Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder
This double-blind, placebo-controlled study (n=9) of psilocybin (up to 21mg/70kg) found no adverse effects and improvements in OCD symptoms. Immediate improvements on the Yale-Brown Obsessive Compulsive Scale (YBOCS) varied between 23-100% reductions. Positive results were also observed after the 24 hours reported in the study.
Authors
- Moreno, F. A.
- Wiegand, C. B.
- Taitano, E. K.
Published
Abstract
Anecdotal reports suggest that psychedelic agents may relieve symptoms of obsessive-compulsive disorder (OCD). This modified double-blind study investigated the safety, tolerability, and clinical effects of psilocybin, a potent 5-HT(1A) and 5-HT(2A/2C) agonist, in patients with OCD. Nine subjects with DSM-IV-defined OCD and no other current major psychiatric disorder participated in up to 4 single-dose exposures to psilocybin in doses ranging from sub-hallucinogenic to frankly hallucinogenic. Low (100 microg/kg), medium (200 microg/kg), and high (300 microg/kg) doses were assigned in that order, and a very low dose (25 microg/kg) was inserted randomly and in a double-blind fashion at any time after the first dose. Testing days were separated by at least 1 week. Each session was conducted over an 8-hour period in a controlled environment in an outpatient clinic; subjects were then transferred to a psychiatric inpatient unit for overnight observation. The Yale-Brown Obsessive Compulsive Scale (YBOCS) and a visual analog scale measuring overall obsessive-compulsive symptom severity were administered at 0, 4, 8, and 24 hours post-ingestion. The Hallucinogen Rating Scale was administered at 8 hours, and vital signs were recorded at 0, 1, 4, 8, and 24 hours after ingestion. The study was conducted from November 2001 to November 2004. Nine subjects were administered a total of 29 psilocybin doses. One subject experienced transient hypertension without relation to anxiety or somatic symptoms, but no other significant adverse effects were observed. Marked decreases in OCD symptoms of variable degrees were observed in all subjects during 1 or more of the testing sessions (23%-100% decrease in YBOCS score). Repeated-measures analysis of variance for all YBOCS values revealed a significant main effect of time on Wilks lambda (F = 9.86, df = 3,3; p = .046), but no significant effect of dose (F = 2.25, df = 3,3; p = .261) or interaction of time and dose (F = 0.923, df = 9,45; p = .515). Improvement generally lasted past the 24-hour timepoint. In a controlled clinical environment, psilocybin was safely used in subjects with OCD and was associated with acute reductions in core OCD symptoms in several subjects.
Research Summary of 'Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder'
βBlossom's Take
Introduction
OCD affects roughly 2% to 3% of the population and carries a high burden of disability; many patients remain symptomatic despite standard treatments. Potent serotonin reuptake inhibitors (SRIs) and cognitive behavioural therapy are effective for some patients but typically produce only partial improvement, with an estimated 40% to 60% of adequately treated patients failing to respond fully. Anecdotal case reports and historical observations have suggested that indole-based hallucinogens such as psilocybin and LSD can produce acute reductions in obsessive and compulsive symptoms, and pharmacologically these compounds are notable agonists at 5-HT1A, 5-HT2A, and 5-HT2C receptors — sites implicated in serotonergic treatments for OCD. Moreno and colleagues designed a small proof-of-concept study to evaluate the safety, tolerability, and potential therapeutic effects of psilocybin in symptomatic, treatment-resistant OCD patients. The study also aimed to explore whether the intensity of the psychedelic experience related to changes in obsessive-compulsive symptom severity during testing. This investigation was positioned as a Phase I, exploratory evaluation to inform whether further controlled trials would be warranted.
