Psilocybin in the treatment of depressive disorders

“Abstract background: clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. methods: in this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. the primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks. results: prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. at the 6.5-month follow- up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60–80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. the psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. conclusions: in conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress.”

“Background psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. methods in this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. there was no control group. psychological support was provided before, during, and after each session. the primary outcome measure for feasibility was patient-reported intensity of psilocybin’s effects. patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item quick inventory of depressive symptoms (qids) serving as the primary efficacy outcome. this trial is registered with isrctn, number isrctn14426797. findings psilocybin’s acute psychedelic effects typically became detectable 30–60 min after dosing, peaked 2–3 h after dosing, and subsided to negligible levels at least 6 h after dosing. mean self-rated intensity (on a 0–1 scale) was 0·51 (sd 0·36) for the low-dose session and 0·75 (sd 0·27) for the high-dose session. psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. the adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). relative to baseline, depressive symptoms were markedly reduced 1 week (mean qids difference −11·8, 95% ci −9·15 to −14·35, p=0·002, hedges’ g=3·1) and 3 months (−9·2, 95% ci −5·69 to −12·71, p=0·003, hedges’ g=2) after high-dose treatment. marked and sustained improvements in anxiety and anhedonia were also noted. interpretation this study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeuti…”

“© british association for psychopharmacology. cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. the effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. this randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. instructions to participants and staff minimized expectancy effects. participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. high-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. at 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. community observer ratings showed corresponding changes. mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes. trial registration clinicaltrials.gov identifier: nct00465595”

“© 2017 the author(s). psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. here, cerebral blood flow (cbf) and blood oxygen-level dependent (bold) resting-state functional connectivity (rsfc) were measured with functional magnetic resonance imaging (fmri) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (trd). quality pre and post treatment fmri data were collected from 16 of 19 patients. decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. whole-brain analyses revealed post-treatment decreases in cbf in the temporal cortex, including the amygdala. decreased amygdala cbf correlated with reduced depressive symptoms. focusing on a priori selected circuitry for rsfc analyses, increased rsfc was observed within the default-mode network (dmn) post-treatment. increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex rsfc was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex rsfc. these data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. the post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. a ‘reset’ therapeutic mechanism is proposed.”

“Psilocybin, the clinically most researched classic psychedelic has recently been tested for its safety and efficacy in a clinical population of treatment resistant depression. the efficacy of psilocybin in clinical depression previously demonstrated in the elecrophysiologic and neuroimaging findings as also in neuropsychological assessments is further validated by the findings of this rigorously conducted randomized trial. mechanism of action of psilocybin and efficacy in treatment resistant depression are discussed in this paper. ethical issues of conducting clinical trials with psychedelics are also discussed with particular emphasis on their relative safety and absence of addiction potential. implications of these issues for conduct of larger trials for establishing risk benefit ratio in treatment resistant depression are further suggested.”

“Objective: to identify patients’ perceptions of the value of psilocybin as a treatment for depression. method: twenty patients enrolled in an open-label trial of psilocybin for treatment-resistant depression participated in a semistructured interview at 6-month follow-up. thematic analysis was used to identify patients’ experiences of the treatment and how it compared with previous treatments. results: two main change processes were identified in relation to the treatment. the first concerned change from disconnection (from self, others, and world) to connection, and the second concerned change from avoidance (of emotion) to acceptance. a third theme concerned comparison between psilocybin and conventional treatments. patients reported that medications and some short-term talking therapies tended to reinforce their sense of disconnection and avoidance, whereas treatment with psilocybin encouraged connection and acceptance. conclusions: these results suggest that psilocybin treatment for depression may wor…”

“Background the amygdala is a key structure in serotonergic emotion-processing circuits. in healthy volunteers, acute administration of the serotonin 1a/2a/2c receptor agonist psilocybin reduces neural responses to negative stimuli and induces mood changes toward positive states. however, it is little-known whether psilocybin reduces amygdala reactivity to negative stimuli and whether any change in amygdala reactivity is related to mood change. methods this study assessed the effects of acute administration of the hallucinogen psilocybin (.16 mg/kg) versus placebo on amygdala reactivity to negative stimuli in 25 healthy volunteers using blood oxygen level-dependent functional magnetic resonance imaging. mood changes were assessed using the positive and negative affect schedule and the state portion of the state-trait anxiety inventory. a double-blind, randomized, cross-over design was used with volunteers counterbalanced to receive psilocybin and placebo in two separate sessions at least 14 days apart. results amygdala reactivity to negative and neutral stimuli was lower after psilocybin administration than after placebo administration. the psilocybin-induced attenuation of right amygdala reactivity in response to negative stimuli was related to the psilocybin-induced increase in positive mood state. conclusions these results demonstrate that acute treatment with psilocybin decreased amygdala reactivity during emotion processing and that this was associated with an increase of positive mood in healthy volunteers. these findings may be relevant to the normalization of amygdala hyperactivity and negative mood states in patients with major depression.”

