Psychedelics for the Treatment of Psychiatric Disorders: Interpreting and Translating Available Evidence and Guidance for Future Research
Publication: American Journal of Psychiatry
Abstract
During the past decade, there has been extraordinary public, media, and medical research interest in psychedelics as promising therapeutics for difficult-to-treat psychiatric disorders. Short-term controlled trial data suggest that certain psychedelics are effective and safe in the treatment of major depressive disorder, treatment-resistant depression, and posttraumatic stress disorder. Preliminary evidence also supports efficacy in other psychiatric disorders (e.g., tobacco and alcohol use disorders). Notwithstanding the interest and promise of psychedelics, concerns have arisen with respect to the interpretability and translatability of study results. For example, aspects related to short- and long-term safety, abuse liability, and the essentiality of the psychedelic “trip” and psychological support are, inter alia, insufficiently characterized with psychedelic agents. The overarching aims in this overview are 1) to review methodological aspects that affect inferences and interpretation of extant psychedelic studies in psychiatric disorders, and 2) to provide guidance for future research and development of psychedelic treatment in psychiatry, critical to study interpretation and clinical implementation.
During the past decade, there has been rejuvenated interest in the therapeutic potential of serotonergic psychedelics and 3,4-methylenedioxymethamphetamine (MDMA) for selected psychiatric disorders (1). For convenience, we refer to serotonergic psychedelics and MDMA as “psychedelics” throughout this paper. Hitherto, positive short-term controlled trial evidence exists for psychological support combined with psilocybin in major depressive disorder (MDD), treatment-resistant depression (TRD), and alcohol use disorder (AUD) (2–12). In addition, early-phase controlled trial evidence supports the combination of psychological support and lysergic acid diethylamide (LSD) in AUD and end-of-life-related anxiety and depression (2–12).
There are more than 75 ongoing studies registered on ClinicalTrials.gov (as of March 2024) that are evaluating the aforementioned as well as related psychedelics (e.g., N,N-dimethyltryptamine). Ongoing studies are enrolling participants with diagnoses including substance use disorder, tobacco use disorder, anxiety disorders, compulsive and personality disorders, and other mental disorders (13–25).
Notwithstanding the preliminary evidence for psychedelics in psychiatric disorders, legitimate concerns are raised with respect to the interpretability and translatability of extant controlled studies. For example, there remains a lack of adequate well-controlled short- and long-term studies for most psychedelics. Also, inadequate characterization of safety and abuse liability, compromised blinding integrity, and the essentiality of psychotherapy and the “psychedelic trip” as part of the therapeutic paradigm are unresolved matters, potentially confounding data interpretation and translation.
Our overarching aims in this overview are twofold: 1) to review methodological aspects that affect inferences and interpretation of extant psychedelic studies in psychiatric disorders, and 2) to provide guidance for future research and development of psychedelic treatment in psychiatry, critical to study interpretation and clinical implementation (2, 26, 27). This paper is not intended as a review of clinical trials or the pharmacology of psychedelics, as multiple comprehensive reviews have been published recently (9, 28–30).
Methodological Aspects That Affect Inferences and Interpretation of Extant Studies With Psychedelics
Generalizability of Controlled Trial Evidence With Psychedelics
The majority of adequately controlled and rigorous studies involving psychedelics have evaluated a relatively small number of clinical presentations and psychiatric diagnoses (e.g., “psychological distress” as part of a life-threatening illness, MDD, TRD, AUD, and substance use disorder). A common feature across these studies is the criteria for eligibility, especially specific exclusionary criteria. For example, participants with severe personality disturbance or a personal or family history of psychosis or mania have been routinely excluded from psychedelic trials. In addition, persons determined to be at high risk for suicide as well as persons with a relatively high number of prior treatment failures (including neurostimulation) are also usually excluded (3, 31).
Consequently, the generalizability of results obtained from psychedelic studies is considerably affected. This limitation, however, as it relates to generalizability or ecological validity of psychedelic study results, is not dissimilar from most clinical trials conducted with conventional pharmacotherapy in psychiatry. For example, it is estimated that more than 80% of persons with MDD encountered in real-world clinical practice would be ineligible for enrollment in a clinical trial evaluating conventional antidepressants (32–34). Separately, psychedelic clinical trials may be unnecessarily restrictive given preliminary evidence supporting the safety of psychedelics in persons with bipolar II disorder, psychiatric and medical comorbidity, higher levels of treatment resistance, and active suicidal ideation (2, 4, 35, 36).
Blinding Integrity and Choosing an Adequate Placebo
The overarching objective of study blinding is to eliminate the bias associated with expectancy by equally distributing the expectancy effects across treatment arms (37). The integrity of study blinding refers to the success of establishing and maintaining concealment of treatment arm allocation. Study blinding is assessed simply by asking participants, investigators, and/or data analysis personnel to guess treatment assignment. Blinding is especially critical when the prespecified primary outcome measure of interest is subjective and/or the treatment results in atypical physiologic effects.
Most clinical trials in psychiatry do not report on subject expectancy or the integrity of study blinding. Studies that have evaluated blinding have consistently reported attenuated effects of the primary treatment (37–40). There is no universally accepted method to assess blinding integrity or objective standard on how functional unblinding would be considered in the statistical analytic plan. Intensified efforts have sought to determine a reliable and valid method to evaluate blinding in clinical trials (41).
The profound and non-ordinary effects of psychedelics on consciousness, cognitive processing, and sensory perception are highly apparent to the participant and health care provider. Furthermore, the extraordinary media attention, along with dramatic testimonials of “life-changing” experiences of persons taking psychedelics, creates a profound expectancy that intersects with compromised blinding integrity, resulting in “activated expectancy bias” (37, 42, 43).
For example, results from randomized, double-blind, controlled studies with both LSD and MDMA have reported that most participants accurately guess with a high level of certainty their treatment assignment (11, 18). Compromised blinding integrity in such studies may result in participant disappointment, especially if they are invested in being assigned to the active treatment. Consequently, the subjective disappointment may be predicted to worsen outcome in the placebo arm (i.e., nocebo) and enhance the estimated treatment effect (44–46).
Compromised blinding integrity with psychedelics, however, does not invalidate extant findings (11, 18). For example, a recently published open-label randomized study reported that intravenous ketamine is not inferior to ECT in adults with nonpsychotic TRD (47). Hence, the benefit observed with a treatment that is susceptible to unblinding (e.g., ketamine, psychedelics) may be validly explained by direct pharmacologic effects in addition to contextual and expectancy factors.
Several tactics may improve blinding integrity in psychedelic research. For example, as recommended by the U.S. Food and Drug Administration (FDA), the inclusion of an active placebo that produces a physiological response (e.g., a subperceptual dose of a psychedelic drug, niacin, dextromethorphan, or a benzodiazepine) could possibly assist in preserving participant blinding. As stated earlier, however, a subperceptual dose may also inadvertently amplify nocebo effects, which would need to be taken into consideration (45, 46, 48, 49). The use of third-party independent off-site raters, who are unfamiliar with the experience of each participant during the treatment session, may also assist in reducing functional unblinding.
Is the Psychedelic Trip Essential, or Is It Best Conceptualized as a Treatment-Emergent Adverse Event?
It has been asserted that the psychedelic experience explains and/or contributes to the therapeutic effect of psychedelics. This assertion is partly supported by testimonials in which the psychedelic experience is reported as being “life-changing” and sui generis. The psychedelic experience is also hypothesized to be a critical aspect of psychedelic-assisted psychotherapy, in which “integrating” the psychedelic experience is critical to the therapeutic process (50). Association between the psychedelic experience and therapeutic outcomes has been interpreted as evidence that the “trip” is critical (51, 52).
A separate hypothesis, however, is that the psychedelic experience may be critical for some persons, but may be inessential for others (53–61). Also, tacit to the foregoing is the assumption that the absence of a psychedelic effect would render a psychedelic treatment inefficacious (50). Notwithstanding the therapeutic importance that is often attributed to the psychedelic experience, existing controlled trial data neither confirm nor refute the hypothesis that the psychedelic trip is a sine qua non of a therapeutic effect with psychedelics (62).
