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Letter to the Editor: What Is in a Name? The Many Meanings of “Psychedelic”
... Classic psychedelics, such as psilocybin and lysergic acid amide (LSD), act primarily as agonists of serotonin receptors, particularly the serotonin (5-hydroxytryptamine; 5-HT) 2 A receptor (5-HT 2AR), leading to dramatic acute changes in cognitive processes and sensory perception [15][16][17]. Other agents with different mechanisms of action but similarly dramatic effects on consciousness are sometimes also described as psychedelics [18]; we adopt this usage here. Early evidence on the effects of psychedelics in the treatment of SUDs is promising [19]. ...
Purpose of Review
Despite national efforts to curb the opioid crisis, the clinical and societal challenges continue to grow. FDA-approved medications for opioid use disorder (OUD) are effective but are associated with high rates of treatment discontinuation and relapse. A collection of agents with acute effects on consciousness, collectively (if variably) categorized as 'psychedelics', have emerged as potential treatments for substance use disorders, including OUD. Psychedelics are typically administered alongside psychotherapy, though the role and necessity of concurrent psychotherapy remains a topic of debate. This review examines trials involving both classical and non-classical psychedelics for OUD treatment, aiming to evaluate the evidence for the importance of psychotherapy and identify the most effective therapeutic approaches, if any.
Recent Findings
No studies were identified that directly compared different psychotherapy modalities or assessed the effects of psychedelics with versus without concurrent psychotherapy. Most research examining the impact of psychedelics on alleviating opioid withdrawal symptoms did not incorporate a psychotherapy component. However, the few studies that investigated the effects of psychedelics (ketamine and LSD) on opioid use and abstinence adopted a psychedelic-assisted therapy model.
Summary
There is insufficient high-quality evidence to support or oppose the necessity of concurrent psychotherapy in psychedelic trials for OUD. Future clinical trials should be structured to explore the interplay between psychedelic treatment and psychotherapy.
... Psychedelic-assisted therapy studies to date have emphasized the importance of "set" (i.e., the participant's internal state at the time of the session), and "setting" (i.e., the many extrinsic, non-pharmacological factors that influence a participant's experience in a non-ordinary state of consciousness; O'Donnell et al., 2023). Of note, the phrase "set and setting" originally applied to the psychedelic experience itself (Hartogsohn, 2017); however, within the context of MDMA-Assisted Therapy, the concept is no less important for the non-drug psychotherapy sessions, consistent with the "common factors" model of psychotherapy delineated by Frank et al. (1993). ...
Results from multiple recent studies support further evaluation of 3,4-methylenedioxymethamphetamine (MDMA) in conjunction with psychotherapy (i.e., MDMA-Assisted Therapy) in the treatment of post-traumatic stress disorder (PTSD). In two Phase 3 trials, MDMA-Assisted Therapy comprised a short-term, intensive psychotherapy that included three sessions directly facilitated by MDMA (referred to as “experimental sessions”), as well as a number of non-drug psychotherapy sessions. This treatment model aimed to harness the potential of MDMA to facilitate recall and processing of traumatic memories, and to increase learning in a social context, integrating “top-down” and “bottom-up” approaches to trauma-focused care. To date, the conceptual framework for this treatment has not been described in the scientific literature. This omission has contributed to misunderstandings about both the theoretical underpinnings of this modality and the therapeutic approach that emerges from it. This paper delineates the psychotherapeutic concepts, theories, and historical antecedents underlying the inner-directed approach to MDMA-Assisted Therapy for PTSD. Broadly speaking, this therapeutic framework centered the concept of the participant’s inner healing intelligence as the primary agent of change, with the therapeutic relationship being the core facilitative condition fostering the participant’s self-directed movement toward recovery and growth. Corollaries to this holistic, self-directed, relational, and trauma-informed framework include a non-pathologizing approach to the participant’s embodied experience (including the possibility of intense emotional and somatic expression, experiences of multiplicity, suicidal ideation, and multigenerational and transpersonal experiences), as well as the therapists’ own psychodynamic, somatic, and transpersonal awareness, empathic attunement, relational skillfulness, and cultural humility. The use of MDMA in conjunction with this psychotherapy platform outperformed the use of placebo with psychotherapy in Phase 2 and 3 trials, as measured by symptom reduction in participants with PTSD. However, within-group comparisons also identified significant symptom reduction in participants who did not receive MDMA, lending empirical support to the psychotherapy model itself. In addition to comparative efficacy trials, future research should investigate which elements of the conceptual framework and therapeutic approach underlie the clinical benefit in individuals with PTSD.
... Despite interest in dissociative and psychedelic medicines as a novel category of rapidly-acting mental health treatments (Johnston et al., 2023;Lepow et al., 2023;Nayak et al., 2023;O'Donnell et al., 2023), several issues have limited broader adoption of ketamine as a psychiatric intervention. Most significantly, ketamine has not yet been approved by the FDA for use as an antidepressant. ...
Background: Improving safe and effective access to ketamine therapy is of high priority given the growing burden of mental illness. Telehealth-supported administration of sublingual ketamine is being explored toward this goal.