“© 2017, the american society for experimental neurotherapeutics, inc. psilocybin and other 5-hydroxytryptamine2aagonist classic psychedelics have been used for centuries as sacraments within indigenous cultures. in the mid-twentieth century they were a focus within psychiatry as both probes of brain function and experimental therapeutics. by the late 1960s and early 1970s these scientific inquires fell out of favor because classic psychedelics were being used outside of medical research and in association with the emerging counter culture. however, in the twenty-first century, scientific interest in classic psychedelics has returned and grown as a result of several promising studies, validating earlier research. here, we review therapeutic research on psilocybin, the classic psychedelic that has been the focus of most recent research. for mood and anxiety disorders, three controlled trials have suggested that psilocybin may decrease symptoms of depression and anxiety in the context of cancer-related psychiatric distress for at least 6 months following a single acute administration. a small, open-label study in patients with treatment-resistant depression showed reductions in depression and anxiety symptoms 3 months after two acute doses. for addiction, small, open-label pilot studies have shown promising success rates for both tobacco and alcohol addiction. safety data from these various trials, which involve careful screening, preparation, monitoring, and follow-up, indicate the absence of severe drug-related adverse reactions. modest drug-related adverse effects at the time of medication administration are readily managed. us federal funding has yet to support therapeutic psilocybin research, although such support will be important to thoroughly investigate efficacy, safety, and therapeutic mechanisms.”

“Plant-based psychedelics, such as psilocybin, have an ancient history of medicinal use. after the first english language report on lsd in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. used most notably as aids to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as lsd showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programs. since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with lsd and three separate clinical trials of psilocybin for depressive symptoms. in this circumspective piece, rlc-h and gmg share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.”

“Psilocybin is a naturally occurring alkaloid, pharmacologically similar to the classic hallucinogen lysergic acid diethylamide (lsd). although primarily used as a recreational drug or an entheogen in particular cultural settings, recent population based studies have shown that it does not lead to serious physical or mental health problems or dependent use. in view of recent work demonstrating psilocybin’s potential to increase subjective sense of wellbeing and because of its novel mechanism of 5-ht2a serotonin receptor agonism, it is being explored for possible therapeutic utility in mood and anxiety disorders.”

“Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with ssris attenuates amygdala responses (ma, 2015). we hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. in this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. psychological support was provided before, during and after these sessions and 19 completed fmri scans one week prior to the first session and one day after the second and last. neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with ssris. this suggests fundamental differences in these treatments’ therapeutic actions, with ssris mitigating negative emotions and psilocybin allowing patients to confront and work through them. based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions. trial registration: isrctn, number isrctn14426797. this article is part of the special issue entitled ‘psychedelics: new doors, altered perceptions’.”

“© 2017 the author(s) rationale: depressed patients robustly exhibit affective biases in emotional processing which are altered by ssris and predict clinical outcome. objectives: the objective of this study is to investigate whether psilocybin, recently shown to rapidly improve mood in treatment-resistant depression (trd), alters patients’ emotional processing biases. methods: seventeen patients with treatment-resistant depression completed a dynamic emotional face recognition task at baseline and 1 month later after two doses of psilocybin with psychological support. sixteen controls completed the emotional recognition task over the same time frame but did not receive psilocybin. results: we found evidence for a group × time interaction on speed of emotion recognition (p = .035). at baseline, patients were slower at recognising facial emotions compared with controls (p < .001). after psilocybin, this difference was remediated (p = .208). emotion recognition was faster at follow-up compared with baseline in patients (p = .004, d = .876) but not controls (p = .263, d = .302). in patients, this change was significantly correlated with a reduction in anhedonia over the same time period (r = .640, p = .010). conclusions: psilocybin with psychological support appears to improve processing of emotional faces in treatment-resistant depression, and this correlates with reduced anhedonia. placebo-controlled studies are warranted to follow up these preliminary findings.”

