-
Psychiatry Research Nov 2023The aim of this review was to determine the effect of psilocybin on depressive symptoms in patients diagnosed with life-threatening illnesses or major depressive... (Meta-Analysis)
Meta-Analysis Review
The aim of this review was to determine the effect of psilocybin on depressive symptoms in patients diagnosed with life-threatening illnesses or major depressive disorder. Systematic searches were conducted to search for randomized clinical trials and open-label trials that evaluated depression symptoms after psilocybin therapy. Data was pooled using a random-effects model. The primary outcome was the standardized mean difference (SMD) in depression severity, determined by calculating the change in depression ratings from baseline to the primary endpoint in the psilocybin arm versus the control arm. The literature search yielded 1734 studies, and 13 studies (n = 686) were included in either qualitative and/or quantitative analyses. The meta-analysis included 9 studies (pooled n = 596) and yielded a large effect size in favour of psilocybin (SMD = -0.78; p<0.001). Risk ratios for response and remission were large and significant in favour of psilocybin. A review of open-label trials showed robust decreases in depressive symptoms following psilocybin administration. These findings provide preliminary evidence for antidepressant efficacy with psilocybin-assisted psychotherapy, however, further studies are needed to evaluate safety and efficacy and to optimize treatment protocols.
Topics: Humans; Psilocybin; Depression; Depressive Disorder, Major; Psychotherapy; Antidepressive Agents; Hallucinogens
PubMed: 37844352
DOI: 10.1016/j.psychres.2023.115531 -
Neuropharmacology Sep 2023This Special Issue of Neuropharmacology on psychedelics provides a timely and comprehensive update on progress following the previous Neuropharmacology Special Issue...
This Special Issue of Neuropharmacology on psychedelics provides a timely and comprehensive update on progress following the previous Neuropharmacology Special Issue "Psychedelics: New Doors, Altered Perceptions". Remarkable advances have been made in basic and clinical research on psychedelics in the five years since 2018. It is partly based on the seminar series focused on psilocybin organized by the National Institutes of Health (NIH), USA from April to June 2021, the "NIH Psilocybin Research Speaker Series". Participants were world leading experts, including scientists, medical practitioners, clinical psychologists and oncologists, and attendees from additional disciplines of patient advocacy, law, government science policy and regulatory policy. To provide a global perspective, their contributions are complemented with reviews by some of the world's most eminent scientists in the field. The US Food and Drug Administration (FDA) has granted two breakthrough therapy designations for psilocybin in treatment resistant depression (TRD) in 2018 and major depressive disorder (MDD) in 2019, as well as for MDMA for the treatment of post-traumatic stress disorder (PTSD) in 2017. Clinical trials are in progress to assess the therapeutic value of psilocybin in MDD and TRD, and in other indications such as cancer-related anxiety and depression, anorexia, PTSD, substance use disorders and various types of chronic pain. The contributors' insights should assist basic and applied science for transition of psychedelics from bench to potential mainstream therapies. The implications are global, because FDA approval of these new medicines will increase international interest and efforts.
Topics: Humans; Hallucinogens; Psilocybin; Depressive Disorder, Major; Substance-Related Disorders; Anxiety
PubMed: 37247807
DOI: 10.1016/j.neuropharm.2023.109610 -
JAMA Sep 2023Psilocybin shows promise as a treatment for major depressive disorder (MDD).
IMPORTANCE
Psilocybin shows promise as a treatment for major depressive disorder (MDD).
OBJECTIVE
To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD.
DESIGN, SETTING, AND PARTICIPANTS
In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days' duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing.
INTERVENTIONS
Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support.
MAIN OUTCOMES AND MEASURES
The primary outcome was change in central rater-assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment.
RESULTS
A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,-12.3 [95% CI, -17.5 to -7.2]; P <.001) and from baseline to day 8 (mean difference, -12.0 [95% CI, -16.6 to -7.4]; P < .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, -2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs.
CONCLUSIONS AND RELEVANCE
Psilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin-when administered with psychological support-may hold promise as a novel intervention for MDD.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03866174.