Methods: In this longitudinal study, moderately-to-severely depressed patients received four doses of ketamine at home over four weeks within a supportive digital health context. Treatment was structured to resemble methods of therapeutic psychedelic trials. Patients receiving a second course of treatment were also examined. Symptoms were assessed using the Patient Health Questionnaire (PHQ-9) for depression. We conducted preregistered machine learning and symptom network analyses to investigate outcomes (osf.io/v2rpx).
Results: A sample of 11,441 patients was analyzed, demonstrating a modal antidepressant response from both non-severe (n = 6384, 55.8 %) and severe (n = 2070, 18.1 %) baseline depression levels. Adverse events were detected in 3.0-4.8 % of participants and predominantly neurologic or psychiatric in nature. A second course of treatment helped extend improvements in patients who responded favorably to initial treatment. Improvement was most strongly predicted by lower depression scores and age at baseline. Symptoms of Depressed mood and Anhedonia sustained depression despite ongoing treatment.
Limitations: This study was limited by the absence of comparison or control groups and lack of a fixed-dose procedure for ketamine administration.
Conclusions: At-home, telehealth-supported ketamine administration was largely safe, well-tolerated, and associated with improvement in patients with depression. Strategies for combining psychedelic-oriented therapies with rigorous telehealth models, as explored here, may uniquely address barriers to mental health treatment.
... Most modern studies of PAP, including our own, have combined one or two doses of psilocybin with a substantial amount of psychological support ; this combination has been described as the 'psychedelic medicine' paradigm (Kelley et al., 2023). It is widely believed that this intensive support is necessary for full therapeutic benefit, although opinions vary as to whether it is an essential ingredient for clinical improvement or merely a requirement for psychological safety. ...
Novel treatments are required for the 30-50% of individuals with obsessive-compulsive disorder (OCD) who remain resistant to first-line pharmacological and psychotherapeutic treatments. Recent pilot data suggest benefit from psilocybin-assisted psychotherapy (PAP) and from imagery rescripting (ImRs). We explore psychological mechanisms of change underpinning both interventions that appear to allow for reprocessing of negative emotions and core beliefs associated with past aversive events. A next critical step in PAP is the development of psychotherapeutic frameworks grounded in theory. We propose that basing PAP on an ImRs framework may provide synergistic benefits in symptom reduction, modification of core beliefs, and value-based living.
Background
Traditional treatments for post-traumatic stress disorder (PTSD) often show limited success with high dropout. Ketamine, an N-methyl-D-aspartate antagonist known for rapid antidepressant effects, has decreased PTSD symptoms in some studies but not in others. Administering ketamine in ways that parallel psychedelic-assisted treatments—including preparatory, integration, sensory immersion, and psychotherapy sessions—could decrease PTSD symptoms meaningfully.
Methods
A retrospective sample of 117 screened outpatients with elevated PTSD Checklist for DSM-5 (PCL-5) scores received intravenous ketamine in supportive environments. The protocol included preparation, intention-setting, and integration sessions accompanying at least six administrations. Administration sessions included eye shades and evocative music paralleling typical psychedelic therapy trials.
Results
Mean PCL scores decreased from 52.54 (SD = 12.01) to 28.78 (SD = 16.61), d = 1.64. Patients tolerated treatment well, with no serious adverse events. Covariates, including age, gender, days between PCL assessments, number of psychiatric medications, and suicidal ideation were not significant moderators; concomitant psychotherapy did reach significance, d = 0.51. Of the 117 patients’ final PCL scores, 88 (75.21%) measures suggested clinically meaningful improvement and 72 (61.54%) suggested remission of PTSD symptoms.
Conclusion
Intravenous ketamine in supportive environments, with hallmarks of psychedelic therapy, preceded large reductions in PTSD symptoms. These results highlight ketamine’s potential when delivered in this manner, suggesting environmental factors might account for some variation seen in previous work. Given the molecule’s cost, minimal interaction with other psychiatric medications, and legal status, intravenous ketamine in a psychedelic paradigm may be a promising option for PTSD unresponsive to other treatments.
The extremes of human experiences, such as those occasioned by classic psychedelics and psychosis, provide a rich contrast for understanding how components of these experiences impact well-being. In recent years, research has suggested that classic psychedelics display the potential to promote positive enduring psychologic and behavioral changes in clinical and nonclinical populations. Paradoxically, classic psychedelics have been described as psychotomimetics. This review offers a putative solution to this paradox by providing a theory of how classic psychedelics often facilitate persistent increases in well-being, whereas psychosis leads down a "darker" path. This will be done by providing an overview of the overlap between the states (i.e., entropic processing) and their core differences (i.e., self-focus). In brief, entropic processing can be defined as an enhanced overall attentional scope and decreased predictability in processing stimuli facilitating a hyperassociative style of thinking. However, the outcomes of entropic states vary depending on level of self-focus, or the degree to which the associations and information being processed are evaluated in a self-referential manner. We also describe potential points of overlap with less extreme experiences, such as creative thinking and positive emotion-induction. Self-entropic broadening theory offers a heuristically valuable perspective on classic psychedelics and their lasting effects and relation to other states by creating a novel synthesis of contemporary theories in psychology. SIGNIFICANCE STATEMENT: Self-entropic broadening theory provides a novel theory examining the psychedelic-psychotomimetic paradox, or how classic psychedelics can be therapeutic, yet mimic symptoms of psychosis. It also posits a framework for understanding the transdiagnostic applicability of classic psychedelics. We hope this model invigorates the field to provide more rigorous comparisons between classic psychedelic-induced states and psychosis and further examinations of how classic psychedelics facilitate long-term change. As a more psychedelic future of psychiatry appears imminent, a model that addresses these long-standing questions is crucial.