Whether the psychedelic trip is intrinsic to the therapeutic effect of psychedelics is not only of conceptual interest, but also has substantial and critical implications for the clinical research and development of psychedelics, safety monitoring, ethical conduct of studies, and the implementation of psychedelics in clinical practice (50). For example, hallucinogen persisting perception disorder (HPPD) (i.e., flashbacks), a relatively uncommon toxicity associated with psychedelics, is an unnecessary risk if it is determined that the psychedelic trip is not required. Furthermore, a significant proportion of the cost, infrastructure, and human resources required to safely implement psychedelics derives from the safety concern of the psychedelic trip.
Precedent exists for psychiatric drug development to prematurely and erroneously embrace a phenomenological characteristic of a treatment as critical to its therapeutic effect rather than accurately understanding the phenomenon as a treatment-emergent adverse event. For example, dissociation associated with N-methyl-d-aspartate (NMDA) antagonists in MDD and drug-induced movement disorders associated with antipsychotics were originally believed to be intrinsic to their therapeutic effect. This belief was subsequently refuted, however, and these effects have been more accurately understood as treatment-emergent adverse events (19, 63, 64). Moreover, persons receiving NMDA antagonists dosed to achieve dissociation, or receiving antipsychotics dosed to achieve drug-induced movement disorders, guided by an erroneous understanding of the mechanism of action of these agents, were (and are) exposed to unnecessary harm (65–71).
Additional lines of evidence suggesting the non-essentiality of the psychedelic experience derive from mechanistic research that has observed that the molecular mechanisms mediating the hallucinogenic, antidepressant, and synaptoplasticity effects of psychedelics are dissociable (72). It was also observed, in the chronic unpredictable stress model of depression, that pretreatment with the serotonergic 5-HT2A/2C antagonist ketanserin failed to abolish psilocybin-mediated anti-anhedonia effects, suggesting that receptors other than 5-HT2A (known to mediate the psychedelic effects) may be critical to the therapeutic effect (73, 74).
More recently, case reports of persons benefiting from psychedelics in the absence of a psychedelic trip provide observational evidence supporting the hypothesis that the trip may not be intrinsic or required for therapeutic effect at the individual level (61). A further consideration is that several non-hallucinogenic psychedelics (i.e., biased β-arrestin activation) are in various phases of preclinical and clinical development for psychiatric disorders (61, 75).
Psychological Interventions and Psychedelics: Psychedelic-Assisted Psychotherapy or Psychotherapy-Assisted Psychedelic Therapy
Replicated evidence supports the superior efficacy of combining psychological support, psychoeducation, or manual-based psychotherapy with conventional pharmacotherapy, when compared to pharmacotherapy alone, in subpopulations of persons with MDD and other mental disorders (3, 76). Unique to the psychedelic paradigm is the assumption that psychological interventions are also a sine qua non in the preparation for and integration of the psychedelic experience in order to achieve optimal therapeutic outcomes (77–82).
Against this background, however, it is not established that the therapeutic effects of psychedelics are a result of, or partially mediated by, any specific component of the psychological intervention. There is also no evidence to determine the correct “dose” or modality of psychotherapy that is necessary to optimize safety and efficacy outcomes with psychedelics (83). The improvement in symptoms reported in persons receiving subperceptual doses of psychedelics in combination with supportive psychotherapy suggests that the psychotherapy may contribute in part to the overall therapeutic effect.
Future research could address this fundamental issue by comparing outcomes among participants randomized to one of three arms: protocolized psychotherapy alone, psychedelic treatment alone, and combination psychotherapy and psychedelic treatment (84, 85). Ascertaining the role of psychological treatments combined with psychedelics is not only a theoretical issue but, as addressed earlier with other aspects of psychedelics, has implications for accessibility, affordability, availability, and scalability of psychedelic treatments (48, 84, 85).
Priority Vistas Crucial to the Future of Psychedelic Development and Implementation in Psychiatry
The Need for Adequate and Well-Controlled Trials in Well-Defined Psychiatric Populations
Many cautionary lessons were learned from both the history of psychedelics in the 1960s and the promotion of recreational cannabis during the past two decades. For example, in the 1960s, the lack of adequate well-controlled trials with psychedelics, insufficient attention to safety concerns, and countercultural attitudes resulted in increased recreational use and risk to the general population. In response to these issues, psychedelics were subsequently scheduled by the Drug Enforcement Agency, largely prohibiting and reducing both academic and commercial development of these agents (86).
Similar to psychedelics, public policy and laws related to the possession and distribution of recreational cannabis have changed significantly during the past two decades. Evidence indicates that coinciding with these changes across the cannabis landscape was an increase in the nonmedical use of cannabis in the general population (87, 88). Despite the increased use of cannabis in the general population, there remains minimal evidence supporting cannabis to safely treat any psychiatric disorder (89). Instead, data indicate that recreational cannabis has been associated with hazardous mental health effects in the general population as well as those living with preexisting psychiatric disorders (90, 91).
Toward the aim of developing psychedelics for psychiatric disorders, it is imperative to enroll well-defined medical and psychiatric populations into controlled trials, with priority given to short- and long-term safety (42, 43, 92–94). Defining the population carefully also informs the risk-benefit analysis as it relates to treatment approval and implementation. Guidance from the FDA clearly states that although there are unique aspects to studying psychedelics, the foundational constructs and evidence standards should be no different from those of other psychotropic agents (48).
An additional strategic priority for research is to identify predictors of acute response as well as the durability of the effect. Separately, strategies that may prolong the therapeutic effect of psychedelics, other than repeat dosing, require empirical evaluation. Finally, psychedelics have not been studied in pediatric populations. In keeping with the Pediatric Research Equity Act, the safety and efficacy of any product seeking an indication in adults would require a safety and effectiveness assessment in younger populations unless it is “waived, deferred, or inapplicable” by the FDA (95).
Safety of Psychedelics
The most common adverse events associated with psychedelics are headaches, tachycardia, gastrointestinal, and psychological (96). Results from both controlled studies and testimonials indicate that a significant proportion of persons treated with psychedelics may experience psychologically distressing outcomes (97). Moreover, the altered state of consciousness induced by psychedelics may result in extraordinary vulnerability to boundary violations (26, 98).
Although it is asserted that psychedelics have a relatively large therapeutic index, the short- and long-term safety of psychedelics in the treatment of psychiatric disorders has been insufficiently characterized (96). In keeping with the FDA guidance, a trial duration of at least 12 weeks is recommended with psychedelics to ascertain safety (48). In addition, the teratogenic effects of psychedelics as well as their safety in combination with other pharmacological agents requires more thorough characterization.
Three specific aspects pertaining to the safety of psychedelics that require further evaluation include HPPD, risk for cardiovascular and valvular heart disease, and abuse potential (99–103).
Hallucinogen persisting perception disorder.
HPPD is defined and operationalized in DSM-5-TR and involves the repeated reexperience of perceptual disturbances from prior hallucinogen exposure after the effects of the hallucinogen have subsided (104, 105). HPPD has been subcategorized into two types: HPPD type 1 refers to short-term reversible hallucinatory experiences and perceptual disturbances that do not impair function, and HPPD type 2 refers to longer-duration (and in some cases irreversible or slowly reversible) hallucinatory experiences and perceptual disturbances, resulting in significant functional impairment (104).
It is estimated that approximately 5%–50% of recreational users of psychedelics experience HPPD type 1 and 1%–4% experience HPPD type 2 (104). Risk factors for HPPD are also not well characterized; it is suggested that LSD may have a greater risk for HPPD compared to other psychedelics. Preliminary evidence also suggests that persons with a primary psychotic disorder are at greater risk for HPPD (106, 107). Moreover, there is no established treatment for HPPD; second-generation antipsychotics, benzodiazepines, anticonvulsants, and opioid antagonists have been reported to be effective for HPPD in case reports (104).
