown with less directive, supportive approaches predominating in completed trials to date. ⁸²

Studies to date have focused on using psychedelics as monotherapy requiring a full washout of antidepressants, antipsychotics and mood stabilizers. From a safety perspective, this is based on the theoretical risk of inducing serotonin syndrome or serotonin toxicity; however, the actual clinical relevance and risk remain unknown, with only case reports and one small pilot study in healthy controls providing guidance.^12,22,85,86 Downregulation of 5HT2A receptors may also occur with chronic use of serotonin reuptake inhibitors that may theoretically reduce acute psychedelic effects.²¹ Nevertheless, concerns regarding combining a monoaminergic antidepressant with a potent 5HT2A receptor agonist are appreciable. Specifically, combining antidepressants with ayahuasca may pose a high risk of serotonin syndrome and hypertensive crisis because in addition to DMT, ayahuasca contains MAOIs (harmaline and harmine).^53,85,87 There have also been concerns regarding seizures if psychedelics are combined with lithium, based on naturalistic data from online reports.⁸⁸ Of note, this naturalistic study did not find safety concerns with other mood stabilizers, namely lamotrigine, that was not associated with seizures or other adverse effects. Drug–drug interactions may also negatively impact potential antidepressant efficacy as any psychotropic that has significant antagonist effects on the 5HT2A receptor (e.g. atypical second antipsychotics and some antidepressants), would block the putative pharmacodynamic target of psychedelics.^21,22,89

When using moderate to high psychedelic doses, acute psychotomimetic effects would be anticipated in close to 100% of individuals.⁹ Acute psychological effects broadly include changes in six domains: cognition, perception, negative emotion, positive emotion, mystical experience and social connectedness.⁹ All domains may vary greatly among individuals with a reliable dose–response effect and increased intensity at high doses. Drawing the line between therapeutic effect and adverse effect is challenging, as acute psychological effects (both positive and negative) may be a key component in mediating the psychedelic-induced antidepressant effects. The subjective characterization of therapeutic effect versus adverse effect may also impact how adverse effects are reported by investigators with differing views on this categorization with inconsistencies observed between published trials reviewed herein. Additionally, given the challenges of using safety data from homogenous clinical trial samples (e.g., without comorbidities, history of psychosis, substance use disorders, personality disorders, lack of demographic diversity, etc.), adverse effects and safety concerns might be more common in real-world clinical settings including more complex patients.⁹⁰

Cognitive changes associated with psychedelics include increased flexibility and creativity, but may also include disorganized and distractible thought patterns. Perceptual disturbances may be hallucinatory (primarily visual and auditory) or dissociative (derealization, depersonalization and time distortion). Negative emotions include anxiety, irritability, agitation, paranoia and mood lability. These negative emotions may be markedly distressing and cause patients to want to leave the dosing session, which is why close monitoring is thought to be required. Conversely, acute positive emotions are also observed with elevated mood, euphoria and general feelings of improved wellbeing. Spiritual and mystical experiences are also common and unique to psychedelics, and have been associated with sustained psychological benefits.^39,91 Lastly, social connectedness with enhanced empathy and general openness to others are also commonly observed.⁹¹ The relative importance of these acute effects to longer-term benefits is an active area of research. Of interest, some preclinical models have even called into question if acute psychedelic, mind-altering effects are necessary for antidepressant benefits.^21,92

A major concern with psychedelic use is the risk of harm to self and others while in an altered state of consciousness. Case reports and media coverage have highlighted tragic adverse outcomes of physical harm to others and self (including lethal harm).¹² Clinical trials to date suggest that these are rare events that are preventable with adequate participant screening, monitoring and safety protocols. Identified case reports of treatment-emergent suicidality have occurred outside of clinical trial settings, with the exception of one reported suicide in a participant receiving a very low dose of psilocybin.^39,93 Nevertheless, more trials are needed to better determine the frequency of these likely rare but serious adverse events, and to delineate safety protocols required to prevent them.

Given the concerns for potentially serious adverse effects, contraindications for clinical use of psychedelics relate to risk factors for greater psychological adverse effects and exacerbating pre-existing disorders. Specifically, personal history of psychosis, mania, hypomania or violence were exclusion criteria in all clinical trials identified. Further, first or second-degree relatives with psychosis or bipolarity are a common exclusion criterion in most studies. However, these exclusion criteria are based on a theoretical risk of vulnerability to adverse reactions. Given the high prevalence of treatment resistance with bipolar depression, it is important to determine whether psychedelics may be safely and effectively used in this population.

