Acknowledgments
Effort for authors was provided by The Center for Psychedelic and Consciousness Research which is funded by the Steven and Alexandra Cohen Foundation, Tim Ferriss, Matt Mullenweg, Craig Nerenberg, and Blake Mycoskie, and by NIH grant T32DA07209.
Introduction
Classic psychedelics are serotonergic agonists that can produce profound changes in perception, mood, and cognition. The past two decades have been marked by a renewal of interest in these compounds for their potential to produce rapid and long-lasting improvements in a variety of mental health conditions including treatment-resistant depression (TRD). Psychedelics have been used sacramentally in non-Western cultures for thousands of years but did not receive widespread attention or recognition in the West until the 1940s when the psychoactive properties of lysergic acid diethylamide (LSD) were recognized by Swiss chemist Albert Hofmann. A first wave of clinical research in the 1940s–1970s suggested that these compounds may have had considerable therapeutic potential, but studies were halted in response to political and cultural pressures resulting from widespread use of psychedelics outside of clinics and laboratories ( ). With the passage of the Controlled Substances Act in the United States, psychedelics were relegated to Schedule I, a category reserved for substances with no recognized clinical benefit and substantial associated risk. Thus, for several decades following this shutdown, psychedelics were known primarily as illicit drugs of abuse with little attention paid to previously documented clinical benefits.
After a decades-long hiatus in clinical experimentation involving these substances, a second wave of research began in the late 1990s with increasing numbers of high-quality human and laboratory studies being published. Phase I studies demonstrated that psychedelics had a favorable safety profile, and growing numbers of phase II studies are demonstrating therapeutic potential for various mental health conditions including cancer-related psychosocial distress, alcohol and nicotine use disorders, major depressive disorder (MDD), and TRD ( ; ; ; ; ).
This chapter will focus on the more recent literature with classic psychedelic compounds, whose effects are primarily mediated by serotonin 2A (5-HT 2A ) receptor agonism or partial agonism. A variety of terms have been used to refer to these substances since their first description in medical literature. Initially called “psychotomimetic” agents, this term fell out of favor when it became apparent that their effects could not accurately be described as psychotic phenomena. “Hallucinogen” later gained popularity and is still widely used today including in the Diagnostic and Statistical Manual (DSM). However, this term suggests that the primary effect of these drugs is to produce true hallucinations, when such phenomena are in fact uncommon with most drugs in this class. An additional weakness of this label is that it is often used to refer to a broader category of psychoactive drugs that work by other mechanisms, such as 3,4-Methylenedioxymethamphetamine (MDMA), and dissociatives like ketamine and phencyclidine. The term “psychedelic” was coined by English psychiatrist Humphrey Osmond in the 1950s and is currently preferred among researchers working with these compounds ( ). The Greek root delos , meaning “to manifest,” is thought to more adequately capture these drugs’ potential “mind-manifesting” or therapeutic effects.
A number of key differences set psychedelic-assisted treatment apart from most currently available psychiatric treatments. Unlike first-line pharmacotherapies for MDD, which can take weeks of continuous use to produce clinically meaningful improvement, psychedelics appear to be capable of improving symptoms rapidly, as soon as one day after a single drug administration. Large effect sizes are apparent after just one or two doses and many patients appear to experience sustained improvement for months without the need for repeated drug administration. Additionally, treatment with psychedelics is typically delivered under the supervision of two therapists or “facilitators” with substantial adjunctive psychotherapy before and after drug administration ( ). This model is thought to be necessary for safety and efficacy, especially as clinical research with these drugs has shifted from healthy volunteers to clinical populations. This hybrid model contrasts with the typical delivery of care in the United States, where pharmacotherapy and psychotherapy have been gradually siloed over the last several decades. It has also posed challenges to conducting “gold-standard” placebo-controlled clinical trials with these drugs.
Though the use of these substances remains prohibited outside of laboratory settings in most of North America and Europe, multiple groups are currently conducting phase II and III studies to determine whether psychedelics can be a safe and effective treatment for MDD. Psychedelics are of particular interest in the possible treatment of TRD given that their mechanisms of action are distinct from existing treatments. In this chapter, we will review the chemistry, mechanisms of action, and recent clinical trial data on these compounds with special focus on their applications in individuals with TRD.
Chemistry
Most psychedelics relevant to our discussion of TRD are classified as tryptamines, which can be identified by their indole ring and structural similarity to serotonin and its precursor tryptophan. Naturally occurring tryptamines include N,N -dimethyltryptamine ( N,N -DMT), 5-methoxy- N,N -dimethyltryptamine (5-MeO-DMT), psilocybin, and psilocybin’s active metabolite psilocin. The synthetic ergoline LSD is also a tryptamine psychedelic. The second category of classic psychedelics is that of phenethylamines, of which mescaline is the naturally occurring exemplar.
Early clinical research focused principally on LSD, whose psychoactive properties were accidentally discovered in 1943 by Swiss chemist Albert Hoffman. In the process of attempting to isolate clinically useful compounds from the ergot fungus, lysergic acid was discovered ( ). Hofmann developed a synthetic process that allowed him to create novel ergolines by combining lysergic acid with a variety of other compounds. His 25th synthetic compound, LSD-25, was made with diethylamine. LSD-25 did not immediately appear to have any useful effects in animal models, and sat untouched for several years until Hoffman unintentionally ingested it and discovered its striking psychoactive effects. It was hypothesized that LSD’s effect profile may have had phenomenological similarity to psychosis and thus could be of interest to psychiatric researchers and clinicians. Sandoz Laboratories (now Novartis), subsequently distributed samples of LSD to clinicians and researchers worldwide under the trade name Delysid.