Methods
This single-centre Phase I study was approved by the institutional Human Subjects Committee and the FDA, and conducted from November 2001 to November 2004. Nine adults (7 male, 2 female) meeting DSM-IV criteria for current OCD were recruited. Inclusion required at least one prior adequate SRI trial of at least 12 weeks without significant improvement; subjects had a mean of 3.4 ± 1.9 prior treatment failures and baseline Yale-Brown Obsessive Compulsive Scale (YBOCS) scores between 18 and 36 (mean 24.1 ± 5.9). Exclusion criteria included current major psychiatric disorders other than OCD, current substance abuse/dependence, personal or family history of psychosis, and relevant medical or neurological disorders. For safety, participants were required to have tolerated at least one prior exposure to indole-based psychedelics. Antidepressants were discontinued for at least 2 weeks (6 weeks for fluoxetine) and other medications/supplements were stopped before testing. Testing took place in an outpatient psychopharmacology setting with overnight observation in a hospital unit. Rapport-building sessions occurred before dosing. Psilocybin was administered orally in a modified dose-escalation, partially blinded protocol with up to four sessions per subject spaced at least 1 week apart. Doses were 25 µg/kg (very low dose, VLD), 100 µg/kg (low dose, LD), 200 µg/kg (medium dose, MD), and 300 µg/kg (high dose, HD). LD, MD, and HD were given in ascending order; VLD was inserted randomly after the first dose and was double blind. Subjects wore eyeshades, listened to a standardised music programme, and were accompanied by trained sitters throughout each 8-hour session. Primary clinical measures were YBOCS and a visual analogue scale (VAS) for overall obsessive-compulsive symptom severity, recorded at baseline and 4, 8, and 24 hours post-ingestion. The Hallucinogen Rating Scale (HRS) was administered at 8 hours to characterise subjective psychedelic effects across subscales (somaesthesia, affect, volition, cognition, perception, intensity). Vital signs were monitored at baseline and 1, 4, 8, and 24 hours. Statistical analysis used repeated-measures multivariate analysis of variance (ANOVA) to assess main effects of time, dose, and time-by-dose interactions; within-subjects linear contrasts tested dose–response on HRS intensity. Pearson correlations evaluated relationships between HRS intensity and changes in YBOCS. Significance was set at p ≤ .05, with trends at p ≤ .1.
Results
Safety and tolerability: Overall the procedures were tolerated. One subject experienced transient hypertension after a medium dose (readings up to 142/105 mm Hg) without associated anxiety or somatic symptoms. Two participants declined further participation after the first session because of discomfort with hospitalisation. No other adverse reactions were reported. All nine subjects received the LD; seven received VLD and MD; six completed all four doses. Primary clinical outcomes: Repeated-measures ANOVA across all YBOCS values showed a significant main effect of time (Wilks lambda F = 9.86, df = 3,3; p = .046), indicating change in symptom severity over the assessment period, but there was no significant main effect of dose (F = 2.25, df = 3,3; p = .261) nor a significant time-by-dose interaction (F = 0.923, df = 9,45; p = .515). Individual subject responses varied, with marked decreases in YBOCS scores of 23% to 100% during one or more sessions. A contrast comparing baseline versus post-ingestion YBOCS for all doses combined was significant (F = 9.37, df = 1,5; p = .028). Examining individual doses, time effects were significant for LD (p = .004) and MD (p = .006), but not for VLD (p = .128) or HD (p = .406). Changes in obsessive and compulsive symptom subscales mirrored total YBOCS findings. Analysis of baseline to 24-hour YBOCS scores also showed a significant main effect of time (F = 7.89, df = 1,5; p = .038) without dose or interaction effects. Secondary and exploratory findings: VAS scores showed mixed results; the omnibus repeated-measures ANOVA for all doses combined was nonsignificant, but a contrast of baseline versus post-ingestion VAS was significant (F = 11.41, df = 1,5; p = .020), and LD produced a significant time effect (p = .010). The HRS intensity subscale demonstrated a significant linear dose effect (F = 12.36, df = 1,5; p = .017), and total HRS and all subscales except volition showed significant linear dose effects, indicating that subjective psychedelic intensity increased with dose. Importantly, there were no significant correlations between HRS total or subscale scores and reductions in YBOCS or VAS scores. Duration of effect and follow-up: OCD ratings were obtained only up to 24 hours after dosing prior to the next session, so duration beyond that was not prospectively measured. Nevertheless, 88.9% of subjects had at least one testing dose that produced a ≥ 25% decrease in YBOCS at 24 hours, and 66.7% had at least one dose giving ≥ 50% decrease at 24 hours. Two participants reported symptomatic improvement lasting most of the week after testing. One subject achieved long-term remission as assessed at 6-month follow-up. There was no statistically significant order effect across test days (p = .133). The investigators noted that the VLD elicited stronger-than-expected clinical effects, undermining its validity as a placebo comparator.