In addition to acute psychological effects, psychedelics may also transiently cause increases in blood pressure, acute gastrointestinal side effects and headaches that may persist a few days after a dosing session. Studies evaluated blood pressure regularly during dosing sessions and found relatively mild and transient increases with no hypertensive crises observed. Ayahuasca is specifically associated with significant nausea and emesis in approximately half of the study participants. However, investigators described this as potentially an essential part of the ayahuasca experience (in line with traditional practices⁹⁴) and report the subjective distress related to emesis as mild. A theoretical concern of possible drug-induced valvular disease due to 5HT2B effects of LSD and psilocin has also been recently suggested.⁹⁵

In a systematic review evaluating the long-term effects of psychedelics, data from time points greater than 2 weeks after a dosing session were synthesized from 34 contemporary clinical trials.⁹⁶ While long-term clinical benefits were observed, limited aversive side effects were noted by study participants past the 2-week point. While there are no documented cases within the short-term clinical trials reviewed herein, the concern of developing a hallucinogen use disorder is of theoretical concern.^8,12 Expert opinion suggests a low risk of developing physical or psychological dependence with prescribed clinical use.^8,12,97 Another potential long-term risk of concern is hallucinogen-persisting perception disorder (HPPD), an uncommon adverse effect seen in individuals who regularly use psychedelics, as in hallucinogen use disorders.^98–100 However, no cases of HPPD were identified in the included trials.^101,102 HPPD is likely very rare with the controlled protocols used in clinical trials, especially when personal and family histories of psychosis are exclusion criteria. Concerns remain for patients who might require repeated doses to maintain therapeutic benefits. For example, if a patient needs multiple doses per year for relapse prevention, or for treatment or relapse/recurrence, the threshold for use that may be associated with HPPD risk remains unclear.⁹⁹

Research in the 1960s also raised concerns about chromosomal damage and risk of cancer with LSD, but these findings have never been replicated in human clinical trials.^103,104 As with any potentially carcinogenic substance, the effects are likely more relevant with repeated doses and prolonged exposure. Hence the unknown risk of repeated doses to treat mood episode relapse over time warrants further investigation.

Currently, no psychedelics are available by routine prescription in Canada. The only way to access psilocybin at this time is through a Subsection 56(1) Exemption issued by the federal Minister of Health under the Controlled Drugs and Substance Act (CDSA) or through the special access program (SAP).^105,106 A Subsection 56(1) exemption is typically only granted for human use as part of Health Canada approved clinical trials. Recently, a small number of exemptions were granted to allow patients with refractory distress associated with life-threatening illness, especially cancer, to consume psilocybin mushrooms with the support of a therapist. However, the Exemption Office has provided clear and direct guidance to the public and providers that these exemptions are exceptionally rare and that the proper route for access is through clinical trials. Further, exemptions have been typically only granted for medically ill patients, usually near the end of life, along with a small number of therapists for experiential training.

In 2022, following substantial advocacy to reclassify psilocybin and other psychedelics under the SAP, the federal government reclassified psychedelics to permit applications for access through the SAP outside of clinical trials for serious or life-threatening illnesses.¹⁰⁶ Given the recency of these changes to the SAP, it remains unclear the criteria for approving SAP applications for patients with MDD in the absence of terminal medical illness. It is also unclear if this change to the SAP will be followed by additional policy changes that may allow for easier access to psychedelics as part of off-label clinical care. Notably, a limited number of districts, such as Oregon and California, have recently decriminalized specific psychedelics, creating avenues for legal use as part of off-label clinical care outside of Canada.^107,108

While clinical trials may be an optimal avenue to provide access to psychedelics safely, Health Canada requires rigorous toxicology and animal testing of any substance prior to allowing its use in clinical trials.¹⁰⁹ This cost for testing is typically prohibitive and is not routinely completed for natural psilocybin. Sourcing psilocybin (with adequate pharmacological and toxicology testing) for clinical trials has proven to be a significant barrier to research locally. Given these barriers, and despite the tremendous interest and investment in psilocybin from physicians, researchers, industry and patients, only two registered psilocybin clinical trials have received Health Canada approval in the past 40 years.^110,111

Considering the challenges in accessing psychedelics, clinicians are often confronted with the ethical dilemma of a harm reduction approach, when patients request monitoring and support for self-sourced, illegal psychedelics. Importantly, current federal laws strictly prohibit any healthcare provider involvement, including but not limited to, monitoring dosing sessions, facilitating access or encouraging use in the absence of a Subsection 56(1) exemption or SAP approval.¹⁰⁵ Additionally, self-sourced psychedelics may contain potentially dangerous impurities and an unknown dosage of active ingredients leading to unpredictable outcomes. Accordingly, CANMAT strongly recommends against any physician involvement in such practices, outside of approved clinical trials or the SAP, given the significant medico-legal and ethical concerns.

Lastly, a significant ethical concern, which is not unique to the Canadian context, is the self-administration of psychedelics by therapists, as part of a therapist training program, also known as “experiential training.” A small number of individual therapists in Canada have received exemptions for psilocybin and MDMA therapy training programs, under the assumption that first-hand psychedelic experience is essential to be a competent therapist. Proponents of experiential training believe that it would be beneficial, or should even be required, for psychedelic therapists.^7,38,112,113 However, this view is formed without empirical evidence to support the relevance or utility of experiential training. On the contrary, many concerns have been raised about such practices given the allegiance effect that may bias clinical trial results, and human rights concerns restricting therapists who are prescribed psychotropics from participating in the training.^112–114 Additionally, there are concerns that history may repeat itself, given the catastrophic effects of investigator personal psychedelic use contributing to the demise of psychedelic research in the 1960s, as most typified by Timothy Leary's personal use.^{7,9,112,115,116}

In summary, several ethical, medico-legal and regulatory challenges continue to influence the potential translation of preliminary findings from psychedelic clinical trials to clinical practice. Moving forward, balancing patient, provider and societal safety with ethical access will be paramount in Canada and globally.