Cardiovascular safety and valvular heart disease.
The cardiovascular safety of psychedelics also requires more thorough analysis (108). Results from a phase 1 open-label single ascending dose study in healthy control subjects (N=12) evaluating psilocybin doses ranging from 19 mg to 59 mg failed to observe a clinically relevant increase in the QTcF interval (109). Moreover, psilocin (the dephosphorylated metabolite of psilocybin) is not predicted to be torsadogenic, insofar as psilocin and its metabolite (4-hydroxyindole-3-acetic acid) do not meaningfully affect human ether-a-go-go (hERG) potassium channel function (110). However, case reports of cardiac arrhythmia, cardiac arrest, contractile dysfunction, and myocardial infarction associated with psilocybin and MDMA provide impetus for comprehensive cardiac safety evaluation (109–111).
Elevated levels of serotonin and/or pharmacologic interventions that increase serotonergic activity via the 5-HT2B receptor have been associated with valvular heart disease, with consequent regurgitant blood flow, cardiac insufficiency, and pulmonary hypertension (108, 112–116). Drug-induced valvular heart disease has been reported with antimigraine ergot alkaloids (e.g., ergotamine) and subsequently reported with agents indicated for Parkinson’s disease (e.g., pergolide), hyperprolactinemia (e.g., cabergoline), Dravet syndrome, and Lennox-Gastaut syndrome (i.e., fenfluramine), all of which are known to be 5-HT2B agonists (115, 117).
Whether psilocybin, via its dephosphorylated metabolite psilocin, or LSD and/or MDMA result in the profibrotic process characteristic of valvular heart disease is unknown. It is known, however, that the affinity for 5-HT2B receptors with psychedelics is several orders of magnitude lower than for 5-HT2A receptors (118, 119). In the interim, the FDA recently issued guidance to commercial developers and academic trial practitioners to evaluate the cellular, structural, and functional effects of psychedelic agents on cardiac valves (101). It is also the position of the FDA that participants enrolled in clinical trials with psychedelics should be evaluated with echocardiography, and persons with preexisting valvular heart disease or pulmonary hypertension should be excluded from trial enrollment.
Abuse Potential Assessment
Psychedelics are currently Schedule I substances under the Controlled Substances Act, indicating that these agents have potential for abuse and no accepted medical use. The liability for misuse of psychedelics among persons who receive these treatments for psychiatric disorders is not sufficiently documented, especially with longer-term use.
Although evidence indicates that psychedelics have minimal abuse liability, evaluation in psychiatric populations for risk of abuse, misuse, diversion, and gateway activity requires further evaluation (48, 120). Abuse potential assessment of psychedelics will be especially critical if psychedelics are eventually rescheduled under the Controlled Substances Act.
Infrastructure and Personnel
Two aspects pertinent to psychedelic treatment as it relates to infrastructure and personnel are “set and setting” and health care provider training (e.g., core competencies and scope of practice).
Set and setting.
The term “set and setting” was popularized by Timothy Leary in the 1960s (121, 122). Despite the controversy surrounding Leary’s role in psychedelics, set and setting has remained a central premise as it relates to influencing outcomes with psychedelics. The ritualistic and religious origins of psychedelics were the historical background supporting recommendations for adequate set and setting to increase the probability of a desired therapeutic outcome and reduce adverse experiences when administering psychedelics (123–127).
Set and setting refers to achieving a sufficient “mind set” as it relates to participant expectation, establishing support and reassurance, and providing education on anticipated as well as unanticipated therapeutic effects, both desired and adverse. Setting refers to the interpersonal and structural setting, with tactics to reduce overactivation of the participant and facilitate inward reflection and experience via multiple tactics (e.g., living room–like setting that seems less clinical, dimly lit room, eye shades, headphones, use of a curated playlist) (19).
Notwithstanding the importance given to set and setting with psychedelic research, there is no empirical evidence that any aspects of set and setting are specific to psychedelics and/or critical to the safe or effective administration of psychedelics. It is likely that emphasis on set and setting contributes to expectancy bias. Until evidence supports unique contributory effects of set and setting, the administration of psychedelics should be in a safe and supportive environment, with researchers encouraged to record methodological aspects implemented to inform future studies. Similar to the role of psychological intervention and psychedelic “trips,” ascertaining the necessity of set and setting is also critical from an implementation, accessibility, and scalability perspective. For example, although ketamine is available in many centers and private clinics, it is not accessible or scalable in part due to the requirement for a specialty setting for its implementation (19).
Health care provider training: core competencies and scope of practice.
The FDA has provided guidance to commercial sponsors, academic investigators, and trial practitioners on minimum requirements for health care provider training, core competencies, and scope of practice (48). Briefly, it is recommended that studies evaluating psychedelics have two monitors who are health care providers with graduate-level training and, at a minimum, one provider with expertise in psychotherapy (e.g., psychiatrist, M.S.W. practitioner, psychiatric nurse practitioner, clinical or counseling psychologists [Ph.D. or Psy.D.]) (48). The FDA also recommends that if the lead monitor is not a physician, a physician must be on call and accessible to the investigating center (48). Basic training in safety monitoring and supportive interventions in psychoeducation would be expected of all treating staff.
At least one provider should be licensed to practice psychotherapy in their local jurisdiction. Additional training specific to psychedelic-assisted psychotherapy is also recommended given the unique aspects of administering psychedelics. As reviewed earlier, however, it has been inadequately determined whether psychedelic-assisted psychotherapy is an essential component of administering psychedelics. It is known that psychedelic-assisted psychotherapy increases expectancy and performance bias, and future trials should attempt to quantify the contribution of psychotherapy to overall outcomes with psychedelics. The FDA guidance has encouraged the use of factorial designs to assist in separating the contribution of psychedelic treatment and psychotherapy to overall health outcomes (48).
Posology, Treatment Administration Paradigm, and Microdosing
The effects of psychedelics are related to dose, plasma concentration, and 5-HT2A receptor occupancy (51). The dose-response relationship of psychedelics with respect to safety and efficacy is not adequately ascertained. The minimum and maximum recommended starting and target dose with respect to efficacy and safety of psychedelics is also unknown. Results from the Compass study evaluating psilocybin in TRD provided additional preliminary evidence of a dose-efficacy relationship (31). There is suggestive evidence (using indirect comparison with meta-analytic methods) that higher doses of psilocybin and repeat doses may be more effective than single-dose administration (128). Lastly, the optimal dosing paradigm (e.g., acute single dose, acute repeat dose, or chronic intermittent dosing) for psychedelics is also not known.
The use of the term “microdosing” has no consensus definition or objective pharmacologic meaning (129). Microdosing has generally referred to the self-administration of a psychedelic at a dose that does not affect sensory function, engender hallucinogenic experiences, or cause functional impairment (27). It is reported that most individuals who microdose psychedelics administer 10–20 µg of LSD or 0.1–0.3 g of dried psilocybin-containing mushrooms 1–4 times per week (37, 130).
Microdosing of psychedelics has a lengthy history, and its popularity has been amplified by social media chat groups and “influencers” (28). Results from in-person and online surveys as well as observational studies have reported benefits in creativity, problem-solving performance, cognitive flexibility, reduced anxiety, well-being, and social interaction among persons microdosing psychedelics (131–140). Notwithstanding these survey data, these samples do not usually include participants with a psychiatric disorder confirmed with a structured clinical interview.
In addition, there is no rigorous controlled trial evidence supporting the efficacy or safety of microdosing of any psychedelic for any psychiatric disorder (141, 142). A relatively small placebo-controlled trial (N=109) in participants without a psychiatric disorder who were recruited via online/offline forums failed to detect any benefit of microdosing with any psychedelics (any psychedelic chosen by the participant) across psychological measures when compared to placebo (143).
