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Proceedings of the National Academy of... Apr 2021Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the...
Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the psychedelic compound psilocybin produces not only powerful alterations of consciousness, but also rapid and persistent antidepressant effects. How psilocybin exerts its therapeutic actions is not known, but it is widely presumed that these actions require altered consciousness, which is known to be dependent on serotonin 2A receptor (5-HT2AR) activation. This hypothesis has never been tested, however. We therefore asked whether psilocybin would exert antidepressant-like responses in mice and, if so, whether these responses required 5-HT2AR activation. Using chronically stressed male mice, we observed that a single injection of psilocybin reversed anhedonic responses assessed with the sucrose preference and female urine preference tests. The antianhedonic response to psilocybin was accompanied by a strengthening of excitatory synapses in the hippocampus-a characteristic of traditional and fast-acting antidepressants. Neither behavioral nor electrophysiological responses to psilocybin were prevented by pretreatment with the 5-HT2A/2C antagonist ketanserin, despite positive evidence of ketanserin's efficacy. We conclude that psilocybin's mechanism of antidepressant action can be studied in animal models and suggest that altered perception may not be required for its antidepressant effects. We further suggest that a 5-HT2AR-independent restoration of synaptic strength in cortico-mesolimbic reward circuits may contribute to its antidepressant action. The possibility of combining psychedelic compounds and a 5-HT2AR antagonist offers a potential means to increase their acceptance and clinical utility and should be studied in human depression.
Topics: Animals; Depression; Drug Evaluation, Preclinical; Hallucinogens; Hippocampus; Ketanserin; Male; Mice, Inbred C57BL; Psilocybin; Receptors, Serotonin, 5-HT2; Serotonin 5-HT2 Receptor Agonists; Stress, Psychological; Mice
PubMed: 33850049
DOI: 10.1073/pnas.2022489118 -
Canadian Journal of Psychiatry. Revue... Jan 2023Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for... (Review)
Review
OBJECTIVE
Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence and provide a consensus recommendation for the clinical use of psychedelic treatments for major depressive disorder.
METHODS
A systematic review was conducted to identify contemporary clinical trials of serotonergic psychedelics for the treatment of major depressive disorder and cancer-related depression. Studies published between January 1990 and July 2021 were identified using combinations of search terms, inspection of bibliographies and review of other psychedelic reviews and consensus statements. The levels of evidence for efficacy were graded according to the Canadian Network for Mood and Anxiety Treatments criteria.
RESULTS
Only psilocybin and ayahuasca have contemporary clinical trials evaluating antidepressant effects. Two pilot studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator (escitalopram with supportive psychotherapy) in major depressive disorder, with additional randomized controlled trials showing efficacy specifically in cancer-related depression (Level 3 evidence). There was only one open-label trial of psilocybin in treatment-resistant unipolar depression (Level 4 evidence). Small sample sizes and functional unblinding were major limitations in all studies. Adverse events associated with psychedelics, including psychological (e.g., psychotomimetic effects) and physical (e.g., nausea, emesis and headaches) effects, were generally transient.
CONCLUSIONS
There is currently only low-level evidence to support the efficacy and safety of psychedelics for major depressive disorder. In Canada, as of 2022, psilocybin remains an experimental option that is only available through clinical trials or the special access program. As such, Canadian Network for Mood and Anxiety Treatments considers psilocybin an experimental treatment and recommends its use primarily within clinical trials, or, less commonly, through the special access program in rare, special circumstances.