Most contemporary clinical research with psychedelics has used tryptamines other than LSD. Psilocybin has been most commonly used, and though it occurs naturally in the Psilocybe genus of mushrooms ( ), most research with psilocybin is conducted using synthetically prepared drug. N,N -DMT also occurs naturally in small concentrations in many plants and animals. It is the principal constituent of ayahuasca, a plant decoction that is used ceremonially in cultures in the Amazon Basin ( ). Ayahuasca is most commonly prepared using a combination of Psychotria viridis , which contains N,N -DMT, and the Banisteriopsis caapi vine, containing harmala alkaloids. When taken alone, orally ingested N,N -DMT has no effect due to rapid metabolism by peripheral monoamine oxidase (MAO). Harmala alkaloids have an MAO-inhibiting effect and when taken together with N,N -DMT allow it to pass through peripheral circulation and exert effects centrally. Though ayahuasca has been studied for its therapeutic potential in MDD and TRD ( ; ), it is an unlikely candidate for clinical use in the West due to the challenges of standardizing the dosage of a heterogeneous plant brew.
In some contexts, compounds like MDMA and glutamatergic dissociatives like ketamine and dextromethorphan have been discussed for their “psychedelic” effects, but due to their differing mechanisms of action, these will be excluded from this discussion. It is worthwhile noting, however, that a phase III trial of MDMA for the treatment of PTSD is currently ongoing and uses an integrated psychotherapy approach similar to that which is commonly used with classic psychedelics ( Clinicaltrials.gov identifier NCT04077437 ).
Pharmacokinetics
Psychedelic compounds vary in their pharmacokinetic profiles. Here we will briefly review the pharmacokinetics of the three psychedelic compounds most commonly encountered in clinical psychedelic research.
Psilocybin
Following oral administration, psilocybin is absorbed in the stomach and the intestinal tract, where it is rapidly dephosphorylated by alkaline phosphatases to its active metabolite, psilocin. Onset of effects occurs by 30 min following moderate oral doses (0.28–0.43 mg/kg), with peak effects occurring around 2–3 h, and total duration of effects lasting somewhat more than 6 h ( ). Noticeable subjective effects occur at plasma concentrations of about 4–6 μg/mL ( ). Laboratory studies have demonstrated that doses of up to 0.6 mg/kg have been well tolerated in healthy adults ( ). The LD 50 of psilocybin is estimated to be on the order of grams per kilogram in humans, indicating a very large therapeutic index ( ). Psilocin is renally excreted with a terminal elimination half-life of roughly 3 h ( ).
LSD
LSD has good oral bioavailability. Following a typical dose (100–250 μg), onset of subjective effects occurs within 30–45 min and peak effects are reached within 1–2.5 h. Total duration of effects is about 9–12 h ( ). One study with a small number of subjects found oral absorption to be somewhat decreased when taken with a full meal ( ). The longer duration of action makes LSD somewhat less practical for clinical use when compared to psilocybin. LSD undergoes hepatic metabolism and renal excretion of metabolites. LSD has a half-life of roughly 3.6 h ( ). LSD binds 5-HT 2A and 5-HT 2B receptors for an extended period of time, which explains its protracted period of effects despite its short half-life ( ). Similar to psilocybin, the LD 50 of LSD is orders of magnitude larger than the effective dose. A case series of 8 individuals who accidentally took massive overdoses of LSD after mistaking the substance for cocaine found that the patients suffered from coma, hyperthermia, and gastric bleeding, though all 8 survived without long-term consequences despite having reached serum LSD concentrations of 1000–7000 μg/100 mL ( ).
N,N -DMT
As noted elsewhere, N,N -DMT has limited oral bioavailability due to rapid breakdown by gastrointestinal MAO. However, parenteral administration, usually achieved by smoking or intravenous injection, readily produces strong but short-lived psychedelic effects. Intravenous administration at 0.2–0.4 mg/kg produces almost immediate onset of intense perceptual effects that resolve within 30 min ( ). In addition to MAO metabolism, parenterally administered N,N -DMT undergoes hepatic CYP-based metabolism, which is less rapid ( ). N,N -DMT is the chief psychedelic constituent of the plant brew ayahuasca. have described the pharmacology of ayahuasca, which contains harmaline, harmine, and tetrahydroharmine—compounds that inhibit MAO and thus allow N,N -DMT to be absorbed and to exert effects centrally. Because different ayahuasca preparations vary in their composition, pharmacokinetics may be variable between batches. Typical doses described in research have ranged from 0.3 to 1 mg/kg of N,N -DMT with varying amounts of MAO inhibiting compounds ( ; ). Initial effects are noticeable at 30–45 min after oral administration of ayahuasca, with peak effects occurring 1.5–2 h after ingestion ( ). Effects gradually taper until about 6 h after drug ingestion.