Notwithstanding the absence of adequate and well-controlled studies with psychedelic microdosing, evidence provides a rationale for hypothesizing that microdosing may be potentially beneficial (144). For example, a study in which healthy adults (N=18) received three sessions of placebo or LSD at two doses (13 µg and 26 µg) reported that both doses of LSD increased reward-related brain activity (during the monetary incentive delay task) compared with placebo (19, 108, 145, 146). The potential for implementation in a less restrictive environment that has greater scale and cost-effectiveness is an appealing aspect of microdosing if it is shown to be safe and effective. More frequent microdosing does, however, introduce additional safety concerns, especially as it relates to organ toxicity during long-term exposure (e.g., valvular heart disease) (108, 118, 147).
Characterizing the Pharmacodynamics and Pharmacokinetics of Psychedelic Agents
Psychedelics have been inadequately evaluated with respect to pharmacodynamics and pharmacokinetics (19, 148, 149). It is also not sufficiently established whether psychedelics are best conceptualized as psychoplastogens or neuroplastogens (that is, are the molecular and cellular effects that mediate therapeutic and psychedelic effects overlapping or are they dissociable?) (96). As with other interventions, studies with psychedelics should evaluate the effect of a high-fat meal and drug-disease and drug-drug interactions on the pharmacokinetics of psychedelics.
Combining psychedelics with other serotonin-mimetic agents could increase risk for serotonin syndrome and vasopressor effects (148, 150). A concern with coadministration of serotonergic psychedelics with 5-HT2A antagonists is that they may mitigate efficacy of the psychedelic agent. For example, ketanserin attenuates molecular, cellular, and behavioral effects of serotonergic psychedelics that are thought to mediate antidepressive effects (151). It is separately reported that ketanserin reduces the subjective experience and duration of psychedelics (152, 153). It is not known, however, whether coadministering a 5-HT2A antagonist with a serotonergic psychedelic attenuates the efficacy of psychedelic treatment despite attenuating the psychedelic experience (61).
Eligibility for serotonergic psychedelic treatment in adults with depressive disorders typically requires a person to have had prior antidepressant exposure. Chronic antidepressant exposure results in 5-HT2A receptor downregulation, which may attenuate the efficacy of serotonergic psychedelics. In keeping with this view, it is reported that exposure to serotonergic antidepressants is associated with a decrease in head-twitch response (a surrogate marker of psychedelic action) with psychedelics in animal models (154, 155).
Survey data of persons with prior antidepressant exposure have reported decreased subjective effects with subsequent administration of psychedelics (156–158). Results from a 2-week randomized, double-blind, placebo-controlled trial in healthy volunteers, however, determined that the subjective positive experience of psilocybin (25 mg) was not attenuated but instead significantly reduced adverse drug effects such as anxiety, compared to placebo pretreatment (159).
Separately, it is reported that persons receiving psilocybin concomitantly with serotonergic antidepressants exhibit attenuated subjective experiences but manifest a similar antidepressant response when compared to those receiving psychedelics who had no prior antidepressant exposure (160). Similarly, results from an open-label study with psilocybin in a small sample of adults with TRD (N=19) indicated that psilocybin safety and efficacy were not meaningfully affected by combining psilocybin with conventional antidepressants (161).
Cost-Effectiveness
It remains unclear how treatment with psilocybin and other psychedelics will be implemented within the existing mental health infrastructure, how it will be disbursed, and whether it is cost-effective. In addition to aspects of implementation, ascertaining cost-effectiveness will be critical to psychedelic development (162). Hitherto most cost-effectiveness studies with psychedelics have evaluated MDMA, with relatively few evaluating serotonergic psychedelics (163–166).
Taken together, results for psychedelics suggest that price scenarios that reduce current therapist and treatment acquisition by more than 50% would render psilocybin a cost-effective treatment in depression (162). The foregoing underscores the importance of ascertaining whether psychedelics can be safely and effectively implemented with support but without contemporaneous psychotherapy (84). Without a realistic cost-effectiveness estimate that is competitive relative to other agents, psychedelics will not be implemented at scale, greatly reducing their societal impact.
Conclusions
Psychedelics hold tremendous promise to improve the quality of life of persons affected by psychiatric disorders, with the potential for a more rapid, robust, and/or enduring therapeutic effect as part of an intermittent dosing paradigm. Multiple methodological aspects affect the generalizability and interpretability of extant studies with psychedelics. The aspects reviewed here do not negate the validity of study findings but instead provide the basis for considering vistas for future research and development that need to be prioritized. Careful attention to these aspects will improve the probability that the short- and long-term efficacy and safety signals with psychedelics will be fully ascertained and quantified accurately, that public trust in these treatments will be safeguarded, that they will be appropriately regulated, and that their access and availability will be cost-effective.
References
1.
Nutt D, Erritzoe D, Carhart-Harris R: Psychedelic psychiatry’s brave new world. Cell 2020; 181:24–28
2.
Rosenblat JD, Husain MI, Lee Y, et al: The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force report: serotonergic psychedelic treatments for major depressive disorder. Can J Psychiatry 2023; 68:5–21
3.
McIntyre RS, Alsuwaidan M, Baune BT, et al: Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry 2023; 22:394–412
4.
Rosenblat JD, Meshkat S, Doyle Z, et al: Psilocybin-assisted psychotherapy for treatment resistant depression: a randomized clinical trial evaluating repeated doses of psilocybin. Med 2024; 5:190–200.e5
5.
Goodwin GM, Hellerstein DJ, Young AH: Psilocybin for treatment-resistant depression (reply). N Engl J Med 2023; 388:e22
6.
Raison CL, Sanacora G, Woolley J, et al: Single-dose psilocybin treatment for major depressive disorder: a randomized clinical trial. JAMA 2023; 330:843–853
7.
Carhart-Harris R, Giribaldi B, Watts R, et al: Trial of psilocybin versus escitalopram for depression. N Engl J Med 2021; 384:1402–1411
8.
Davis AK, Barrett FS, May DG, et al: Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry 2021; 78:481–489
9.
Haikazian S, Chen-Li DCJ, Johnson DE, et al: Psilocybin-assisted therapy for depression: a systematic review and meta-analysis. Psychiatry Res 2023; 329:115531
10.
Sicignano D, Hernandez AV, Schiff B, et al: The impact of psychedelics on patients with alcohol use disorder: a systematic review with meta-analysis. Curr Med Res Opin 2024; 40:293–302
11.
Bogenschutz MP, Ross S, Bhatt S, et al: Percentage of heavy drinking days following psilocybin-assisted psychotherapy vs placebo in the treatment of adult patients with alcohol use disorder: a randomized clinical trial. JAMA Psychiatry 2022; 79:953–962
12.
Holze F, Gasser P, Müller F, et al: Lysergic acid diethylamide-assisted therapy in patients with anxiety with and without a life-threatening illness: a randomized, double-blind, placebo-controlled phase II study. Biol Psychiatry 2023; 93:215–223
13.
Ot’alora G M, Grigsby J, Poulter B, et al: 3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: a randomized phase 2 controlled trial. J Psychopharmacol 2018; 32:1295–1307
14.
Mithoefer MC, Wagner MT, Mithoefer AT, et al: The safety and efficacy of (+/-)3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. J Psychopharmacol 2011; 25:439–452
15.
Mithoefer MC, Wagner MT, Mithoefer AT, et al: Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. J Psychopharmacol 2013; 27:28–39
16.
Mithoefer MC, Mithoefer AT, Feduccia AA, et al: 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry 2018; 5:486–497
17.
Oehen P, Traber R, Widmer V, et al: A randomized, controlled pilot study of MDMA (±3,4-methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic post-traumatic stress disorder (PTSD). J Psychopharmacol 2013; 27:40–52
18.
Mitchell JM, Ot’alora G M, van der Kolk B, et al: MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat Med 2023; 29:2473–2480
19.
McIntyre RS, Rosenblat JD, Nemeroff CB, et al: Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry 2021; 178:383–399
20.