“To date, pharmacological treatments for mood and anxiety disorders and for drug dependence show limited efficacy, leaving a large number of patients suffering severe and persistent symptoms. preliminary studies in animals and humans suggest that ayahuasca, psilocybin and lysergic acid diethylamide (lsd) may have antidepressive, anxiolytic, and antiaddictive properties. thus, we conducted a systematic review of clinical trials published from 1990 until 2015, assessing these therapeutic properties. electronic searches were performed using the pubmed, lilacs, and scielo databases. only clinical trials published in peer-reviewed journals were included. of these, 151 studies were identified, of which six met the established criteria. reviewed studies suggest beneficial effects for treatment-resistant depression, anxiety and depression associated with life-threatening diseases, and tobacco and alcohol dependence. all drugs were well tolerated. in conclusion, ayahuasca, psilocybin and lsd may be useful pharmacological tools for the treatment of drug dependence, and anxiety and mood disorders, especially in treatment-resistant patients. these drugs may also be useful pharmacological tools to understand psychiatric disorders and to develop new therapeutic agents. however, all studies reviewed had small sample sizes, and half of them were open-label, proof-of-concept studies. randomized, double-blind, placebo-controlled studies with more patients are needed to replicate these preliminary findings.”

“© 2016 informa uk limited, trading as taylor & francis group. introduction: evidence based treatment for substance use disorders (sud) includes psychotherapy and pharmacotherapy. however, these are only partially effective. hallucinogens, such as psilocybin, may represent potential new treatment options for sud. this review provides a summary of (human) studies on the putative therapeutic effects of psilocybin, and discusses the receptor systems, brain regions and cognitive and emotional processes mediating psilocybin’s effects. psilocybin’s chemical structure is similar to that of serotonin. dysregulations in the serotonin system are associated with alterations in stress hormones, such as cortisol, and mood disorders. after psilocybin administration cortisol levels spike and activate the executive control network, with subsequent increased control over emotional processes, and relief of negative thinking and persistent negative emotions. preliminary data of ongoing alcohol and smoking addiction studies in humans shows promising effects of psilocybin administration on substance use. importantly, psilocybin has a low risk of toxicity and dependence and can be used safely under controlled clinical conditions. areas covered: this paper is a narrative review based on the search terms: psilocybin, substance use disorder, addiction, depression, serotonin. literature on potential efficacy and mechanisms of action of psilocybin in sud is discussed. expert commentary: recent positive findings with psilocybin need confirmation in well-designed placebo controlled randomized trials employing a large sample size.”

“Rationale:previous research suggests that classical psychedelic compounds can induce lasting changes in personality traits, attitudes and beliefs in both healthy subjects and patient populations.aim:here we sought to investigate the effects of psilocybin on nature relatedness and libertarian–authoritarian political perspective in patients with treatment-resistant depression (trd).methods:this open-label pilot study with a mixed-model design studied the effects of psilocybin on measures of nature relatedness and libertarian–authoritarian political perspective in patients with moderate to severe trd (n=7) versus age-matched non-treated healthy control subjects (n=7). psilocybin was administered in two oral dosing sessions (10 mg and 25 mg) 1 week apart. main outcome measures were collected 1 week and 7–12 months after the second dosing session. nature relatedness and libertarian–authoritarian political perspective were assessed using the nature relatedness scale (nr-6) and political perspective questionnair…”

“Introduction: it is a basic principle of the ‘psychedelic’ treatment model that the quality of the acute experience mediates long-term improvements in mental health. in the present paper we sought to test this using data from a clinical trial assessing psilocybin for treatment-resistant depression (trd). in line with previous reports, we hypothesized that the occurrence and magnitude of oceanic boundlessness (obn) (sharing features with mystical-type experience) and dread of ego dissolution (ded) (similar to anxiety) would predict long-term positive outcomes, whereas sensory perceptual effects would not. material and methods: twenty patients with treatment resistant depression underwent treatment with psilocybin (two separate sessions: 10mg and 25mg psilocybin). the altered states of consciousness (asc) questionnaire was used to assess the quality of experiences in the 25mg psilocybin session. from the asc, the dimensions obn and ded were used to measure the mystical-type and challenging experiences, respectively. the self-reported quick inventory of depressive symptoms (qids-sr) at 5 weeks served as the endpoint clinical outcome measure, as in later time points some of the subjects had gone on to receive new treatments, thus confounding inferences. in a repeated measure anova, time was the within-subject factor (independent variable), with qids-sr as the within-subject dependent variable in baseline, 1-day, 1-week, 5-weeks. obn and ded were independent variables. obn-by-time and ded-by-time interactions were the primary outcomes of interest. results: for the interaction of obn and ded with time (qids-sr as dependent variable), the main effect and the effects at each time point compared to baseline were all significant (p = 0.002 and p = 0.003, respectively, for main effects), confirming our main hypothesis. furthermore, pearson’s correlation of obn with qids-sr (5 weeks) was specific compared to perceptual dimensions of the asc (p < 0.05). discussion: this report further bolsters the view that the quality of the acute psychedelic experience is a key mediator of long-term changes in mental health. more specifically, future therapeutic work with psychedelics may consider investigating ways which enhance mystical-type experience and reduce anxiety, given the growing evidence that this serves the efficacy of the treatment model.”