Mechanisms of action
Research from a variety of disciplines has informed the current understanding of the mechanisms of action of psychedelics. While understanding of the biological mechanisms of acute psychedelic effects has improved substantially in the past two decades, the mechanisms of long-term therapeutic effects remain less clear. For example, multiple lines of evidence have demonstrated that 5-HT 2A –mediated signaling is crucial for the acute subjective effects of psilocybin. However, we do not yet know whether psychedelics directly induce longer-term changes in serotonergic functioning or whether such changes are associated with clinical improvement weeks or months after intervention. We also do not yet know whether subjective experience of the acute drug state is necessary for therapeutic efficacy, or if subjective effects are merely an epiphenomenon of some neurobiological mechanism that is actually driving clinical improvement. A second key point is that psychedelics are typically delivered together with a psychotherapeutic intervention. Contextual factors or psychological “set and setting” have long been believed to be important for treatment efficacy, though empirical study of this idea remains challenging. Both psychological and neurobiological factors are likely at play in the immediate and sustained treatment effects, and it is likely that these are synergistic.
Biological mechanisms of action
5-HT 2A receptor agonism is central to the effects of psychedelics. These receptors are present throughout the brain but exist in high concentrations in the claustrum and layers III and V of many cortical areas, especially the frontal and temporal lobes ( ; ). Low concentrations are found in lower structures like the basal ganglia and amygdala. Blocking 5-HT 2A receptors with a selective antagonist such as ketanserin abolishes subjective effects of classic psychedelics in humans ( ). Furthermore, binding affinity for 5-HT 2A receptors is correlated with the intensity of observed drug effects ( ). Preclinical evidence suggests that downstream glutamatergic signaling at mGluR2/3 receptors secondary to 5-HT 2A agonism is also necessary for the action of psychedelics ( ). Blocking or knocking out these receptors effectively negates observed psychedelic effects. It is notable that 5-HT 2A receptors are also present in large quantities elsewhere in the body including the peripheral nervous system, the cardiovascular system, and in platelets ( ; ). The effect of psychedelics in other tissues is an ongoing area of study.
Individual psychedelics vary in their binding affinity to other receptors, though these are generally thought to be less critical in the production of drug effects than 5-HT 2A receptors. For example, psilocin binds to 5-HT 2C , 5-HT 1A , and 5-HT 1B receptors ( ). LSD on the other hand has partial agonism at 5-HT 2A receptor, and also binds 5-HT 1A , 5-HT 2C , 5-HT 2B , and dopamine D1 and D2 receptors ( ). N,N -DMT, which is found in minute quantities in the human body, acts as an endogenous sigma-1 agonist in addition to its 5-HT agonism ( ). The exact role of these receptors in the action of psychedelics is still being determined. 5-HT 1A and 5-HT 2C in particular may be of particular importance ( ).
Changes in serotonin and glutamate signaling may explain the clinical efficacy of psychedelics for major depressive disorder. Similar to the proposed mechanism of action of typical serotonergic antidepressants, improvements in mood may be mediated by direct effects of psychedelics at 5-HT receptors. 5-HT 2A agonism leads to receptor desensitization and internalization ( ; ). Downstream glutamate signaling may also produce antidepressant effects in a manner similar to glutamatergic antidepressants such as ketamine ( ). Furthermore, 5HT 2A and mGlu2/3 sites have interactive and potentially synergistic effects, suggesting that psychedelics may result in more powerful antidepressant effects than a drug that works by other mechanism alone ( ).
Functional magnetic resonance imaging (fMRI) studies have revealed that psilocybin acutely decreases resting state functional connectivity in the default mode network (DMN), as well as areas of the brain involved in emotion processing including the amygdala and the anterior cingulate cortex ( ). Decreases in DMN connectivity appear to persist at least 2 days following psilocybin administration in healthy subjects ( ). Conversely, found that DMN connectivity was increased one week after psilocybin administration. Barrett and colleagues ( ) found that resting state functional connectivity increased 1 week after psilocybin administration in healthy subjects, and that this pattern persisted at the one-month follow-up timepoint. Whether classic psychedelics are unique in their ability to produce such changes in functional connectivity has been challenged by recent findings that hallucinogens that work by other mechanisms also seem to be able to produce such changes ( ; ). The DMN has been implicated in the pathophysiology of MDD in that individuals with depression may exhibit abnormally high levels of connectivity in the DMN ( ). DMN hyperconnectivity, and low levels of connectivity between the DMN and the cognitive control network have been associated with higher response rates to MDD treatment ( ). DMN connectivity has been shown to normalize following transcranial magnetic stimulation treatment for MDD ( ).
Psychedelics have also been shown to affect amygdala function. Increased amygdala response to negative affective stimuli has been associated with depression. A recent fMRI study in 12 healthy volunteers demonstrated that amygdala function in response to affective stimuli varied over the course of 1 month following psilocybin administration ( ). At 1 week, amygdala response to facial affect stimuli were reduced compared to baseline. These findings were associated with increased positive affect as measured by the Profile of Mood States (POMS). Though amygdala response returned to baseline at 1 month, mean POMS remained elevated compared to baseline.
Psychedelic compounds have also been found to produce potent antiinflammatory effects, which may be a key mechanism of action for the improvement of TRD and other conditions involving inflammation. Although serotonin is known to have pro-inflammatory effects throughout the body, 5-HT 2A agonism by classic psychedelics such as LSD and ( R )-2,5-dimethoxy-4-iodoamphetamine (DOI) has been shown to suppress TNFα expression and nuclear translocation of NF-κB in vitro, with similar findings in vivo ( ; ). hypothesize that these effects can be explained by functional selectivity, meaning that different agonists at the same receptor can produce different downstream effects. In the case of psychedelics, binding at 5-HT 2A may result in recruiting antiinflammatory pathways rather than pro-inflammatory pathways typically activated by serotonin. Inflammation is hypothesized as one pathophysiologic pathway contributing to TRD. Patients with TRD have been found to have elevated levels of inflammatory markers including interleukin-6 (IL-6), which may have promise as a marker of treatment response (and notably is also reduced by suppression of TNFα) ( ).
