Psilocybin can occasion mystical-type experiences with participant-attributed increases in well-being. However, little research has examined enduring changes in traits. This study administered ...psilocybin to participants who undertook a program of meditation/spiritual practices. Healthy participants were randomized to three groups (25 each): (1) very low-dose (1 mg/70 kg on sessions 1 and 2) with moderate-level (“standard”) support for spiritual-practice (LD-SS); (2) high-dose (20 and 30 mg/70 kg on sessions 1 and 2, respectively) with standard support (HD-SS); and (3) high-dose (20 and 30 mg/70kg on sessions 1 and 2, respectively) with high support for spiritual practice (HD-HS). Psilocybin was administered double-blind and instructions to participants/staff minimized expectancy confounds. Psilocybin was administered 1 and 2 months after spiritual-practice initiation. Outcomes at 6 months included rates of spiritual practice and persisting effects of psilocybin. Compared with low-dose, high-dose psilocybin produced greater acute and persisting effects. At 6 months, compared with LD-SS, both high-dose groups showed large significant positive changes on longitudinal measures of interpersonal closeness, gratitude, life meaning/purpose, forgiveness, death transcendence, daily spiritual experiences, religious faith and coping, and community observer ratings. Determinants of enduring effects were psilocybin-occasioned mystical-type experience and rates of meditation/spiritual practices. Psilocybin can occasion enduring trait-level increases in prosocial attitudes/behaviors and in healthy psychological functioning.
Trial Registration
ClinicalTrials.gov Identifier NCT00802282
Psilocybin is being studied for use in treatment-resistant depression.
In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of ...a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits).
A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval CI, -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups.
In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).
Two sessions of psilocybin‐assisted psychotherapy resulted in reduced heavy‐drinking days and other alcohol‐related problems relative to placebo plus psychotherapy in a randomized trial involving ...patients with alcohol use disorder (AUD). There were no serious adverse events associated with psilocybin administration, and no signs of psychotic disturbances. Study results were published online Aug. 24, 2022, in JAMA Psychiatry.
Recent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression.
To test the antidepressant effects of ayahuasca, we ...conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing.
We observed significant antidepressant effects of ayahuasca when compared with placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared with placebo at D1 and D2 (p = 0.04), and at D7 (p < 0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen's d = 0.84; D2: Cohen's d = 0.84; D7: Cohen's d = 1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64% v. 27%; p = 0.04). Remission rate showed a trend toward significance at D7 (36% v. 7%, p = 0.054).
To our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression. This study is registered at http://clinicaltrials.gov (NCT02914769).
Introduction
Curiosity toward the effects of psychedelic drugs on neural activation has increased due to their potential therapeutic benefits, particularly serotonergic psychedelics that act as ...5-HT2A receptor agonists such as LSD, psilocybin, and MDMA. However, the pattern of their effects on neural activity in various brain regions in both clinical and healthy populations is still not well understood, and primary studies addressing this issue have sometimes generated inconsistent results.
Objectives
The present meta-analysis aims to advance our understanding of the most widely used serotonergic psychedelics – LSD, psilocybin, and MDMA – by examining their effects on the functional activation throughout the whole brain among both clinical and healthy participants.
Methods
We conducted this meta-analysis by applying multilevel kernel density analysis (MKDA) with ensemble thresholding to quantitatively combine existing functional magnetic resonance imaging (fMRI) studies that examined whole-brain functional activation of clinical or healthy participants who were administered a serotonergic psychedelic.
Results
Serotonergic psychedelics, including LSD, psilocybin, and MDMA, exhibited significant effects (α=0.05) on neural activation in several regions throughout the cerebral cortex and basal ganglia, including effects that may be common across and unique within each drug.
Conclusions
These observed effects of serotonergic psychedelics on neural activity advance our understanding of the functional neuroanatomy associated with their administration and may inform future studies of both their adverse and therapeutic effects, including emerging clinical applications for the treatment of several psychiatric disorders.
Disclosure of Interest
None Declared
Abstract
Decades ago, the classical psychedelics psilocybin and LSD entered the therapeutic setting and already then showed their therapeutic potential in the treatment of psychiatric disorders. For ...thousands of years another psychedelic, ayahuasca, is being used by tribes in western Amazonia for healing and divination, and in recent years its use has expanded worldwide.
Research into the therapeutic potential of these substances has re-emerged and (preliminary) findings are promising, showing that after one or two administrations remission is reached in depressed patients that were labeled as treatment-resistant. This is a remarkable finding as the therapeutic effects of treatment with conventional pharmacological agents like SSRIs take longer to lead to remission, with one-third of the patients failing to reach this stage.