Discussion
Moreno and colleagues conclude that, when administered in a supportive clinical environment with monitoring, psilocybin appeared safe and was generally well tolerated in this small sample of treatment-resistant OCD patients. The study found transient reductions in obsessive-compulsive symptoms following psilocybin administration, with many subjects experiencing clinically meaningful decreases at 24 hours after at least one dose. These observations are consistent with prior anecdotal reports and case histories suggesting rapid symptomatic improvement after exposure to indole hallucinogens. The investigators highlight several methodological limitations that temper interpretation. The sample was small and the design was an open, modified dose-escalation Phase I protocol rather than a fully randomised, placebo-controlled trial. The ascending order of LD, MD, and HD (with VLD inserted randomly) and the partial blinding could have influenced expectations of both participants and raters. Requirement that participants tolerate prior psychedelic exposure and overnight hospitalisation may have introduced selection bias. The unexpectedly active response to the VLD precluded its use as an effective placebo control. Measurements of symptoms were limited to 24 hours post-ingestion, so duration of benefit beyond that window was not systematically assessed. Regarding mechanisms, the authors note that although psilocybin is a 5-HT1A/2A/2C agonist and preclinical data support adaptive receptor and gene-expression changes after hallucinogen exposure, it remains unclear which receptor(s) or pathways mediate any anti-obsessional effect. They also acknowledge alternative explanations such as expectancy/placebo effects, distraction or pleasurable experience during intoxication, or psychological insights and altered cognition arising from the psychedelic state. Several participants described psychologically or spiritually meaningful experiences, and some reported symptomatic relief extending beyond the acute psychedelic period, a finding that raises mechanistic questions but cannot be resolved from this dataset. The investigators recommend cautious future research: screening to minimise risk in vulnerable individuals, careful preparation and debriefing, and continuity of support post-session. They propose that, given the burden of treatment-resistant OCD and the limitations of current therapies, further studies using standard randomised, blinded, placebo-controlled designs — including assessments of repeated dosing and longer-term outcomes — are warranted to better characterise efficacy, safety, and duration of benefit.
Conclusion
In this small proof-of-concept Phase I study, psilocybin administered in a monitored clinical setting was generally safe and associated with transient reductions in obsessive-compulsive symptoms among treatment-resistant OCD patients. Methodological constraints — notably small sample size, the modified dose-escalation and blinding scheme, selection criteria, and short prospective follow-up — limit definitive conclusions. The authors suggest that the observed acute benefits, together with the high unmet need in refractory OCD, justify further investigation with rigorous, randomised, placebo-controlled trials to determine efficacy and the duration of therapeutic effects from repeated psilocybin exposure.