Phillips JL, Norris S, Talbot J, et al: Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry 2019; 176:401–409
21.
Fava M, Freeman MP, Flynn M, et al: Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry 2020; 25:1592–1603
22.
Murrough JW, Iosifescu DV, Chang LC, et al: Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013; 170:1134–1142
23.
Loo C, Glozier N, Barton D, et al: Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial. Br J Psychiatry 2023; 223:533–541
24.
Nikolin S, Rodgers A, Schwaab A, et al: Ketamine for the treatment of major depression: a systematic review and meta-analysis. EClinicalMedicine 2023; 62:102127
25.
Reif A, Bitter I, Buyze J, et al: Esketamine nasal spray versus quetiapine for treatment-resistant depression. N Engl J Med 2023; 389:1298–1309
26.
Seybert C, Cotovio G, Madeira L, et al: Psychedelic treatments for mental health conditions pose challenges for informed consent. Nat Med 2023;29:2167–2170
27.
Schimmers N, Breeksema JJ, Smith-Apeldoorn SY, et al: Psychedelics for the treatment of depression, anxiety, and existential distress in patients with a terminal illness: a systematic review. Psychopharmacology (Berl) 2022; 239:15–33
28.
Ledwos N, Rosenblat JD, Blumberger DM, et al: A critical appraisal of evidence on the efficacy and safety of serotonergic psychedelic drugs as emerging antidepressants: mind the evidence gap. J Clin Psychopharmacol 2022; 42:581–588
29.
Zafar R, Siegel M, Harding R, et al: Psychedelic therapy in the treatment of addiction: the past, present and future. Front Psychiatry 2023; 14:1183740
30.
Lewis BR, Byrne K: A review of MDMA-assisted therapy for posttraumatic stress disorder. Focus (Am Psychiatr Publ) 2023; 21:247–256
31.
Goodwin GM, Aaronson ST, Alvarez O, et al: Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med 2022; 387:1637–1648
32.
Preskorn SH, Macaluso M, Trivedi M: How commonly used inclusion and exclusion criteria in antidepressant registration trials affect study enrollment. J Psychiatr Pract 2015; 21:267–274
33.
Wells KB: Treatment research at the crossroads: the scientific interface of clinical trials and effectiveness research. Am J Psychiatry 1999; 156:5–10
34.
Zimmerman M, Chelminski I, Posternak MA: Generalizability of antidepressant efficacy trials: differences between depressed psychiatric outpatients who would or would not qualify for an efficacy trial. Am J Psychiatry 2005; 162:1370–1372
35.
Aaronson ST, van der Vaart A, Miller T, et al: Single-dose synthetic psilocybin with psychotherapy for treatment-resistant bipolar type II major depressive episodes: a nonrandomized controlled trial. JAMA Psychiatry 2023:e234685
36.
Ellis S, Bostian C, Feng W, et al: Single-dose psilocybin for US military veterans with severe treatment-resistant depression: a first-in-kind open-label pilot study. J Affect Disord 2024; 369:381–389
37.
Szigeti B, Nutt D, Carhart-Harris R, et al: The difference between “placebo group” and “placebo control”: a case study in psychedelic microdosing. Sci Rep 2023; 13:12107
38.
Baethge C, Assall OP, Baldessarini RJ: Systematic review of blinding assessment in randomized controlled trials in schizophrenia and affective disorders 2000–2010. Psychother Psychosom 2013; 82:152–160
39.
Colagiuri B, Sharpe L, Scott A: The blind leading the not-so-blind: a meta-analysis of blinding in pharmacological trials for chronic pain. J Pain 2019; 20:489–500
40.
Fergusson D, Glass KC, Waring D, et al: Turning a blind eye: the success of blinding reported in a random sample of randomised, placebo controlled trials. BMJ 2004; 328:432
41.
Bang H, Ni L, Davis CE: Assessment of blinding in clinical trials. Control Clin Trials 2004; 25:143–156
42.
Rucker JJ: Evidence versus expectancy: the development of psilocybin therapy. BJPsych Bull 2024; 48:110–117
43.
Butler M, Jelen L, Rucker J: Expectancy in placebo-controlled trials of psychedelics: if so, so what? Psychopharmacology 2022; 239:3047–3055
44.
Kaertner LS, Steinborn MB, Kettner H, et al: Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing. Sci Rep 2021; 11:1941
45.
Aday JS, Carhart-Harris RL, Woolley JD: Emerging challenges for psychedelic therapy. JAMA Psychiatry 2023; 80:533–534
46.
Aday JS, Heifets BD, Pratscher SD, et al: Great expectations: recommendations for improving the methodological rigor of psychedelic clinical trials. Psychopharmacology (Berl) 2022; 239:1989–2010
47.
Anand A, Mathew SJ, Sanacora G, et al: Ketamine versus ECT for nonpsychotic treatment-resistant major depression. N Engl J Med 2023; 388:2315–2325
48.
US Food and Drug Administration, Center for Drug Evaluation and Research: Psychedelic Drugs: Considerations for Clinical Investigations. June 2023. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/psychedelic-drugs-considerations-clinical-investigations
49.
Marks M, Cohen IG: How should the FDA evaluate psychedelic medicine? N Engl J Med 2023; 389; 1733–1735
50.
McIntyre RS: 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. Expert Opin Drug Saf 2023; 22:885–889
51.
Nutt DJ, Peill JM, Weiss B, et al: Psilocybin and other classic psychedelics in depression. Curr Top Behav Neurosci 2024; 66:149–174
52.
Nygart VA, Pommerencke LM, Haijen E, et al: Antidepressant effects of a psychedelic experience in a large prospective naturalistic sample. J Psychopharmacol 2022; 36:932–942
53.
Roseman L, Nutt DJ, Carhart-Harris RL: Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Front Pharmacol 2017; 8:974
54.
Barrett FS, Griffiths RR: Classic hallucinogens and mystical experiences: phenomenology and neural correlates. Curr Top Behav Neurosci 2018; 36:393–430
55.
Yaden DB, Griffiths RR: The subjective effects of psychedelics are necessary for their enduring therapeutic effects. ACS Pharmacol Transl Sci 2021; 4:568–572
56.
Griffiths RR, Johnson MW, Carducci MA, et al: Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol 2016; 30:1181–1197
57.
Ross S, Bossis A, Guss J, et al: Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol 2016; 30:1165–1180
58.
Johnson MW, Garcia-Romeu A, Cosimano MP, et al: Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol 2014; 28:983–992
59.
Griffiths RR, Richards WA, McCann U, et al: Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berl) 2006; 187:268–283
60.
Griffiths RR, Johnson MW, Richards WA, et al: Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. J Psychopharmacol 2018; 32:49–69
61.
Rosenblat JD, Leon-Carlyle M, Ali S, et al: Antidepressant effects of psilocybin in the absence of psychedelic effects. Am J Psychiatry 2023; 180:395–396
62.
von Rotz R, Schindowski EM, Jungwirth J, et al: Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo-controlled, double-blind, randomised clinical trial. EClinicalMedicine 2022; 56:101809
63.
Chen G, Chen L, Zhang Y, et al: Relationship between dissociation and antidepressant effects of esketamine nasal spray in patients with treatment-resistant depression. Int J Neuropsychopharmacol 2022; 25:269–279
64.
Hack LM, Zhang X, Heifets BD, et al: Ketamine’s acute effects on negative brain states are mediated through distinct altered states of consciousness in humans. Nat Commun 2023; 14:6631
65.
Majeed A, Xiong J, Teopiz KM, et al: Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials. Expert Opin Emerg Drugs 2021; 26:63–74
66.
Fava M, Stahl S, Pani L, et al: REL-1017 (esmethadone) as adjunctive treatment in patients with major depressive disorder: a phase 2a randomized double-blind trial. Am J Psychiatry 2022; 179:122–131
67.