Topics: Adult; Humans; Female; Male; Depressive Disorder, Major; Hallucinogens; Psilocybin; Mental Health; Niacin
PubMed: 37651119
DOI: 10.1001/jama.2023.14530 -
Anesthesiology Oct 2023Chronic pain is a public health concern that affects approximately 1.5 billion people globally. Conventional therapeutic agents including opioid and non-opioid... (Review)
Review
Chronic pain is a public health concern that affects approximately 1.5 billion people globally. Conventional therapeutic agents including opioid and non-opioid analgesics have been associated with adverse side effects, issues with addiction, and ineffective analgesia. Novel agents repurposed to treat pain via different mechanisms are needed to fill the therapeutic gap in chronic pain management. Psychedelics such as lysergic acid diethylamide and psilocybin (the active ingredient in psychedelic mushrooms) are thought to alter pain perception through direct serotonin receptor agonism, anti-inflammatory effects, and synaptic remodeling. This scoping review was conducted to identify human studies in which psychedelic agents were used for the treatment of pain. Twenty-one articles that assessed the effects of psychedelics in treating various pain states were included. The present scarcity of clinical trials and small sample sizes limit their application for clinical use. Overall, psychedelics appear to show promise for analgesia in patients with certain headache disorders and cancer pain diagnoses. Future studies must aim to examine the combined effects of psychotherapy and psychedelics on chronic pain.
Topics: Humans; Hallucinogens; Chronic Pain; Pain Management; Pain Perception; Analgesia; Drug-Related Side Effects and Adverse Reactions
PubMed: 37698433
DOI: 10.1097/ALN.0000000000004673 -
Current Neuropharmacology 2024Post-traumatic stress disorder (PTSD) is a mental health condition that can occur following exposure to a traumatic experience. An estimated 12 million U.S. adults are... (Review)
Review
Post-traumatic stress disorder (PTSD) is a mental health condition that can occur following exposure to a traumatic experience. An estimated 12 million U.S. adults are presently affected by this disorder. Current treatments include psychological therapies (e.g., exposure-based interventions) and pharmacological treatments (e.g., selective serotonin reuptake inhibitors (SSRIs)). However, a significant proportion of patients receiving standard-of-care therapies for PTSD remain symptomatic, and new approaches for this and other trauma-related mental health conditions are greatly needed. Psychedelic compounds that alter cognition, perception, and mood are currently being examined for their efficacy in treating PTSD despite their current status as Drug Enforcement Administration (DEA)- scheduled substances. Initial clinical trials have demonstrated the potential value of psychedelicassisted therapy to treat PTSD and other psychiatric disorders. In this comprehensive review, we summarize the state of the science of PTSD clinical care, including current treatments and their shortcomings. We review clinical studies of psychedelic interventions to treat PTSD, trauma-related disorders, and common comorbidities. The classic psychedelics psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT) and DMT-containing ayahuasca, as well as the entactogen 3,4-methylenedioxymethamphetamine (MDMA) and the dissociative anesthetic ketamine, are reviewed. For each drug, we present the history of use, psychological and somatic effects, pharmacology, and safety profile. The rationale and proposed mechanisms for use in treating PTSD and traumarelated disorders are discussed. This review concludes with an in-depth consideration of future directions for the psychiatric applications of psychedelics to maximize therapeutic benefit and minimize risk in individuals and communities impacted by trauma-related conditions.
Topics: Adult; Humans; Hallucinogens; Stress Disorders, Post-Traumatic; Lysergic Acid Diethylamide; Psilocybin; N-Methyl-3,4-methylenedioxyamphetamine; N,N-Dimethyltryptamine
PubMed: 38284341
DOI: 10.2174/1570159X22666231027111147 -
Pharmacological Research Aug 2023Major depressive disorder (MDD) is a chronic relapsing psychiatric disorder. Conventional antidepressants usually require several weeks of continuous administration to... (Review)
Review
Major depressive disorder (MDD) is a chronic relapsing psychiatric disorder. Conventional antidepressants usually require several weeks of continuous administration to exert clinically significant therapeutic effects, while about two-thirds of the patients are prone to relapse of symptoms or are completely ineffective in antidepressant treatment. The recent success of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine as a rapid-acting antidepressant has propelled extensive research on the action mechanism of antidepressants, especially in relation to its role in synaptic targets. Studies have revealed that the mechanism of antidepressant action of ketamine is not limited to antagonism of postsynaptic NMDA receptors or GABA interneurons. Ketamine produces powerful and rapid antidepressant effects by affecting α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors, adenosine A1 receptors, and the L-type calcium channels, among others in the synapse. More interestingly, the 5-HT2A receptor agonist psilocybin has demonstrated potential for rapid antidepressant effects in depressed mouse models and clinical studies. This article focuses on a review of new pharmacological target studies of emerging rapid-acting antidepressant drugs such as ketamine and hallucinogens (e.g., psilocybin) and briefly discusses the possible strategies for new targets of antidepressants, with a view to shed light on the direction of future antidepressant research.