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SECTION
ment of patients undergoing treatment with SRIs is quite extensive, the rates of remission are minimal, and many patients considered responders have residual symptoms that continue to cause dysfunction and may increase vulnerability to complications and exacerbations.In addition to SRIs, other effective treatments include cognitive behavioral psychotherapy (CBT), combination of SRIs and CBT, and the use of polypharmacy.It is estimated that as many as 40% to 60% of those who are adequately treated will fail to respond to standard therapies.For these reasons, identifying new options for treatments has become a high priority. There are several reported cases concerning the beneficial effects of hallucinogenic drugs (psilocybin and lysergic acid diethylamide [LSD]) in patients with OCD and related disorders.For example, a 34-year-old man had suffered from OCD symptoms (checking and counting compulsions, performing actions a specific number of times, and a variety of other rituals) since age 14. However, he began using freeze-dried psilocybe mushrooms recreationally at age 18 and observed consistently that during the psilocybe mushroom intoxication, he was free of obsessions or compulsions. Repeated use induced tolerance to the psychedelic effects, but the subject continued to experience relief of his OCD symptoms despite the lack of a "high." Chronic use of this hallucinogen led to a symptomatic remission, which lasted for several months after discontinuing use.Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), an indolealkylamine, is the main active compound of many species of the genus Psilocybe, commonly known as "magic mushrooms." Psilocybin binds potently as an agonist to the 5-HT 1A , 5-HT 2A , and 5-HT 2C receptors.Behavioral pharmacology and electrophysiologic research show that agonist activity at 5-HT 2 receptors strongly correlates with a stimulus effect in animals and a hallucinogenic effect in humans.Oral doses ranging from 8 to 20 mg p.o. or 100 to 315 µg/kg are considered safe and able to induce a quantifiable psychedelic experience that lasts, depending on the dose, from 3 to 8 hours.Given a large first-pass metabolism in which psilocybin is converted primarily to psilocin, the latter may actually be responsible for the psychotropic effects observed after psilocybin administration. Given the large body of clinical data suggesting that pharmacologic potency in increasing synaptic 5-HT may underlie the therapeutic effects of some drugs in the treatment of OCD and the anecdotal reports of acute reduction in OCD symptoms with hallucinogens, we hypothesized that agonist activity at 5-HT 1A , 5-HT 2A , and/or 5-HT 2C receptors might underlie the efficacy of drug treatments for OCD. The present study sought to evaluate the safety, tolerability, and potential therapeutic effect of psilocybin administration in OCD patients who had failed to respond to at least 1 adequate treatment trial with SRI agents. Ad-ditionally, we sought to explore the relationship between the intensity of psychedelic experience and the severity of obsessions and compulsions during testing.
METHOD SAFETY AND ETHICAL CONSIDERATIONS
This project was approved by the University of Arizona Human Subjects Committee and the U.S. Food and Drug Administration (FDA). All participants signed informed consent statements, which included a detailed discussion of potential somatic and mental effects of psilocybin. The subject selection and study design were the result of extensive discussions with members of the Human Subjects Committee at the University of Arizona and representatives of the FDA, who had a number of comments geared toward improving the safety of research subjects. The study was conducted from November 2001 to November 2004.
SUBJECTS
Nine subjects (7 male, 2 female) who met criteria for current OCD based on the Structured Clinical Interviewfor the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)were recruited through word-of-mouth, Internet postings, and local advertisement. Their ages ranged from 26 to 62 years (mean ± SD = 40.9 ± 13.2 years); 3 of the subjects were employed, 1 was a housewife, and 5 were unable to work because of their OCD symptomatology. Six of 9 participants lived alone, 2 were living with a significant other, and 1 was married. Subjects were required to have at least 1 "treatment failure," defined as lack of significant improvement after an adequate treatment course with an SRI for at least 12 weeks (based on dose range recommendations published in the Expert Consensus Guidelines for OCD). Subjects had a mean ± SD of 3.4 ± 1.9 treatment failures. Subjects were required to be symptomatic at the time of enrollment and had a baseline Yale-Brown Obsessive Compulsive Scale (YBOCS)score ranging from 18 to 36 (mean ± SD = 24.1 ± 5.9) on the first test day. None of the subjects met criteria for current major psychiatric disorders other than OCD, including current substance abuse/ dependence, and none of the subjects had a personal or family history of psychosis. Due to safety concerns over potential adverse reaction to psychedelic drugs, subjects were required to have tolerated well at least 1 prior exposure to indole-based psychedelics. Two of the subjects (1 and 4) reported a history of clinical benefit with use of psychedelics. Subjects were free of general medical or neurologic conditions based on the clinical history and review of systems; physical examination; electrocardiogram; routine laboratory blood, urine, and pregnancy screenings; and urine testing for drugs of abuse. Subjects were required to abstain from use of antidepressants for at least 2 weeks (6 weeks for fluoxetine) and any pharmaceutical or nutritional supplement for at least 1 week before testing. Additionally, subjects were free of any other prescription or over-the-counter medication or drug of abuse.