Ketamine is a prescription drug used for general anesthesia. In subanesthetic doses, it induces profound psychedelic experiences and hallucinations. The subanesthetic effect of ketamine was the hypothesized therapeutic mechanism in the authors' use of ketamine-assisted psychotherapy for alcoholism. The results of a controlled clinical trial demonstrated a considerable increase in efficacy of the authors' standard alcoholism treatment when supplemented by ketamine psychedelic therapy (KPT). Total abstinence for more than one year was observed in 73 out of 111 (65.8%) alcoholic patients in the KPT group, compared to 24% (24 out of 100 patients) of the conventional treatment control group (p < 0.01). The authors' studies of the underlying psychological mechanisms of KPT have indicated that ketamine-assisted psychedelic therapy of alcoholic patients induces a harmonization of the Minnesota Multiphasic Personality Inventory (MMPI) personality profile, positive transformation of nonverbalized (mostly unconscious) self-concept and emotional attitudes to various aspects of self and other people, positive changes in life values and purposes, important insights into the meaning of life and an increase in the level of spiritual development. Most importantly, these psychological changes were shown to favor a sober lifestyle. The data from biochemical investigations showed that pharmacological action of KPT affects both monoaminergic and opioidergic neurotransmitter metabolism, i.e., those neurochemical systems which are involved in the pathogenesis of alcohol dependence. The data from EEG computer-assisted analysis demonstrated that ketamine increases theta activity in cerebrocortical regions of alcoholic patients. This is evidence of the reinforcement of limbic cortex interaction during KPT session.
Objective:
The authors provide an evidenced-based summary of the literature on the clinical application of psychedelic drugs in psychiatric disorders.
Methods:
Searches of PubMed and PsycINFO via Ovid were conducted for articles in English, in peer-reviewed journals, reporting on "psilocybin," "lysergic acid diethylamide," "LSD," "ayahuasca," "3,4-methylenedioxymethamphetamine," and "MDMA," in human subjects, published between 2007 and July 1, 2019. A total of 1,603 articles were identified and screened. Articles that did not contain the terms "clinical trial," "therapy," or "imaging" in the title or abstract were filtered out. The 161 remaining articles were reviewed by two or more authors. The authors identified 14 articles reporting on well-designed clinical trials investigating the efficacy of lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, and ayahuasca for the treatment of mood and anxiety disorders, trauma and stress-related disorders, and substance-related and addictive disorders as well as in end-of-life care.
Results:
The most significant database exists for MDMA and psilocybin, which have been designated by the U.S. Food and Drug Administration (FDA) as "breakthrough therapies" for posttraumatic stress disorder (PTSD) and treatment-resistant depression, respectively. The research on LSD and ayahuasca is observational, but available evidence suggests that these agents may have therapeutic effects in specific psychiatric disorders.
Conclusions:
Randomized clinical trials support the efficacy of MDMA in the treatment of PTSD and psilocybin in the treatment of depression and cancer-related anxiety. The research to support the use of LSD and ayahuasca in the treatment of psychiatric disorders is preliminary, although promising. Overall, the database is insufficient for FDA approval of any psychedelic compound for routine clinical use in psychiatric disorders at this time, but continued research on the efficacy of psychedelics for the treatment of psychiatric disorders is warranted.
gaps-challenges-and-opportunities for recordings from the NIH-sponsored 2022 workshop Psychedelics as Therapeutics: Gaps, Challenges and Opportunities, in which research into psilocybin, MDMA, and ketamine was included under the rubric of ''psychedelic medicine
- C M Reiff
- E E Richman
- C B Nemeroff
Reiff CM, Richman EE, Nemeroff CB, et al. Psychedelics and psychedelicassisted psychotherapy. Am J Psychiatry 2020;177(5):391-410.
5. Available from: https://www.nimh.nih.gov/news/events/2022/
psychedelics-as-therapeutics-gaps-challenges-and-opportunities for
recordings from the NIH-sponsored 2022 workshop Psychedelics as
Therapeutics: Gaps, Challenges and Opportunities, in which research into
psilocybin, MDMA, and ketamine was included under the rubric of
''psychedelic medicine.'' Of particular interest may be the introduction
and discussion led by Elias Dakwar at the end of ''Theme 2.'' [Last
accessed: July 11, 2023].