Subjective experiences and psychological mechanisms of action
Other explanations for the immediate and long-term effects of psychedelics are related to the complex subjective experiences produced by these drugs, which some people interpret as deeply meaningful, psychologically insightful, emotionally rich, or spiritual in nature ( ). This holds significance for TRD, which for some patients may be related to a sense of chronic adversity or demoralization, personality vulnerabilities, and other factors that would understandably be unresponsive to traditional forms of pharmacotherapy ( ). A variety of instruments have been developed to systematically assess the complex phenomenology of psychedelic experience, including the Mystical Experience Questionnaire (MEQ-30), a validated measure reflecting several qualities of the mystical experience—unity, sacredness or preciousness, authenticity, deeply felt positive mood, transcendence of space or time, and ineffability ( ). Though some researchers regard the description of these experiences as mystical to be unscientific ( ) this description does not imply a supernatural explanation for these phenomena. Several studies have demonstrated dose-dependent relationships between psychedelics and measures of mystical qualities of the experience, with greater mystical qualities being correlated with better long-term outcomes ( ). found that in a sample of 24 adults undergoing psilocybin-assisted psychotherapy for MDD, there was a moderate correlation ( r = 0.41, p < 0.5) between changes in GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at 4 weeks and peak MEQ-30 score.
demonstrated changes in the personality domain of openness that persisted at 14 months following psilocybin administration. Such effects have also been documented as a result of prolonged SSRI treatment, intensive psychotherapy, and contemplative practice, but had not previously been demonstrated secondary to an acute drug intervention ( ; ; ). The authors examined the relationship between mystical experiences and changes in openness, which revealed that individuals who had had a “complete” mystical experience (> 60% of maximum score on each subscale of the States of Consciousness Questionnaire) were significantly more likely to show increases in trait openness assessed with a standardized personality inventory. Those who had an “incomplete” or absent mystical experience were not significantly different from baseline. Low trait openness has been identified as a risk factor for TRD ( ). Erritzoe and colleagues examined changes in personality structure following psilocybin administration in 20 patients with TRD and found that at 3-month follow-up, participants had decreases in neuroticism, and increases in extraversion and openness.
Other psychological changes may also mediate outcomes or otherwise be clinically relevant. Increases in cognitive flexibility have been demonstrated following psilocybin administration and had a mediating effect on long term benefits for mood and anxiety ( ). Increases in capacity for mindfulness secondary to ayahuasca have also been reported ( ).
Clinical studies
Early evidence of efficacy of psychedelics in depressive disorders
The first wave of psychedelic research from the 1940s through 1970s generated numerous published accounts of treatment outcomes for depressive illness. Unfortunately, much of this literature was in the form of case reports or case series, and most clinical trials suffered from lack of methodological rigor ( ). Further, generalizing those earlier results to the clinical entity we now know as MDD is challenging due to differing diagnostic procedures and terminology used by clinicians of that era. The first report of a psychedelic used to treat a depressive illness was published by Condrau in 1949 and described the use of gradually escalating doses of LSD ( ). Despite some improvement, Condrau concluded that the treatment did not demonstrate substantial efficacy. Subsequent reports of psychedelics for the treatment of so called “depressive,” “neurotic,” and “psychoneurotic” disorders were subsequently published by other researchers.
Rucker and colleagues completed a systematic review of the extensive literature from this period and summarized findings from 20 studies on psychedelic treatment effects in patients with depressive disorders ( ). The majority of studies used LSD, with a minority using mescaline and none reporting on findings with psilocybin. A variety of treatment approaches, dosing and dosing regimens were used. A notable distinction was made between “psycholytic” therapies, which employed low doses of psychedelic to facilitate regular psychotherapy sessions, vs. “psychedelic therapy,” which resembled the high dose treatment used in contemporary studies. 19 of 21 studies reported on the number of patients who seemed to improve—of a combined 423 patients, 335 (79.2%) were reported to have improved. Unfortunately, calculating effect size from these studies is not possible because only one research group used a continuous measure of depressive severity. Whether improvement was sustained was also not apparent. Ascertaining the risk of adverse events from this body of literature was challenging due to inconsistencies in classifying and reporting such findings.
Fortunately, the second wave of psychedelic research has been characterized by much greater attention to methodological rigor. Initial studies in healthy subjects convincingly established that psychedelics could be administered safely in a laboratory setting ( ; ; ). In 2006, Griffiths et al. demonstrated that a single dose of psilocybin in healthy volunteers produced mystical type experiences that were associated with increases in positive mood at the 2 month follow-up assessment ( ). Three subsequent studies examined the effects of psilocybin in individuals with cancer-related psychological distress and demonstrated rapid and sustained decreases in depressive symptoms ( ; ; ). Later studies demonstrated similar findings in patients with MDD and TRD ( ; ).