Akbar D, Rhee TG, Ceban F, et al: Dextromethorphan-bupropion for the treatment of depression: a systematic review of efficacy and safety in clinical trials. CNS Drugs 2023; 37:867–881
68.
Fava M, Stahl SM, De Martin S, et al: Esmethadone-HCl (REL-1017): a promising rapid antidepressant. Eur Arch Psychiatry Clin Neurosci 2023; 273:1463–1476
69.
Gardner DM, Murphy AL, O’Donnell H, et al: International consensus study of antipsychotic dosing. FOC 2014; 12:235–243
70.
Cha DS, McIntyre RS: Treatment-emergent adverse events associated with atypical antipsychotics. Expert Opin Pharmacother 2012; 13:1587–1598
71.
Samaha AN, Reckless GE, Seeman P, et al: Less is more: antipsychotic drug effects are greater with transient rather than continuous delivery. Biol Psychiatry 2008; 64:145–152
72.
Moliner R, Girych M, Brunello CA, et al: Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nat Neurosci 2023; 26:1032–1041
73.
Jaster AM, de la Fuente Revenga M, González-Maeso J: Molecular targets of psychedelic-induced plasticity. J Neurochem 2022; 162:80–88
74.
Hesselgrave N, Troppoli TA, Wulff AB, et al: Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci U S A 2021; 118:e2022489118
75.
Lewis V, Bonniwell EM, Lanham JK, et al: A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Cell Rep 2023; 42:112203
76.
Cuijpers P, Miguel C, Harrer M, et al: Cognitive behavior therapy vs control conditions, other psychotherapies, pharmacotherapies and combined treatment for depression: a comprehensive meta-analysis including 409 trials with 52,702 patients. World Psychiatry 2023; 22:105–115
77.
Carhart-Harris RL, Kaelen M, Whalley MG, et al: LSD enhances suggestibility in healthy volunteers. Psychopharmacology (Berl) 2015; 232:785–794
78.
Crowe M, Manuel J, Carlyle D, et al: Psilocybin-assisted psychotherapy for treatment-resistant depression: which psychotherapy? Int J Ment Health Nurs 2023; 32:1766–1772
79.
Godes M, Lucas J, Vermetten E: Perceived key change phenomena of MDMA-assisted psychotherapy for the treatment of severe PTSD: an interpretative phenomenological analysis of clinical integration sessions. Front Psychiatry 2023; 14:957824
80.
Lepow L, Morishita H, Yehuda R: Critical period plasticity as a framework for psychedelic-assisted psychotherapy. Focus (Am Psychiatr Publ) 2023; 21:329–336
81.
Palitsky R, Kaplan DM, Peacock C, et al: Importance of integrating spiritual, existential, religious, and theological components in psychedelic-assisted therapies. JAMA Psychiatry 2023; 80:743–749
82.
Smith KW, Sicignano DJ, Hernandez AV, et al: MDMA-assisted psychotherapy for treatment of posttraumatic stress disorder: a systematic review with meta-analysis. J Clin Pharmacol 2022; 62:463–471
83.
Seybert C, Schimmers N, Silva L, et al: Quality of reporting on psychological interventions in psychedelic treatments: a systematic review. Lancet Psychiatry (in press)
84.
Goodwin GM, Malievskaia E, Fonzo GA, et al: Must psilocybin always “assist psychotherapy”? Am J Psychiatry 2024; 181:20–25
85.
Dworkin RH, McDermott MP, Nayak SM, et al: Psychedelics and psychotherapy: is the whole greater than the sum of its parts? Clin Pharmacol Ther 2023; 114:1166–1169
86.
Volkow ND, Gordon JA, Wargo EM. Psychedelics as therapeutics: potential and challenges. JAMA Psychiatry 2023; 80:979–980
87.
Compton WM, Volkow ND, Lopez MF: Medical marijuana laws and cannabis use: intersections of health and policy. JAMA Psychiatry 2017; 74:559–560
88.
Volkow ND, Swanson JM, Evins AE, et al: Effects of cannabis use on human behavior, including cognition, motivation, and psychosis: a review. JAMA Psychiatry 2016; 73:292–297
89.
Hill KP, Gold MS, Nemeroff CB, et al: Risks and benefits of cannabis and cannabinoids in psychiatry. Am J Psychiatry 2022; 179:98–109
90.
Hjorthøj C, Compton W, Starzer M, et al: Association between cannabis use disorder and schizophrenia stronger in young males than in females. Psychol Med 2023; 53:7322–7328
91.
Brittain T: An investigation of the functioning of the two major haemoglobins of the Sphenodon using fast reaction kinetic methods. Biochem J 1988; 251:771–776
92.
Thomas CW, Blanco-Duque C, Bréant BJ, et al: Psilocin acutely alters sleep-wake architecture and cortical brain activity in laboratory mice. Transl Psychiatry 2022; 12:77
93.
Dougherty RF, Clarke P, Atli M, et al: Psilocybin therapy for treatment resistant depression: prediction of clinical outcome by natural language processing. Psychopharmacology (Berl) (Online ahead of print, August 22, 2023)
94.
Spriggs MJ, Giribaldi B, Lyons T, et al: Body mass index (BMI) does not predict responses to psilocybin. J Psychopharmacol 2023; 37:107–116
95.
Center for Drug Evaluation and Research, US Food and Drug Administration: Pediatric Research Equity Act. https://www.fda.gov/drugs/development-resources/pediatric-research-equity-act-prea
96.
Dodd S, Norman TR, Eyre HA, et al: Psilocybin in neuropsychiatry: a review of its pharmacology, safety, and efficacy. CNS Spectr 2022:1–11
97.
Zeifman RJ, Kettner H, Pagni BA, et al: Co-use of MDMA with psilocybin/LSD may buffer against challenging experiences and enhance positive experiences. Sci Rep 2023; 13:13645
98.
Mann JJ: Is psilocybin an effective antidepressant and what is its mechanism of action? Cell Rep Med 2023; 4:100906
99.
Ng J, Lui LMW, Rosenblat JD, et al: Ketamine-induced urological toxicity: potential mechanisms and translation for adults with mood disorders receiving ketamine treatment. Psychopharmacology (Berl) 2021; 238:917–926
100.
Yu WL, Cho CCM, Lung PFC, et al: Ketamine-related cholangiopathy: a retrospective study on clinical and imaging findings. Abdom Imaging 2014; 39:1241–1246
101.
US Food and Drug Administration, Office of the Commissioner: FDA Issues First Draft Guidance on Clinical Trials with Psychedelic Drugs [FDA news release]. June 23, 2023. https://www.fda.gov/news-events/press-announcements/fda-issues-first-draft-guidance-clinical-trials-psychedelic-drugs
102.
Center for Drug Evaluation, Research. US Food and Drug Administration: Premarketing Risk Assessment: Guidance for Industry. FDA, March 2005. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/premarketing-risk-assessment
103.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use: ICH Topic E1. The Extent of Population Exposure to Assess Clinical Safety For Drugs Intended For Long-Term Treatment of Non-Life-Threatening Conditions. October 27, 1994. https://database.ich.org/sites/default/files/E1_Guideline.pdf
104.
Doyle MA, Ling S, Lui LMW, et al: Hallucinogen persisting perceptual disorder: a scoping review covering frequency, risk factors, prevention, and treatment. Expert Opin Drug Saf 2022; 21:733–743
105.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR). Washington, DC, American Psychiatric Association, 2022
106.
G Lerner A, Rudinski D, Bor O, et al: Flashbacks and HPPD: a clinical-oriented concise review. Isr J Psychiatry Relat Sci 2014; 51:296–301
107.
Orsolini L, Papanti GD, De Berardis D, et al: The “endless trip” among the NPS users: psychopathology and psychopharmacology in the hallucinogen-persisting perception disorder: a systematic review. Front Psychiatry 2017; 8:240
108.
McIntyre RS: Serotonin 5-HT2B receptor agonism and valvular heart disease: implications for the development of psilocybin and related agents. Expert Opin Drug Saf 2023; 22:881–883
109.