“Recent research suggests that functional connectivity changes may be involved in the pathophy- siology of psychiatric disorders. hyperconnectivity in the default mode network has been asso- ciated with psychopathology, but psychedelic serotonin agonists like psilocybin may profoundly disrupt these dysfunctional neural network circuits and provide a novel treatment for psychiatric disorders. we have reviewed the current literature to investigate the efficacy and safety of psilocybin-assisted therapy for the treatment of psychiatric disorders. there were seven clinical trials that investigated psilocybin-assisted therapy as a treatment for psychiatric disorders related to anxiety, depression, and substance use. all trials demonstrated reductions in psychiatric rating scale scores or increased response and remission rates. there were large effect sizes related to improved depression and anxiety symptoms. psilocybin may also potentially reduce alcohol or tobacco use and increase abstinence rates in addiction, but the benefits of these two trials were less clear due to open-label study designs without statistical analysis. psilocybin-assisted therapy efficacy and safety appear promising, but more robust clinical trials will be required to support fda approval and identify the potential role in clinical psychiatry.”

“Psilocybin is found in a family of mushrooms commonly known as ‘magic mushrooms’ that have been used throughout history to induce hallucinations. in the late 1950s albert hofmann, of sandoz laboratories, identified and synthesized the psychoactive compounds psilocybin and psilocin which are found in psilocybe mushrooms. psilocybin was marketed by sandoz as indocybin for basic psychopharmacological and therapeutic clinical research. psilocybin saw a rapid rise in popularity during the 1960s and was classed as a schedule i drug in 1970. this led to a significant decrease in psilocybin research. recently, however, preliminary studies with psilocybin have shown promise as potential for the treatment of obsessive compulsive disorder, alcohol addiction, tobacco addiction, and major depressive disorder, and the treatment of depression in terminally ill cancer patients. this review describes in detail the synthesis, metabolism, pharmacology, adverse drug reactions, and importance of psilocybin to neuroscience in the past and present.”

“Recent clinical trials suggest that 3 single biological treatments have effects that persist. based on research showing that the muscles involved in facial expressions can feed back to influence mood, a single trial diminishing glabella frown lines with botulinum toxin demonstrated a significant antidepressant effect for 16 weeks. based primarily on research with animal models of depression suggesting that glutamate may be involved in depression, the n-methyl-d-aspartate antagonist ketamine has been tested in several trials. a single dose decreased depression for up to a week. the reported effects of the use of mushrooms containing psilocybin by a number of cultures around the world has stimulated several trials showing beneficial effects of a single dose of psilocybin for over a year in healthy people, and for up to 3 months in patients with anxiety disorders who have advanced cancer. this article discusses these studies, their rationale, their possible mechanisms of action, the future clinical research required to establish these therapies and the basic research required to optimize single treatments that have lasting effects.”

“Objective to explore whether psilocybin with psychological support modulates personality parameters in patients suffering from treatment-resistant depression (trd). method twenty patients with moderate or severe, unipolar, trd received oral psilocybin (10 and 25 mg, one week apart) in a supportive setting. personality was assessed at baseline and at 3-month follow-up using the revised neo personality inventory (neo-pi-r), the subjective psilocybin experience with altered state of consciousness (asc) scale, and depressive symptoms with qids-sr16. results neuroticism scores significantly decreased while extraversion increased following psilocybin therapy. these changes were in the direction of the normative neo-pi-r data and were both predicted, in an exploratory analysis, by the degree of insightfulness experienced during the psilocybin session. openness scores also significantly increased following psilocybin, whereas conscientiousness showed trend-level increases, and agreeableness did not change. conclusion our observation of changes in personality measures after psilocybin therapy was mostly consistent with reports of personality change in relation to conventional antidepressant treatment, although the pronounced increases in extraversion and openness might constitute an effect more specific to psychedelic therapy. this needs further exploration in future controlled studies, as do the brain mechanisms of postpsychedelic personality change.”