The standard model of treatment
The majority of contemporary clinical studies using psychedelics have adhered to a similar format and set of safety guidelines ( ). Following screening, participants are paired with two clinicians, also called “facilitators,” who are ideally both present for all clinical visits. This begins with one or more preparatory visits lasting a total of 4–8 h during which the participant and facilitators review the participant’s biographical history, discuss potential effects of psychedelics, and build rapport. Drug administration is provided in a room decorated in a comfortable home-like manner ( Fig. 14.1 ).
Contemporary clinical studies with psychedelics
Among the second wave of psychedelic research, the first evidence that psychedelics could have efficacy for depressive disorders came from studies in individuals suffering psychological distress secondary to advanced stage cancer. completed a small ( N = 12) randomized, placebo-controlled crossover study of psilocybin for the treatment of anxiety in patients with advanced-stage cancer. Beck Depression Inventory (BDI) differences following placebo and experimental treatment were not significantly different, but BDI scores dropped by nearly 30% at 1 month and reached significance at 6 months following intervention for the whole group. These results were later expanded upon in larger studies at Johns Hopkins and New York University ( ; ). employed a randomized double-blind crossover design comparing the effects of very low dose (1 or 3 mg/70 kg) versus moderate- to high-dose (22 or 30 mg/70 kg) psilocybin in individuals with depression and anxiety symptoms in the setting of terminal cancer ( N = 51). Eighty-four percent of participants met criteria for a treatment response (≥ 50 reduction on GRID-HAMD compared to baseline) following the high dose session. Sustained response was present in 78% of participants at 6 months, with 65% being in remission. completed a double-blind, placebo-controlled crossover study ( N = 29) comparing the effects of a 0.3 mg/kg (equivalent to 21 mg/70 kg) dose of psilocybin to an active placebo condition (niacin). Similar decreases in depression symptoms were reported with large effect sizes as measured by the BDI and HADS were reported.
Efficacy for MDD and TRD
Extending the results from prior populations with cancer-related psychological distress, completed an open-label pilot study of two doses of psilocybin in 20 participants with TRD. Treatment resistance was defined as having failed medication trials lasting 6 weeks or longer from at least two classes of antidepressants. Participants had a mean estimated illness duration of 17.7 years (SD 8.4). The preliminary report ( ) on the first 12 patients indicated a mean of 4.7 prior medication trials, though the later report on the complete group did not include this information. The majority had attempted at least one form of psychotherapy. A 10 mg “safety dose” and a moderately high dose of 25 mg were given about 1 week apart in combination with supportive psychotherapy before and after drug administration. Mean BDI score at baseline was 34.5 (SD 7.3), which corresponded with severe depressive symptoms. One week following the high dose psilocybin administration, mean BDI decreased to 11.8 (SD 11.1; Cohen’s d = 2.5). At three-month follow up, mean BDI was 15.2 (SD 11.0; Hedge’s g = 2.0). Mean BDI was 19.2 (SD 13.9; Cohen’s d = 1.4) at 3 months, and 19.5 (SD 13.9; Cohen’s d = 1.4) at 6 months.
Psilocybin was generally well tolerated in this study, with only mild side effects such as transient anxiety, nausea, and headache. Three participants experienced transient paranoia during the acute drug administration period. One participant experienced a return of significant depressive symptoms during the 3-month follow-up period and was referred to a general practitioner for treatment. Notably, six participants resumed psychiatric medications between the 3- and 6-month timepoint, five resumed psychotherapy, and five participants sought and received additional psilocybin-containing products from sources outside of the study. Removing the five participants who received additional psilocybin from analyses did not significantly alter the main results. Despite the limitations of the open-label design, this study served as a proof of concept that psilocybin can be safely administered to individuals with TRD, and suggested that it may be of clinical utility. However, the resumption of other forms of treatment and the use of psilocybin outside of the study limit the conclusions.
conducted a randomized, waitlist-controlled trial of two moderate to high doses of psilocybin for MDD. Though this study did not explicitly test the intervention in a treatment-resistant group, the mean number of years with depression was 21.5 (SD 12.2), and the mean number of months in the current depressive episode was 24.4 (SD 22.0). Eligible participants were randomized to an immediate treatment group or an 8-week delay period, during which they were monitored by in-person or phone visits. All participants received two moderate to high weight-based doses of psilocybin about 2 weeks apart (20 mg/70 kg and 30 mg/70 kg). Staff provided approximately 13 h of supportive psychotherapy during the preparatory and follow-up period. There were large significant differences in GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores between the immediate and delayed treatment groups at study weeks 5 and 8. For the full sample, GRID-HAMD scores (mean and SD) decreased from 22.8 (3.9) to 8.9 (7.4) at 4 weeks after the second psilocybin administration. At 4 weeks after the second psilocybin administration, 71% of participants had a clinically significant response to the intervention (≥ 50% reduction in GRID-HAMD score compared to baseline), and 58% were in remission (≤ 7 GRID-HAMD score). A different measure of depression (QIDS-SR) documented large, rapid, and significant decrease in depression score from baseline to day 1 after session the first psilocybin session, which remained statistically significantly reduced through the week 4 follow-up. Psilocybin was well tolerated with no serious adverse events. Almost all of participants reported transient challenging emotional experiences during the drug administration session; however, other studies have shown that such experiences after psilocybin are not uncommon. About one third of participants reported mild to moderate headache after the subjective psilocybin effects had subsided on session days.