Topics: Animals; Mice; Ketamine; Depressive Disorder, Major; Psilocybin; Antidepressive Agents; Disease Models, Animal; Receptors, N-Methyl-D-Aspartate
PubMed: 37379962
DOI: 10.1016/j.phrs.2023.106837 -
Chinese Medical Journal Dec 2023Posttraumatic stress disorder (PTSD) and depression are highly comorbid. Psilocybin exerts substantial therapeutic effects on depression by promoting neuroplasticity....
BACKGROUND
Posttraumatic stress disorder (PTSD) and depression are highly comorbid. Psilocybin exerts substantial therapeutic effects on depression by promoting neuroplasticity. Fear extinction is a key process in the mechanism of first-line exposure-based therapies for PTSD. We hypothesized that psilocybin would facilitate fear extinction by promoting hippocampal neuroplasticity.
METHODS
First, we assessed the effects of psilocybin on percentage of freezing time in an auditory cued fear conditioning (FC) and fear extinction paradigm in mice. Psilocybin was administered 30 min before extinction training. Fear extinction testing was performed on the first day; fear extinction retrieval and fear renewal were tested on the sixth and seventh days, respectively. Furthermore, we verified the effect of psilocybin on hippocampal neuroplasticity using Golgi staining for the dendritic complexity and spine density, Western blotting for the protein levels of brain derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR), and immunofluorescence staining for the numbers of doublecortin (DCX)- and bromodeoxyuridine (BrdU)-positive cells.
RESULTS
A single dose of psilocybin (2.5 mg/kg, i.p.) reduced the increase in the percentage of freezing time induced by FC at 24 h, 6th day and 7th day after administration. In terms of structural neuroplasticity, psilocybin rescued the decrease in hippocampal dendritic complexity and spine density induced by FC; in terms of neuroplasticity related proteins, psilocybin rescued the decrease in the protein levels of hippocampal BDNF and mTOR induced by FC; in terms of neurogenesis, psilocybin rescued the decrease in the numbers of DCX- and BrdU-positive cells in the hippocampal dentate gyrus induced by FC.
CONCLUSIONS
A single dose of psilocybin facilitated rapid and sustained fear extinction; this effect might be partially mediated by the promotion of hippocampal neuroplasticity. This study indicates that psilocybin may be a useful adjunct to exposure-based therapies for PTSD and other mental disorders characterized by failure of fear extinction.