Dahmane E, Hutson PR, Gobburu JVS: Exposure-response analysis to assess the concentration-QTc relationship of psilocybin/psilocin. Clin Pharmacol Drug Dev 2021; 10:78–85
110.
Hackl B, Todt H, Kubista H, et al: Psilocybin therapy of psychiatric disorders is not hampered by hERG potassium channel-mediated cardiotoxicity. Int J Neuropsychopharmacol 2022; 25:280–282
111.
Dominic P, Ahmad J, Awwab H, et al: Stimulant drugs of abuse and cardiac arrhythmias. Circ Arrhythm Electrophysiol 2022; 15:e010273
112.
Lam NT, Balachandran K: The mechanobiology of drug-induced cardiac valve disease. J Long Term Eff Med Implants 2015; 25:27–40
113.
Ayme-Dietrich E, Lawson R, Da-Silva S, et al: Serotonin contribution to cardiac valve degeneration: new insights for novel therapies? Pharmacol Res 2019; 140:33–42
114.
Setola V, Dukat M, Glennon RA, et al: Molecular determinants for the interaction of the valvulopathic anorexigen norfenfluramine with the 5-HT2B receptor. Mol Pharmacol 2005; 68:20–33
115.
Jin C, Sharma AN, Thevakumar B, et al: Carcinoid heart disease: pathophysiology, pathology, clinical manifestations, and management. Cardiology 2021; 146:65–73
116.
Papoian T, Jagadeesh G, Saulnier M, et al: Regulatory forum review: Utility of in vitro secondary pharmacology data to assess risk of drug-induced valvular heart disease in humans: regulatory considerations. Toxicol Pathol 2017; 45:381–388
117.
Cavero I, Guillon JM: Safety pharmacology assessment of drugs with biased 5-HT2B receptor agonism mediating cardiac valvulopathy. J Pharmacol Toxicol Methods 2014; 69:150–161
118.
Rouaud A, Calder AE, Hasler G: Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: comparison to known cardiotoxins. J Psychopharmacol 2024; 38:217–224
119.
Rickli A, Moning OD, Hoener MC, et al: Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. Eur Neuropsychopharmacol 2016; 26:1327–1337
120.
Nutt D, King LA, Saulsbury W, et al: Development of a rational scale to assess the harm of drugs of potential misuse. Lancet 2007; 369:1047–1053
121.
Leary T, Litwin GH, Metzner R: Reactions to psilocybin administered in a supportive environment. J Nerv Ment Dis 1963; 137:561–573
122.
Dyck E, Farrell P: Psychedelics and psychotherapy in Canada: Humphry Osmond and Aldous Huxley. Hist Psychol 2018; 21:240–253
123.
Golden TL, Magsamen S, Sandu CC, et al: Effects of setting on psychedelic experiences, therapies, and outcomes: a rapid scoping review of the literature. Curr Top Behav Neurosci 2022; 56:35–70
124.
Gukasyan N, Nayak SM: Psychedelics, placebo effects, and set and setting: insights from common factors theory of psychotherapy. Transcult Psychiatry 2022; 59:652–664
125.
Winkelman MJ: The evolved psychology of psychedelic set and setting: inferences regarding the roles of shamanism and entheogenic ecopsychology. Front Pharmacol 2021; 12:619890
126.
Cavarra M, Falzone A, Ramaekers JG, et al: Psychedelic-assisted psychotherapy: a systematic review of associated psychological interventions. Front Psychol 2022; 13:887255
127.
Carhart-Harris RL, Roseman L, Haijen E, et al: Psychedelics and the essential importance of context. J Psychopharmacol 2018; 32:725–731
128.
Yu CL, Liang CS, Yang FC, et al: Trajectory of antidepressant effects after single- or two-dose administration of psilocybin: a systematic review and multivariate meta-analysis. J Clin Med 2022; 11:938
129.
Sellers EM, Romach MK: Psychedelics: science sabotaged by social media. Neuropharmacology 2023; 227:109426
130.
Kuypers KP, Ng L, Erritzoe D, et al: Microdosing psychedelics: more questions than answers? An overview and suggestions for future research. J Psychopharmacol 2019; 33:1039–1057
131.
Prochazkova L, Lippelt DP, Colzato LS, et al: Exploring the effect of microdosing psychedelics on creativity in an open-label natural setting. Psychopharmacology (Berl) 2018; 235:3401–3413
132.
Anderson T, Petranker R, Christopher A, et al: Psychedelic microdosing benefits and challenges: an empirical codebook. Harm Reduct J 2019; 16:43
133.
Lea T, Amada N, Jungaberle H, et al: Microdosing psychedelics: motivations, subjective effects and harm reduction. Int J Drug Policy 2020; 75:102600
134.
Kuypers KPC: The therapeutic potential of microdosing psychedelics in depression. Ther Adv Psychopharmacol 2020; 10:2045125320950567
135.
Fadiman J, Korb S: Might microdosing psychedelics be safe and beneficial? An initial exploration. J Psychoactive Drugs 2019; 51:118–122
136.
Hutten NRPW, Mason NL, Dolder PC, et al: Self-rated effectiveness of microdosing with psychedelics for mental and physical health problems among microdosers. Front Psychiatry 2019; 10:672
137.
Lyes M, Yang KH, Castellanos J, et al: Microdosing psilocybin for chronic pain: a case series. Pain 2023; 164:698–702
138.
Bershad AK, Schepers ST, Bremmer MP, et al: Acute subjective and behavioral effects of microdoses of lysergic acid diethylamide in healthy human volunteers. Biol Psychiatry 2019; 86:792–800
139.
Cameron LP, Nazarian A, Olson DE: Psychedelic microdosing: prevalence and subjective effects. J Psychoactive Drugs 2020; 52:113–122
140.
Lea T, Amada N, Jungaberle H: Psychedelic microdosing: a subreddit analysis. J Psychoactive Drugs 2020; 52:101–112
141.
Vollenweider FX, Kometer M: The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci 2010; 11:642–651
142.
Marschall J, Fejer G, Lempe P, et al: Psilocybin microdosing does not affect emotion-related symptoms and processing: a preregistered field and lab-based study. J Psychopharmacol 2022; 36:97–113
143.
Szigeti B, Kartner L, Blemings A, et al: Self-blinding citizen science to explore psychedelic microdosing. Elife 2021; 10:e62878
144.
Higgins GA, Carroll NK, Brown M, et al: Low doses of psilocybin and ketamine enhance motivation and attention in poor performing rats: evidence for an antidepressant property. Front Pharmacol 2021; 12:640241
145.
Hamill J, Hallak J, Dursun SM, et al: Ayahuasca: psychological and physiologic effects, pharmacology and potential uses in addiction and mental illness. Curr Neuropharmacol 2019; 17:108–128
146.
Riba J, Valle M, Urbano G, et al: Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. J Pharmacol Exp Ther 2003; 306:73–83
147.
Tagen M, Mantuani D, van Heerden L, et al: The risk of chronic psychedelic and MDMA microdosing for valvular heart disease. J Psychopharmacol 2023; 37:876–890
148.
Sarparast A, Thomas K, Malcolm B, et al: Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review. Psychopharmacology 2022; 239:1945–1976
149.
Meshkat S, Teopiz KM, Di Vincenzo JD, et al: 2023, Clinical efficacy and safety of zuranolone (SAGE-217) in individuals with major depressive disorder. J Affect Disord 2023; 340; 893:898
150.
Malcolm B, Thomas K: Serotonin toxicity of serotonergic psychedelics. Psychopharmacology 2022; 239:1881–1891
151.
Li K, Liu X, Zhang M, et al: Effects of ketanserin, M100907 and olanzapine on hallucinogenic like action induced by 2,5-dimethoxy-4-methylamphetamine. Behav Pharmacol 2023; 34:92–100
152.