conducted a randomized controlled trial using a double dummy design to compare the antidepressant effects of escitalopram to those of psychedelic-assisted treatment. Patients with moderate to severe MDD were recruited ( N = 59) and randomized to receive either (1) two 25 mg doses of psilocybin in a therapeutic setting, plus 6 weeks of daily placebo, or (2) two doses of placebo in a therapeutic setting, plus 6 weeks of daily escitalopram. Though treatment-resistance was not a criterion for study enrollment, participants had a history of longstanding depressive illness (mean of 22 years in the psilocybin group and 15 years in the escitalopram group). Mean number of prior antidepressant trials was 2.2 (SD 1.6) in the psilocybin group and 1.8 (SD 1.5) in the escitalopram group. Baseline depressive symptoms as measured by the Quick Inventory of Depressive Symptoms Self-Report (QIDS-SR) was 14.5 (SD 3.9) in the psilocybin group and 16.4 (SD 4.1) in the escitalopram group. There were no significant differences in QIDS-SR score between the two treatment groups at 6 weeks. Though secondary outcome measures including other measures of depression such as BDI and HAMD generally favored the psilocybin group, these analyses were not adjusted for multiple comparisons.
The antidepressant effects of ayahuasca have also been studied. reported promising findings in a small ( N = 6) open label pilot of ayahuasca for recurrent depression. In that study, ayahuasca significantly reduced depressive symptoms from baseline to 1, 7, and 21 days after drug administration using the Hamilton Rating Scale for Depression (HAM-D) and several other measures of depression. subsequently reported a randomized parallel group placebo-controlled study of ayahuasca in individuals with TRD ( N = 29). Inclusion criteria required that participants had failed trials of antidepressants from at least two distinct pharmacologic classes, and participants had a mean of almost 4 medication trials. Participants in the ayahuasca arm received a weight-based dose containing 0.36 mg/kg of N,N -DMT. At days 1, 2, and 7 after the session, participants in the ayahuasca group showed significant decreases in depression compared to those in the placebo group, as assessed with the MADRS. A similar difference between the groups was shown on the HAMD at day 7 after the session. Furthermore on the HAMD at day 7, there was a significant difference between the response rate in the ayahuasca vs. placebo groups (57% vs. 20%, respectively, p = 0.04) and a trend toward significance when comparing remission rates (43% vs. 13%, respectively, p = 0.07). There were no serious adverse events recorded. The authors noted that, though participants generally felt safe during treatment, the experience was often physically and psychologically uncomfortable, with 57% experiencing vomiting during the session.
Adverse effects and toxicology
When used in supervised settings with substances of known purity, psychedelics have a low risk of serious adverse reactions ( ). Contrary to long-held popular beliefs about the dangers of psychedelics, these drugs have a very low abuse liability. Preclinical model of drug self-administration in animals have been largely negative ( ). However, others have highlighted the need to better characterize abuse liability of psychedelics in vulnerable populations ( ).
Physiological adverse effects
Somatic effects and physiological adverse events are generally mild. Transient increases in blood pressure are common via 5-HT 2A and 5-HT 1B –mediated vasoconstriction. For this reason, individuals with uncontrolled hypertension have been excluded from most clinical trials using psychedelics. Nausea, loss of appetite, dizziness, and tremor are also common ( ). For psychedelics other than ayahuasca, vomiting is rare. Transient, dose-dependent delayed onset headache is a common side effect of treatment with moderate-high dose psilocybin ( ). Seizures have been reported secondary to ingestion of both LSD and psilocybin-containing mushrooms ( ; ). For this reason, individuals with epilepsy have historically been excluded from clinical trials with psychedelics.
Cases of serotonin syndrome have also been reported secondary to use of psilocybin-containing mushrooms ( ). However, no episodes have been described following psychedelic use in clinical research settings to date. Risk of serotonin syndrome can be reduced by discontinuing other serotonergic medications prior to drug administration. Other case reports of serious but rare adverse events secondary to psychedelics have included rhabdomyolysis, cortical blindness, and vasospasm leading to lower extremity ischemia ( ; ; ).
There has been concern that psychedelics may cause cardiac valvular dysfunction via agonism at 5-HT 2B receptors, which are densely distributed in cardiac valves and regulate growth in these tissues. Other drugs with 5-HT 2B agonism have been associated with valvular heart disease including fenfluramine and MDMA, though it seems that chronic use is required to produce clinically significant changes in valvular function ( ). No cases of valvular heart disease have been attributed directly to use of classic psychedelics to date. The typical course of treatment with psychedelics has involved just a few administrations of the drug and would ostensibly impart a low level of risk, if any. However, other patterns of use may place individuals at greater risk. Growing numbers of recreational users are now taking “microdoses” or very low doses of psychedelics multiple times per week on a chronic bases for supposed performance-enhancing purposes ( ). Even at low doses, it is possible that repeated exposure over time could increase risk for cardiac complications.