PROCEDURE
Testing was performed in the Department of Psychiatry at the University of Arizona Health Sciences Center. Psilocybin sessions were conducted in the outpatient offices of the Psychopharmacology Research Program. As a cautionary measure, subjects were then transferred to the psychiatric inpatient unit of the same hospital for overnight observation and were discharged the next morning. When a bed was not available in the psychiatric unit, subjects were admitted to the medical-surgical units under the care of the psychiatric service and remained under constant supervision by a staff member. Subjects had an opportunity to develop rapport with the study team during screening. All subjects met with the principal investigator (F.A.M.) and whenever possible with the sitters the day before testing. During the initial visit, further rapport was established, the procedure was again discussed, and the testing room and the psychiatric inpatient unit were shown to the subjects. Subjects reported for testing at 8:00 a.m., after having had a light snack. Testing for drugs of abuse and pregnancy (when applicable) was conducted prior to each session. Subjects were escorted to the testing room, where they remained for the next 8 hours. Subjects were allowed to use a nearby restroom, but no other outings were allowed. A light snack was again made available for subjects at about 1:00 p.m. Study drug was ingested at about 8:30 a.m. Subjects received up to 4 different doses, 1 dose per test session, in a modified dose escalation blinded protocol. Doses were 25 (very low dose [VLD]), 100 (low dose [LD]), 200 (medium dose [MD]), and 300 (high dose [HD]) µg/kg of body weight. LD, MD, and HD were assigned in that order, and VLD was inserted randomly and in double-blind fashion at any time after the first dose (LD). Testing days were separated by at least 1 week. Subjects were asked to wear eyeshades, listen to a standardized set of music, and minimize interactions during the sessions. Trained sitters were present at all times and included at least 1 of the investigators; whenever possible, a male and a female sitter were present simultaneously. Toward the end of the 8-hour test, subjects were allowed to modify the music selection, have more conversation, discontinue use of the eyeshades, and gradually debrief with the principal investigator regarding aspects of their experience.
MEASUREMENTS
The YBOCS and a visual analog scale (VAS) for overall obsessive-compulsive symptom severity were administered immediately before psilocybin ingestion (baseline) and at 4, 8, and 24 hours postingestion. The Hallucinogen Rating Scale (HRS)was administered at 8 hours post ingestion. The HRS is a non-theoretically constructed scale, and its item selection is based on reported observations from experienced hallucinogen users who could experience a full range of effects. It measures 6 aspects of the hallucinogenic experience, including the following subscales: somaesthesia, affect, volition, cognition, perception, and intensity. Volition and intensity subscales are compounded by a small number of items and lack the established validity of the other mentioned subscales. Vital signs were monitored at baseline and 1, 4, 8, and 24 hours after psilocybin ingestion.
DATA ANALYSIS
Change in YBOCS and VAS scores was assessed by multivariate analysis of variance (ANOVA) in a repeatedmeasures design. This allowed for an assessment of the main effect of time, dose, and time-by-dose interaction. ANOVA within-subjects linear contrast was utilized to test for dose-response relationship in the HRS intensity subscale. Pearson correlation was used to assess the relationship between HRS intensity score and change in YBOCS score. Results were considered significant when p ≤ .05. Trends are also reported when p ≤ .1. All tests were 2-tailed. Data analysis and graphic presentation utilized SPSSand SYSTATsoftware programs.
SAFETY AND TOLERABILITY
Subjects generally tolerated the procedure well. One subject experienced transient hypertension (132/90, 135/ 90, 142/105, 142/95, and 116/78 mm Hg at 0, 1, 4, 8, and 24 hours, respectively, after ingestion of a medium dose of psilocybin), which was not associated with psychic anxiety or somatic symptoms. Two subjects declined further participation after the first testing session due to discomfort with hospitalization. No other adverse reactions were observed. All 9 subjects received LD, 7 of them also received VLD and MD, and 6 of them received all 4 doses.