Becker AM, Klaiber A, Holze F, et al: Ketanserin reverses the acute response to LSD in a randomized, double-blind, placebo-controlled, crossover study in healthy participants. Int J Neuropsychopharmacol 2023; 26:97–106
153.
Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A, et al: Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 1998; 9:3897–3902
154.
Goodwin GM, Green AR, Johnson P: 5-HT2 receptor characteristics in frontal cortex and 5-HT2 receptor-mediated head-twitch behaviour following antidepressant treatment to mice. Br J Pharmacol 1984; 83:235–242
155.
Metz A, Heal DJ: In mice repeated administration of electroconvulsive shock or desmethylimipramine produces rapid alterations in 5-HT2-mediated head-twitch responses and cortical 5-HT2 receptor number. Eur J Pharmacol 1986; 126:159–162
156.
Bonson KR, Buckholtz JW, Murphy DL: Chronic administration of serotonergic antidepressants attenuates the subjective effects of LSD in humans. Neuropsychopharmacology 1996; 14:425–436
157.
Bonson KR, Murphy DL: Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, monoamine oxidase inhibitors or lithium. Behav Brain Res 1996; 73:229–233
158.
Gukasyan N, Griffiths RR, Yaden DB, et al: Attenuation of psilocybin mushroom effects during and after SSRI/SNRI antidepressant use. J Psychopharmacol 2023; 37:707–716
159.
Becker AM, Holze F, Grandinetti T, et al: Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects. Clin Pharmacol Ther 2022; 111:886–895
160.
Barbut Siva J, Barba T, Kettner H, et al: Interactions between classic psychedelics and serotonergic antidepressants: effects on the acute psychedelic subjective experience, well-being and depressive symptoms from a prospective survey study. J Psychopharmacol 2024; 38:145–155
161.
Goodwin GM, Croal M, Feifel D, et al: Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. Neuropsychopharmacology 2023; 48:1492–1499
162.
McCrone P, Fisher H, Knight C, et al: Cost-effectiveness of psilocybin-assisted therapy for severe depression: exploratory findings from a decision analytic model. Psychol Med 2023; 53:7619–7626
163.
Brendle M, Robison R, Malone DC: Cost-effectiveness of esketamine nasal spray compared to intravenous ketamine for patients with treatment-resistant depression in the US utilizing clinical trial efficacy and real-world effectiveness estimates. J Affect Disord 2022; 319:388–396
164.
Marseille E, Mitchell JM, Kahn JG: Updated cost-effectiveness of MDMA-assisted therapy for the treatment of posttraumatic stress disorder in the United States: findings from a phase 3 trial. PLoS One 2022; 17:e0263252
165.
Marseille E, Kahn JG, Yazar-Klosinski B, et al: The cost-effectiveness of MDMA-assisted psychotherapy for the treatment of chronic, treatment-resistant PTSD. PLoS One 2020; 15:e0239997
166.
Avanceña ALV, Kahn JG, Marseille E: The costs and health benefits of expanded access to MDMA-assisted therapy for chronic and severe PTSD in the USA: a modeling study. Clin Drug Investig 2022; 42:243–252
Information & Authors
Information
Published In
History
Received: 7 November 2023
Revision received: 5 March 2024
Accepted: 4 April 2024
Published online: 20 December 2024
Published in print: January 01, 2025
Keywords
Authors
Competing Interests
Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China; he has served as a speaker and/or consultant for AbbVie, Alkermes, Atai Life Sciences, Axsome, Bausch Health, Biogen, Boehringer Ingelheim, Eisai, Intra-Cellular, Janssen, Kris, Lundbeck, Mitsubishi Tanabe, Neumora Therapeutics, NeuraWell, Neurocrine, NewBridge Pharmaceuticals, Novo Nordisk, Otsuka, Pfizer, Purdue, Sage, Sanofi, Sunovion, Takeda, and Viatris; and he is CEO of Braxia Scientific Corp. Dr. Mansur has received research grant support from CIHR, the PSI Foundation, and the Baszucki Brain Research Fund. Dr. Oliveira-Maia has received research grant support from the European Research Council, European Union’s Horizon 2020 Research and Innovation Programme, FEDER, Fundação para a Ciência e Tecnologia; he has received sponsored research support from Compass Pathways, Janssen, and Schuhfried GmBH; and he has served as a speaker and consultant for Angelini, the European Monitoring Centre for Drugs and Drug Addiction, Janssen, MSD, the National Board of Medical Examination at the Portuguese Medical Association and Portuguese Ministry of Health, and Neurolite AG. Dr. Maletic has served as a consultant for AbbVie/Allergan, Acadia Pharmaceuticals, Alfasigma, Alkermes, Biogen, Boehringer Ingelheim, Cerevel Therapeutics, Corium, Intra-Cellular Therapies, Ironshore, Janssen, LivaNova, Lundbeck, Jazz Pharmaceuticals, Neumora, Neurelis, Noven Pharmaceuticals, Otsuka America Pharmaceutical, Pax Medica, Relmada Therapeutics, Sage, Sunovion, Supernus Pharmaceuticals, and Takeda; and he has served on speakers bureaus for AbbVie, Acadia, Alfasigma, Alkermes, Axsome, Corium, Eisai, Intra-Cellular, Ironshore, Janssen, Lundbeck, Otsuka America Pharmaceutical, Sunovion, Supernus Pharmaceuticals, and Takeda. Dr. Suppes has received grants from Cohen Biosciences, Compass Pathways, and Merck; she has served as a consultant for Impel NeuroPharma, Intracellular Therapies, Merck Research Laboratories, Servier (Australia), and Sunovion; she receives royalties from American Psychiatric Association Publishing, Hogrefe Publishing, Jones and Bartlett, and Wolters Kluwer Health (UpToDate); she has stock options with PsiloTec; and she has received CME honoraria from the Clinical Education Alliance, the CME Institute (Physicians Postgraduate Press, Inc.), CMEology, Integrity Continuing Education, Medscape, Novus Medical Education, and Practicing Clinicians Exchange. Dr. Stahl has received research and/or grant support from Acadia, Allergan/AbbVie, Avanir, Boehringer Ingelheim, Braeburn Pharmaceuticals, Daiichi Sankyo Brazil, Eisai, Eli Lilly, Harmony Biosciences, Indivior, Intra-Cellular Therapies, Ironshore, Neurocrine, Otsuka, Pear Therapeutics, Sage, Shire Sunovion, Supernus, and Torrent; he has served as a consultant for AbbVie, Acadia, Alkermes, Allergan, Axsome, Clearview, Done, Eisai Pharmaceuticals, Gedeon Richter, Intra-Cellular Therapies, Karuna Therapeutics, Levo Therapeutics, Lundbeck, NeuraWell, Neurocrine Biosciences, Otsuka, Relmada Therapeutics, Sage Therapeutics, Sunovion, Supernus, Taliaz, Teva, Tris Pharma, and VistaGen; he has served on speakers bureaus for Acadia, Lundbeck, Neurocrine, Otsuka, Servier, Sunovion, and Teva; and he holds options in Delix, Genomind, Lipidio, and NeuraWell. Dr. Rosenblat has received research grant support from Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, the Brain and Cognition Discovery Foundation, the Canadian Cancer Society, the Canadian Institute of Health Research (CIHR), the Canadian Psychiatric Association, the Joseph M. West Family Memorial Fund, Labatt Brain Health Network, Physician Services Inc. (PSI) Foundation, the University Health Network Centre for Mental Health, the University of Toronto, and Timeposters Fellowship; he has received industry funding for speaker/consultation/research fees from Allergan, Boehringer Ingelheim, Compass, iGan, Janssen, Lundbeck, and Sunovion; and he previously served as chief medical and scientific officer of Braxia Scientific Corp. The other authors report no financial relationships with commercial interests.
Metrics & Citations
Metrics
Citations
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
View Options
View options
PDF/EPUB
View PDF/EPUBLogin options
Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.
Personal login Institutional Login Open Athens loginNot a subscriber?
PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.
Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).