Topics: Humans; Mice; Animals; Psilocybin; Fear; Extinction, Psychological; Brain-Derived Neurotrophic Factor; Bromodeoxyuridine; Hippocampus; Neuronal Plasticity; TOR Serine-Threonine Kinases
PubMed: 37000971
DOI: 10.1097/CM9.0000000000002647 -
European Neuropsychopharmacology : the... Nov 2023Psilocybin is increasingly studied for its antidepressant effect, but its optimal dosage for depression remains unclear. We conducted a systematic review and a... (Meta-Analysis)
Meta-Analysis Review
Psilocybin is increasingly studied for its antidepressant effect, but its optimal dosage for depression remains unclear. We conducted a systematic review and a dose-response meta-analysis to find the optimal dosage of psilocybin to reduce depression scores. Following our protocol (CRD 42022220190) multiple electronic databases were searched from their inception until February 2023, to identify double-blind randomized placebo-controlled (RCTs) fixed-dose trials evaluating the use of psilocybin for adult patients with primary or secondary depression. A one-stage dose-response meta-analysis with restricted cubic splines was used. Cochrane risk of bias was used to assess risk of bias. Our analysis included seven studies with a total of 489 participants. Among these, four studies focused on primary depression (N = 366), including one study with patients suffering from treatment-resistant depression. The remaining three studies examined secondary depression (N = 123). The determined 95% effective doses per day (ED95) were 8.92, 24.68, and 36.08 mg/70 kg for patients with secondary depression, primary depression, and both subgroups, respectively. We observed significant dose-response associations for all curves, each plateauing at different levels, except for the bell-shaped curve observed in the case of secondary depression. Additionally, we found significant dose-response associations for various side effects, including physical discomfort, blood pressure increase, nausea/vomiting, headache/migraine, and the risk of prolonged psychosis. In conclusion, we discovered specific ED95 values for different populations, indicating higher ED95 values for treatment-resistant depression, primary depression, and secondary depression groups. Further RCTs are necessary for each population to determine the optimal dosage, allowing for maximum efficacy while minimizing side effects.
Topics: Adult; Humans; Depression; Psilocybin; Antidepressive Agents; Psychotic Disorders; Randomized Controlled Trials as Topic
PubMed: 37557019
DOI: 10.1016/j.euroneuro.2023.07.011 -
Journal of Affective Disorders Aug 2023Psilocybin therapy is receiving attention as a mental health intervention with transdiagnostic potential. In line with psychotherapeutic research, qualitative research... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Psilocybin therapy is receiving attention as a mental health intervention with transdiagnostic potential. In line with psychotherapeutic research, qualitative research has highlighted the role of reductions in experiential avoidance (and increases in connectedness) within psilocybin therapy. However, no quantitative research has examined experiential avoidance as a mechanism underlying psilocybin therapy's therapeutic effects.
METHOD
Data was used from a double-blind randomized controlled trial that compared psilocybin therapy (two 25 mg psilocybin session plus daily placebo for six weeks) with escitalopram (two 1 mg psilocybin sessions plus 10-20 mg daily escitalopram for six weeks) among individuals with major depressive disorder (N = 59). All participants received psychological support. Experiential avoidance, connectedness, and treatment outcomes were measured at pre-treatment and at a 6 week primary endpoint. Acute psilocybin experiences and psychological insight were also measured.
RESULTS
With psilocybin therapy, but not escitalopram, improvements in mental health outcomes (i.e., well-being, depression severity, suicidal ideation, and trait anxiety) occurred via reductions in experiential avoidance. Exploratory analyses suggested that improvements in mental health (except for suicidal ideation) via reduction in experiential avoidance were serially mediated through increases in connectedness. Additionally, experiences of ego dissolution and psychological insight predicted reductions in experiential avoidance following psilocybin therapy.
LIMITATIONS
Difficulties inferring temporal causality, maintaining blindness to condition, and reliance upon self-report.
CONCLUSIONS
These results provide support for the role of reduced experiential avoidance as a putative mechanism underlying psilocybin therapy's positive therapeutic outcomes. The present findings may help to tailor, refine, and optimize psilocybin therapy and its delivery.
Topics: Humans; Psilocybin; Depressive Disorder, Major; Anxiety; Anxiety Disorders; Treatment Outcome
PubMed: 37146908
DOI: 10.1016/j.jad.2023.04.105 -
Ugeskrift For Laeger Aug 2023This review aims at RCT's of psychedelics used in the treatment of depression and PTSD. Psilocybin has shown an antidepressant effect in cancer patients that was... (Review)
Review
This review aims at RCT's of psychedelics used in the treatment of depression and PTSD. Psilocybin has shown an antidepressant effect in cancer patients that was sustained at 6- and 12-months follow-up. The effect of psilocybin was comparable to escitalopram in one study. Ketamine has shown effect for the treatment of resistant depression. Phase 2 and 3 trials have shown the effect of MDMA on PTSD. No serious adverse events were reported in controlled settings, but larger studies are needed to establish safety and long-term effects.
Topics: Humans; Hallucinogens; Psilocybin; Ketamine; Mental Disorders; Escitalopram
PubMed: 37615227
DOI: No ID Found