Psychological adverse effects
Dysphoric or anxious reactions, also called “challenging experiences” are not uncommon in the setting of moderate-high dose psychedelic use and may be more common among those with depression. found that of 51 participants receiving high dose psilocybin for low mood in the setting of life-threatening cancer, 32% and 26% of their volunteers experienced a transient but significant episode of psychological discomfort or anxiety respectively. One participant reported transient paranoid ideation. In study of psilocybin for TRD, 12 of 19 (63%) of participants reported transient anxiety lasting minutes during acute drug effects, and three participants experienced transient paranoia. In the study of psilocybin for MDD, most participants endorsed experiencing a variety of potentially unpleasant or challenging emotions and physical sensations during psilocybin session ( ). Such effects do not typically last beyond the period of acute drug action and respond well to reassurance. High levels of neuroticism as measured by the Big Five Inventory have been associated with higher likelihood of having challenging experiences with psychedelics among a large group of naturalistic users, which may be relevant for sufferers of TRD ( ). Interestingly, individuals who have challenging experiences under the influence of psychedelics often report that the experience was meaningful and resulted in an overall benefit ( ).
Challenging psychological experiences appear to be more problematic when occurring in an unsupervised natural setting. In a survey of 1993 individuals who self-identified as having had challenging experiences under the influence of psilocybin in naturalistic settings, 2.6% reported that they put themselves or others at risk of physical harm ( ), 2.7% reported seeking urgent medical attention as a result of the experience, and 7.6% sought help for ongoing psychological distress after the experience.
Precipitation of mania and psychosis is perhaps the most serious psychiatric concern associated with psychedelics ( ). surveyed investigators who had administered LSD or mescaline and found the rate of prolonged adverse reactions to be low: only 1 case among approximately 1200 participants had developed psychotic symptoms lasting longer than 48 h. This single adverse event occurred with a participant whose identical twin had schizophrenia and thus may have been genetically predisposed to psychosis. The reaction resolved in 5 days. Though the risk of psychosis is quite low, it cannot be excluded completely, and for this reason most modern psychedelic clinical trials have excluded individuals with personal or family history of bipolar or schizophrenia spectrum disorders. Though transient paranoia can occur during acute drug effects, no cases of protracted psychotic or manic syndromes have been reported in human subjects’ research with psychedelics since the 1990s to date.
Hallucinogen persisting perceptual disorder (HPPD) is defined in the DSM-V as a reexperiencing of drug-like perceptual effects following cessation of hallucinogen use ( ). To meet criteria for this disorder, the symptoms must also be distressing or cause impairment in functioning, and must not be accounted for by another disorder. Qualitative research has identified two possible subtypes of HPPD: 1) a syndrome characterized by brief “flashbacks” of perceptual changes, with long symptom-free intervals between episodes, and 2) a chronic syndrome in which symptoms are present over months or years in varying intensity ( ). The true prevalence of Type I HPPD is difficult to estimate. have highlighted the fact that though millions of doses of psychedelics have been consumed since the 1960s, few large case series have been published. However, early case series have estimated that prevalence may be as high as 1:20 in regular users in the 1960s and 1970s ( ; ). The prevalence of Type 2 HPPD is thought to be very rare, and is estimated to be approximately 1:50,000 ( ). No clear risk factors have been defined, but qualitative interviews with HPPD sufferers indicate that personal or family history of anxiety, preexisting tinnitus, eye floaters, and concentration difficulties may be associated with development of the disorder ( ). conducted a survey of hallucinogen users with unusual visual disturbances that occurred outside of the context of acute drug effects. They found that such experiences were positively associated with the number of prior episodes of hallucinogen use. Compared to other psychedelics, past LSD use was more commonly associated with unusual visual experiences. Notably, there have been no reports of cases of HPPD reported in association with administration of a psychedelic in a clinical trial between the 1990s and the time of this writing.
Drug interactions
Common psychotropic medications can produce clinically significant interactions with psychedelics. Given that psychedelic effects are mediated primarily by 5-HT 2A agonism, most known interactions involve drugs that have an effect on serotonin signaling ( ). However, it is important to note that due to variability in receptor binding profiles, interactions may vary somewhat between different psychedelics, e.g., LSD is known to bind the dopamine D2 receptor while psilocin has no affinity at this site ( ). Survey and case report data suggest that chronic use of selective serotonin reuptake inhibitors (SSRIs) may dampen subjective effects from both psilocybin and LSD, which is of particular relevance given the high rates of use of these medications in patients with TRD (Ruck J. ). This interaction is not completely understood, but can likely be attributed to the fact that chronic SSRI use can result in desensitization and downregulation of 5-HT 2A receptor binding sites ( ; ).
Serotonin syndrome is a risk when multiple serotonergic drugs are used together, though has rarely been reported in the context of psychedelic use. One case report documented the experience of an individual using ayahuasca during treatment with 20 mg of fluoxetine daily, which resulted in symptoms suggestive of serotonin syndrome including confusion, diaphoresis, tremors, and nausea and vomiting ( ). Among psychedelics, ayahuasca in particular may carry higher risk for serotonin syndrome or other interactions due to the MAO inhibiting properties of some of its constituents. Animal studies have shown that chronicity of SSRI use may have differential impact on psychedelic effects—while chronic SSRI treatment reduced signs of intoxication from 5-MeO-DMT, acute SSRI use potentiated signs of LSD intoxication in rats ( ; ). Thus it is possible that risk of potentiated psychedelic effects or serotonin syndrome may be higher in the period immediately following initiation of an SSRI.