The fast onset of positive therapeutic effects by psychedelics increases the interest to discover the mechanism of action behind this. There is a debate about the importance of the psychological experience caused by these agents in the therapeutic outcome, while science also tries to understand the neurobiological correlates. The latter will be addressed in my talk and I will link it to psychedelics’ therapeutic effects.
Disclosure of Interest
None Declared
Introduction
Psilocybin is a naturally occurring psychedelic compound whose effects have been seen in studies for treatment of depression, anxiety and pain management. Given its structural ...similarities to 5-hydroxytryptamine, a monoamine controlling brain modulation of pain input, preliminary studies sought to test serotonergic interactions of psilocybin with headaches.
Objectives
Explore efficacy of psilocybin as treatment for individuals with headaches, including migraines, essential headaches, cluster headaches and unclassified head pains.
Methods
Studies were found from six major databases, with inclusion criteria consisting of participants with any type of headache using psilocybin as a treatment. Each study was independently screened by two reviewers at two stages, with inconsistencies reviewed by a third, senior reviewer.
Results
The systematic review evaluated eight articles. Benefits of macrodosing were explored in one study which reported higher levels of pain relief in comparison to microdosing and conventional pain medications. Top benefits of microdosing as reported by participants included convenience, perceived safety and reduced side effects when compared to hallucinogenic doses of psilocybin. Participants across five studies reported improvements to their headaches as characterized by changes in frequency, intensity, duration and remission period. Reported improvements were clinically significant in the six studies and statistically significant in three papers. With psilocybin intervention, two studies reported a decrease in headache attack frequency, three studies reported a decrease in intensity, and one study indicated a decrease in duration. The greatest benefit reported was for psilocybin taken during a remission period, with the average length of that remission period between headaches extending for 91% of participants. One study focused on the dosages of psilocybin in relation to its efficacy, indicating that there was more headache pain relief amongst macrodosers, with a difference of 12.3% of participants experiencing pain reduction 3 days after dosage in comparison to microdosers. 18% of participants who experienced essential headaches also experienced hallucinations as a result of ingested psilocybin. Others showed a temporary increase in symptoms of anxiety and pain - 5.3% with microdosing and 14.1% macrodosing. One study observed an increase in average arterial pressure after ingestion.
Conclusions
Six of eight screened papers showed that psilocybin was clinically significant in the treatment of headaches as captured through self-reports. While the first controlled study for psilocybin use for headaches was detailed in this study, psilocybin remains illegal in many countries, presenting a need for further regulated research.
Disclosure of Interest
None Declared
Psychedelic drugs are becoming accessible in the US through a patchwork of state legislative reforms. This shift necessitates consensus on treatment models, education and guidance for health care ...professionals, and planning for implementation and regulation.
To assess trends in psychedelics legislative reform and legalization in the US to provide guidance to health care professionals, policy makers, and the public.
Data were compiled from legislative databases (BillTrack50, LexisNexis, and Ballotpedia) from January 1, 2019, to September 28, 2022. Legislation was identified by searching for terms related to psychedelics (eg, psilocybin, MDMA, peyote, mescaline, ibogaine, LSD, ayahuasca, and DMT). Bills were coded by an attorney along 2 axes: which psychedelic drugs would be affected and in what ways (eg, decriminalization, funding for medical research, and right to try). To explore drivers and rates of legislative reform, data were compared with other state indices including 2020 presidential voting margins and marijuana legislative reform.
Twenty-five states have considered 74 bills (69 legislative initiatives, 5 ballot measures); 10 bills were enacted, and 32 were still active. The number of psychedelic reform bills introduced during each calendar year increased steadily from 5 in 2019 to 6 in 2020, 27 in 2021, and 36 in 2022. Nearly all bills specified psilocybin (67 90%), and many also included MDMA (3,4-methylenedioxy-methamphetamine; 27 36%). While bills varied in their framework, most (43 58%) proposed decriminalization, of which few delineated medical oversight (10 of 43 23%) or training and/or licensure requirements (15 of 43 35%). In general, bills contained less regulatory guidance than the enacted Oregon Measure 109. While early legislative efforts occurred in liberal states, the margin between liberal and conservative states has decreased over time (although the difference was not significant), suggesting that psychedelic drug reform is becoming a bipartisan issue. In addition, an analytic model based on marijuana legalization projected that a majority of states will legalize psychedelics by 2034 to 2037.
Legislative reform for psychedelic drugs has been proceeding in a rapid, patchwork fashion in the US. Further consideration should be given to key health care issues such as establishing (1) standards for drugs procured outside the medical establishment, (2) licensure criteria for prescribers and therapists, (3) clinical and billing infrastructure, (4) potential contraindications, and (5) use in special populations like youths, older adults, and pregnant individuals.
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