EFFECT ON OCD SYMPTOMS
Repeated-measures ANOVA for all YBOCS values revealed a significant main effect of time on Wilks lambda (F = 9.86, df = 3,3; p = .046), but no significant effect of dose (F = 2.25, df = 3,3; p = .261) or interaction of time and dose (F = 0.923, df = 9,45; p = .515). Marked decreases in OCD symptoms of variable degree were observed in all subjects during 1 or more sessions (23%-100% reduction in YBOCS score). Contrast comparison of baseline versus postingestion YBOCS scores for all doses combined was also statistically significant (F = 9.37, df = 1,5; p = .028); see Figuresand. Repeated-measures ANOVA for effects of individual doses on YBOCS scores found a significant effect of time for LD (p = .004) and MD (p = .006), but not for VLD (p = .128) or HD (p = .406). Changes in obsessions and compulsions were comparable. ANOVA of baseline to 24 hours YBOCS score also showed a significant effect of time (F = 7.89, df = 1,5; p = .038), but no effect of dose or time-by-dose interaction. VAS scores for all doses combined showed no significant effect of time (F = 3.05, df = 3,3; p = .192) or dose (F = 2.7, df = 3,3; p = .218). Repeated-measures ANOVA for effect of individual doses on VAS scores found a significant effect of time for LD (p = .010), but not for VLD (p = .307), MD (p = .182), or HD (p = .25). Contrast comparison of baseline versus postingestion VAS scores for all doses combined was also statistically significant (F = 11.41, df = 1,5; p = .020). ANOVA of baseline to 24 hours revealed a significant main effect of time (F = 5.38, df = 1,5; p = .068), a nonsignificant effect of dose (F = 1.83, df = 3,3; p = .316), and a significant interaction of time and dose (F = 183.1, df = 3,3; p = .001). The HRS intensity subscale showed a significant linear main effect of dose (F = 12.36, df = 1,5; p = .017) (Figure). Total HRS score and every subscale with the exception of volition also showed a statistically significant linear main effect of dose. There were no significant correlations between HRS total or subscale scores and changes in OCD severity based on YBOCS or VAS scores. OCD measurements were only obtained for up to 24 hours following psilocybin ingestion prior to the next session, and the duration of symptomatic improvement was not prospectively measured; however, 88.9% of subjects maintained a ≥ 25% decrease and 66.7% maintained a ≥ 50% decrease in YBOCS score at 24 hours with at least 1 of the testing doses. Two of the subjects reported that their symptomatic improvement lasted most of the following week after testing. Although there was a numerical difference between baseline scores at test 1 versus other test times, there was no statistically significant order effect when ANOVA with repeated measures was used (p = .133). One subject achieved long-term remission at the end of the 4 test sessions, as measured at 6month follow-up. Post hoc pairwise t test analysis comparing YBOCS scores during screening (25.2 ± 8.6) and baseline scores (24.1 ± 6.3) on test day 1 showed no statistical difference (p = .673), suggesting stability of YBOCS scores prior to psilocybin testing and the lack of anxiety-induced increase in YBOCS score prior to testing.