Topics: Humans; Hallucinogens; Psilocybin; Depressive Disorder, Major; Canada; Anxiety; Neoplasms
PubMed: 35975555
DOI: 10.1177/07067437221111371 -
Neuroscience and Biobehavioral Reviews Aug 2022The use of low doses of psychedelic substances (microdosing) is attracting increasing interest. This systematic review summarises all empirical microdosing research to... (Review)
Review
The use of low doses of psychedelic substances (microdosing) is attracting increasing interest. This systematic review summarises all empirical microdosing research to date, including a set of infrequently cited studies that took place prior to prohibition. Specifically, we reviewed 44 studies published between 1955 and 2021, and summarised reported effects across six categories: mood and mental health; wellbeing and attitude; cognition and creativity; personality; changes in conscious state; and neurobiology and physiology. Studies showed a wide range in risk of bias, depending on design, age, and other study characteristics. Laboratory studies found changes in pain perception, time perception, conscious state, and neurophysiology. Self-report studies found changes in cognitive processing and mental health. We review data related to expectation and placebo effects, but argue that claims that microdosing effects are largely due to expectancy are premature and possibly wrong. In addition, we attempt to clarify definitional inconsistencies in the microdosing literature by providing suggested dose ranges across different substances. Finally, we provide specific design suggestions to facilitate more rigorous future research.
Topics: Affect; Creativity; Hallucinogens; Humans; Mental Health; Personality; Psilocybin
PubMed: 35609684
DOI: 10.1016/j.neubiorev.2022.104706 -
Laeknabladid Sep 2022The hallucinogen psilocybin is a potential novel treatment for treatment-resistant depression (TRD). Our goal is to review current knowledge on psilocybin and its...
The hallucinogen psilocybin is a potential novel treatment for treatment-resistant depression (TRD). Our goal is to review current knowledge on psilocybin and its efficacy in TRD. Literature searches were done on PubMed, Web of Science and Google Scholar, references reviewed in identified articles and other articles found on the website of COMPASS Pathways. Psilocybin treatment consists usually of a single oral administration of 25 mg of psilocybin along with psychological support for 5-8 hours during the ensuing hallucinogenic trip. Common side-effects include headache, nausea, fatigue and insomnia. A systematic review has demonstrated significant antidepressant efficacy in certain groups and a double-blind randomized study found antidepressant efficacy of psilocybin comparable to the SSRI escitalopram. In the phase 2 study of COMPASS Pathways, the psilocybin-COMP360 treatment led to a rapid response and remission as early as three weeks following the treatment for around one third of participants. Recent studies have shown that psilocybin significantly decreases the severity of depressive symptoms and is generally well tolerated. Further research will reveal whether it will be granted a license to treat treatment-resistant depression in the near future. There remains an urgent need for novel treatments for those who do not respond to current antidepressant therapies.
Topics: Antidepressive Agents; Depression; Depressive Disorder, Treatment-Resistant; Hallucinogens; Humans; Psilocybin; Randomized Controlled Trials as Topic
PubMed: 36040772
DOI: 10.17992/lbl.2022.09.706 -
Clinical Pharmacology and Therapeutics Apr 2022The psychedelic psilocybin is being investigated for the treatment of depression and anxiety. Unclear is whether antidepressant treatments interact with psilocybin. The... (Randomized Controlled Trial)
Randomized Controlled Trial
The psychedelic psilocybin is being investigated for the treatment of depression and anxiety. Unclear is whether antidepressant treatments interact with psilocybin. The present study used a double-blind, placebo-controlled, crossover design with two experimental test sessions to investigate the response to psilocybin (25 mg) in healthy subjects after pretreatment with escitalopram or placebo. The treatment order was random and counterbalanced. Pretreatment consisted of 10 mg escitalopram daily for 7 days, followed by 20 mg daily for 7 days, including the day of psilocybin administration, or 14 days of placebo pretreatment before psilocybin administration. Psilocybin treatments were separated by at least 16 days. The outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor (BDNF) levels, electrocardiogram QTc time, whole-blood HTR2A and SCL6A4 gene expression, and pharmacokinetics. Escitalopram pretreatment had no relevant effect on positive mood effects of psilocybin but significantly reduced bad drug effects, anxiety, adverse cardiovascular effects, and other adverse effects of psilocybin compared with placebo pretreatment. Escitalopram did not alter the pharmacokinetics of psilocin. The half-life of psychoactive free (unconjugated) psilocin was 1.8 hours (range 1.1-2.2 hours), consistent with the short duration of action of psilocybin. Escitalopram did not alter HTR2A or SCL6A4 gene expression before psilocybin administration, QTc intervals, or circulating BDNF levels before or after psilocybin administration. Further studies are needed with a longer antidepressant pretreatment time and patients with psychiatric disorders to further define interactions between antidepressants and psilocybin.