Other psychotropic medications have demonstrated variable effects when used in combination with psychedelics. Similar to SSRIs, MAO inhibitors have been observed to reduce subjective effects of LSD ( ; ). Conversely, tricyclic antidepressants (TCAs) appear to potentiate the effects of LSD, which may be related to TCA-mediated increases in dopamine sensitivity in combination with LSD’s action at dopamine receptors ( ). Among mood stabilizing medications, found that individuals taking lithium reported stronger than expected effects from LSD. Curiously, reported that compared to subjects receiving psilocybin alone, those who were given the first-generation antipsychotic haloperidol in combination with psilocybin reported higher rates of psychotic-type symptoms including paranoia, loss of control over body and thought, and thought disorder. Conversely, they observed that risperidone effectively blocked the development of psychotic symptoms associated with psilocybin.
Among other drugs, one case report has suggested that allopurinol may dampen the subjective effects of psychedelics ( ). The mechanism here is less clear but may be related to allopurinol’s inhibition of tryptophan pyrrolase, which may increase central levels of serotonin. Other drugs that are known to inhibit tryptophan pyrrolase include yohimbine, which is known mostly for its α 2 -adrenergic antagonism ( ). Yohimbine has also been found to increase central serotonin levels and to antagonize effects of LSD in rats ( ).
Due to the known interactions with other psychotropics and especially antidepressants, contemporary studies on the effects of psychedelics have typically required subjects to discontinue all psychiatric drugs for a washout period of at least five half-lives. However, changes in 5-HT signaling and receptor density following cessation of antidepressant treatment are not well understood and may persist beyond the acute washout period. This is evidenced by the fact that antidepressant discontinuation symptoms can persist well beyond the washout period following cessation of treatment ( ). Changes in serotonin signaling impact the efficacy of psychedelics in individuals with chronic use, and this warrants further research.
Summary and future directions
Psychedelic-assisted psychotherapy has shown promise for the treatment of MDD and TRD, but larger placebo-controlled studies are needed to determine whether psilocybin has a safety and efficacy profile that would support its widespread clinical use. Two entities, Usona Institute and Compass Pathways are currently conducting phase II studies of their formulations of psilocybin for MDD ( ClinicalTrials.gov identifiers 03866174 & 03775200). The latter will compare the effects of low, medium, and high doses of psilocybin on depressive symptoms in people with TRD, and is scheduled to be completed in December 2021. Both Usona and Compass have received “breakthrough therapy” designation by the United States FDA, which is intended to expedite the FDA’s role in development and review of promising drugs and devices. Should these studies yield favorable results, legislative measures would be required in order to allow the clinical use of these substances. In the United States, psilocybin would need to be reclassified from its current Schedule I designation under the Controlled Substances Act. A recent review and analysis of psilocybin’s abuse potential suggested that a reasonable reclassification would be Schedule IV, which currently includes hypnotic agents including benzodiazepines ( ).
There are many avenues for future research. Clinical studies to date have provided some understanding of the effects of one or two doses of psilocybin in combination with a fixed schedule of psychotherapy, but the understanding of the risks or benefits of subsequent dosing (i.e., repeated dosing weeks or months after the initial intervention in the event of relapse) is limited. Improvements to the current model of treatment are also needed. Current phase II studies require direct involvement of two clinicians (at least one of whom has doctoral level clinical training) during all phases of preparation, drug administration, and follow up care. This represents the costliest component of psychedelic-assisted treatment and would present a significant barrier to accessibility. Even if psychedelic-assisted treatment may offer significant cost savings over the long term compared the current standard of care, high upfront costs are a potential problem. It is not clear at this time whether the FDA will impose specific requirements regarding the type and nature of staff involvement required to administer psychedelics. Other models for psilocybin-assisted therapy have been proposed including psilocybin-assisted group therapy and 1:1 monitoring with as-needed back-up by an additional clinician, but further feasibility studies are needed ( ).
The effects of psychedelics on bipolar depression have not yet been evaluated. Despite concerns outlined earlier with respect to the risk of precipitating mania or psychosis in at-risk populations, bipolar depression has recently gained attention as a potential clinical target for treatment with psychedelics. Psilocybin and other psychedelics may pose too great of a risk of precipitating mania in individuals with bipolar 1 disorder, but risks may be lower in individuals with bipolar 2 disorder. A current exploratory mixed methods study is underway at University of California San Francisco, and at least one clinical trial for this indication is planned at the time of this writing ( ClinicalTrials.gov identifier 04433845).
A practice that has not yet been studied extensively for its effects on mood is that of microdosing psychedelics. Microdosing, which has becoming increasingly popular in the last decade, involves repeated administration of very low doses of psychedelics on an intermittent schedule. Survey data of individuals who have engaged in microdosing found that 71.8% of respondents indicated benefit for depression, and 56.6% reported improvements in anxiety ( ). A recent animal study found that chronic microdoses of N,N -DMT in rats resulted in an “antidepressant-like phenotype” characterized by improvements in fear extinction and weight gain ( ). Human laboratory studies of microdosing LSD have demonstrated safety, but thus far have not demonstrated a substantial effect on mood, perhaps due to a limitations in duration of treatment ( ).
Finally, although psilocybin is furthest on the path to possible approval for clinical use, the safety and efficacy of many other psychedelic drugs have yet to be studied. For example, 5-MeO-DMT has a duration of action between 30 and 90 min, which could make it more conducive for administration in existing outpatient settings. A comparative study examining differences between LSD, psilocybin, and mescaline in healthy subjects is currently underway ( Clinicaltrials.gov identifier 04227756). The coming decades will no doubt see an ongoing increase in clinical and research interest in these substances, and they may hold unique promise for those suffering from depression that has failed to respond to conventional treatment.
References
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