CONCLUSIONS
When administered in a supportive clinical environment, psilocybin appears to be safe and well tolerated. Psilocybin was associated with transient symptomatic reduction of OCD symptoms in subjects with treatment-resistant OCD. These data result from a small proof-of-concept, phase I study designed to explore the safety for human consumption of 4 doses of psilocybin in a small sample of symptomatic OCD patients. The escalating dosing scheme was selected to allow exposure to increasingly higher doses only to individuals who had tolerated previous exposures. A smaller dose (VLD) was hypothesized to have negligible psychedelic effects and was introduced randomly at any time after the first dose. Subjects experienced stronger than anticipated response to this dose, as shown in Figure, and its clinical effects were also greater than anticipated. This response to VLD impedes the use of VLD as a placebo comparator, which clearly represents a major obstacle in our ability to explore clinical effects. Another methodological concern is the fact that the order of the doses was escalating, with the exception of VLD, which was inserted randomly and in doubleblind fashion. This modified blind may have influenced expectations in both subjects and raters. Despite the obvious limitations from design and sample size, the data are suggestive of an acute benefit, worth exploring further. Although we understand the psychedelic mechanism of action of psilocybin, it is not clear which specific receptors or pathways may mediate antiobsessional responses. It may be possible for subjects to experience a decrease in symptoms by the mere artifact of mindset and setting, which are known to affect the psychedelic experience in itself; by the contextual expectation of improvement; or just by the distracting psychedelic effects or a "pleasurable experience." It should be noted that to some of the patients the exposure to a psychedelic agent was perceived as a stressful event; for others, testing repre- sented a time without access to the usual distractions that help reduce their obsessions; and for most, the overnight stay in the hospital represented a significant stressor. Therefore, the setting was ideal not for reduction of stress and obsessions, but rather for safety and monitoring purposes. This issue may have introduced selection bias by allowing participation by only those subjects who tolerated travel and overnight hospitalization. There was, however, no clear dose-response relationship to the change in YBOCS score and no correlation of YBOCS score reduction to the perceived psychedelic intensity based on HRS total score or intensity subscale score. Although the intent of this study was not to conduct psychedelic-facilitated therapy during testing, 5 of the subjects readily described their experiences as very psychologically and spiritually enriching. Four subjects re-ported during HD profound positive transcendental experiences such as exploration of other planets, visiting pastlife reincarnations, and interacting with deities. Most subjects reporting symptom reduction experienced a period of relief that extended beyond the pharmacologically expected life of the drug and beyond the 24-hour rating (see Figure). This lingering effect, which extends clearly beyond the "high" or psychedelic state, raises a number of intriguing mechanistic questions. For example, does the effect result from a residual feeling of well-being due to the experience of temporary symptom distraction or "pleasure," from the psychological insights described above, or from changes in working memory and attention as reported previously, or is the effect directly pharmacologically mediated? Although the explanation is highly speculative, if these are prolonged pharmacologic effects, they may be related to a rapid adaptive cascade of events such as postsynaptic 5-HT receptor down-regulation or early gene expression. A large body of evidence supports the down-regulation of 5-HT 2A receptors in response to hallucinogen administration in animal models and human subjects.LSD has been reported to induce intracellular signal transduction changes that are different from endogenous 5-HT despite binding to the same receptor site.In fact, LSD is reported to decrease gene expression in rat brain after single-dose administration, while no changes in expression of 5-HT 1A , 5-HT 2A , or 5-HT 2C were observed.These changes in gene expression, although reported with a similar compound rather than with psilocybin, may result in physiologic alterations that explain the delayed effect described above. It is also possible that the early changes in gene expression may be different after repeated administration of LSD or similar compounds, leading to the known down-regulation of 5-HT 2A . 28 Ingestion of psilocybin and similar substances will facilitate subjects' experiencing of altered states of consciousness and may lead to the development of powerful insights and profound existential and spiritual questions. Administration of these substances therefore should be approached with caution to minimize exposure to individuals who are vulnerable to psychosis or overvalued ideas. Researchers should carefully consider the subject's mindset prior to exposure, address concerns developed during the psychedelic experience through careful debriefing, and secure a source of supportive continuity afterward. In spite of these concerns, given that OCD is associated with a great deal of human suffering and societal burden, and that treatment-resistant OCD represents a valid indication for irreversible brain surgery, it may be reasonable to consider psilocybin, with its potential benefit, a less burdensome alternative and one worth investigating further. In summary, this study confirms and extends anecdotal reports of acute reduction in OCD symptoms with exposure to psilocybin. Given the chronicity and disease burden of OCD and the high rate of insufficient response to currently approved treatments, future studies involving traditional blinded, randomized, placebo-controlled methodology should explore the efficacy of and duration of therapeutic benefit from a more prolonged exposure to repeated doses of psilocybin in patients with OCD.
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Study Details
- Study Typeindividual
- Populationhumans
- Characteristicsdouble blindplacebo controlledfollow up
- Journal
- Compound
- Topics
- APA Citation
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