Topics: Antidepressive Agents; Brain-Derived Neurotrophic Factor; Citalopram; Cross-Over Studies; Double-Blind Method; Escitalopram; Healthy Volunteers; Humans; Psilocybin
PubMed: 34743319
DOI: 10.1002/cpt.2487 -
Translational Psychiatry Nov 2021Psilocybin has shown promise for the treatment of mood disorders, which are often accompanied by cognitive dysfunction including cognitive rigidity. Recent studies have...
Psilocybin has shown promise for the treatment of mood disorders, which are often accompanied by cognitive dysfunction including cognitive rigidity. Recent studies have proposed neuropsychoplastogenic effects as mechanisms underlying the enduring therapeutic effects of psilocybin. In an open-label study of 24 patients with major depressive disorder, we tested the enduring effects of psilocybin therapy on cognitive flexibility (perseverative errors on a set-shifting task), neural flexibility (dynamics of functional connectivity or dFC via functional magnetic resonance imaging), and neurometabolite concentrations (via magnetic resonance spectroscopy) in brain regions supporting cognitive flexibility and implicated in acute psilocybin effects (e.g., the anterior cingulate cortex, or ACC). Psilocybin therapy increased cognitive flexibility for at least 4 weeks post-treatment, though these improvements were not correlated with the previously reported antidepressant effects. One week after psilocybin therapy, glutamate and N-acetylaspartate concentrations were decreased in the ACC, and dFC was increased between the ACC and the posterior cingulate cortex (PCC). Surprisingly, greater increases in dFC between the ACC and PCC were associated with less improvement in cognitive flexibility after psilocybin therapy. Connectome-based predictive modeling demonstrated that baseline dFC emanating from the ACC predicted improvements in cognitive flexibility. In these models, greater baseline dFC was associated with better baseline cognitive flexibility but less improvement in cognitive flexibility. These findings suggest a nuanced relationship between cognitive and neural flexibility. Whereas some enduring increases in neural dynamics may allow for shifting out of a maladaptively rigid state, larger persisting increases in neural dynamics may be of less benefit to psilocybin therapy.
Topics: Brain Mapping; Cognition; Depressive Disorder, Major; Humans; Magnetic Resonance Imaging; Psilocybin
PubMed: 34750350
DOI: 10.1038/s41398-021-01706-y -
Journal of Affective Disorders Apr 2023COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high global impact. Here, we expand upon the previous report of primary outcomes from a phase 2 study of COMP360 in individuals with TRD-the largest randomised controlled clinical trial of psilocybin-to discuss findings of the exploratory efficacy endpoints.
METHODS
In this phase 2, double-blind trial, 233 participants with TRD were randomised to receive a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), administered alongside psychological support from trained therapists. Efficacy measures assessed patient-reported depression severity, anxiety, positive and negative affect, functioning and associated disability, quality of life, and cognitive function.
RESULTS
At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures. The 10 mg dose produced smaller effects across these measures.
LIMITATIONS
Interpretation of this trial is limited by the absence of an active comparator and the possibility of functional unblinding in participants who received a low dose of psilocybin.
CONCLUSIONS
Three weeks after dosing, psilocybin 25 mg and, to a lesser degree, 10 mg improved measures of patient-reported depression severity, anxiety, affect, and functioning. These results extend the primary findings from the largest randomised clinical trial of psilocybin for TRD to examine other outcomes that are of importance to patients.
Topics: Humans; Psilocybin; Depression; Depressive Disorder, Major; Quality of Life; Anxiety; Patient Reported Outcome Measures
PubMed: 36740140
DOI: 10.1016/j.jad.2023.01.108 -
Scientific Reports Jun 2022Psilocybin microdosing involves repeated self-administration of mushrooms containing psilocybin at doses small enough to not impact regular functioning. Microdose... (Observational Study)
Observational Study
Psilocybin microdosing involves repeated self-administration of mushrooms containing psilocybin at doses small enough to not impact regular functioning. Microdose practices are diverse and include combining psilocybin with substances such as lion's mane mushrooms (Hericium erinaceus; HE) and niacin (vitamin-B3). Public uptake of microdosing has outpaced evidence, mandating further prospective research. Using a naturalistic, observational design, we followed psilocybin microdosers (n = 953) and non-microdosing comparators (n = 180) for approximately 30 days and identified small- to medium-sized improvements in mood and mental health that were generally consistent across gender, age and presence of mental health concerns, as we all as improvements in psychomotor performance that were specific to older adults. Supplementary analyses indicated that combining psilocybin with HE and B3 did not impact changes in mood and mental health. However, among older microdosers combining psilocybin, HE and B3 was associated with psychomotor improvements relative to psilocybin alone and psilocybin and HE. Our findings of mood and mental health improvements associated with psilocybin microdosing add to previous studies of psychedelic microdosing by using a comparator group and by examining the consistency of effects across age, gender, and mental health. Findings regarding the combination of psilocybin, HE and B3 are novel and highlight the need for further research to confirm and elucidate these apparent effects.
Topics: Affect; Hallucinogens; Mental Health; Psilocybin; Self Administration
PubMed: 35773270
DOI: 10.1038/s41598-022-14512-3 -
Nature Neuroscience Jun 2023Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently...
Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants, and that psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers. The effects of psychedelics on neurotrophic signaling, plasticity and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling but are independent of serotonin 2A receptor (5-HT) activation, whereas LSD-induced head twitching is dependent on 5-HT and independent of TrkB binding. Our data confirm TrkB as a common primary target for antidepressants and suggest that high-affinity TrkB positive allosteric modulators lacking 5-HT activity may retain the antidepressant potential of psychedelics without hallucinogenic effects.
Topics: Hallucinogens; Humans; HEK293 Cells; Binding Sites; Molecular Dynamics Simulation; Brain-Derived Neurotrophic Factor; Signal Transduction; Receptor, trkB; Neuronal Plasticity; Antidepressive Agents; Allosteric Regulation; Male; Female; Animals; Mice; Mice, Inbred C57BL; Embryo, Mammalian; Neurons; Lysergic Acid Diethylamide; Psilocybin
PubMed: 37280397
DOI: 10.1038/s41593-023-01316-5 -
Neuropharmacology Nov 2018This review assesses the abuse potential of medically-administered psilocybin, following the structure of the 8 factors of the US Controlled Substances Act (CSA).... (Review)
Review
This review assesses the abuse potential of medically-administered psilocybin, following the structure of the 8 factors of the US Controlled Substances Act (CSA). Research suggests the potential safety and efficacy of psilocybin in treating cancer-related psychiatric distress and substance use disorders, setting the occasion for this review. A more extensive assessment of abuse potential according to an 8-factor analysis would eventually be required to guide appropriate schedule placement. Psilocybin, like other 5-HT2A agonist classic psychedelics, has limited reinforcing effects, supporting marginal, transient non-human self-administration. Nonetheless, mushrooms with variable psilocybin content are used illicitly, with a few lifetime use occasions being normative among users. Potential harms include dangerous behavior in unprepared, unsupervised users, and exacerbation of mental illness in those with or predisposed to psychotic disorders. However, scope of use and associated harms are low compared to prototypical abused drugs, and the medical model addresses these concerns with dose control, patient screening, preparation and follow-up, and session supervision in a medical facility. CONCLUSIONS: (1) psilocybin has an abuse potential appropriate for CSA scheduling if approved as medicine; (2) psilocybin can provide therapeutic benefits that may support the development of an approvable New Drug Application (NDA) but further studies are required which this review describes; (3) adverse effects of medical psilocybin are manageable when administered according to risk management approaches; and (4) although further study is required, this review suggests that placement in Schedule IV may be appropriate if a psilocybin-containing medicine is approved. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.
Topics: Animals; Drug and Narcotic Control; Hallucinogens; Humans; Psilocybin; Substance-Related Disorders
PubMed: 29753748
DOI: 10.1016/j.neuropharm.2018.05.012