Article

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults

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Abstract

IntroductionPsilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults. Methods Eligible healthy adults received 6–8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods. ResultsNo psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied. Conclusions The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild–moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose. Clinical Trials IdentifierNCT02163707.

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... Thus, psilocin-O-glucuronide is the key urinary metabolite with clinical and diagnostic relevance. The remaining 20% of the absorbed psilocin is metabolized by oxidation, where the compound usually undertakes demethylation and deamination to form 4 hydroxyindole-3-acetaldehyde and 4-hydroxyindole-3-acetic acid or 4-hydroxytryptophol (Brown et al., 2017). These metabolites are excreted by the liver and kidney, however, enzymes involved in these reactions are unknown (Brown et al., 2017;Dinis-Oliveira, 2017). ...
... The remaining 20% of the absorbed psilocin is metabolized by oxidation, where the compound usually undertakes demethylation and deamination to form 4 hydroxyindole-3-acetaldehyde and 4-hydroxyindole-3-acetic acid or 4-hydroxytryptophol (Brown et al., 2017). These metabolites are excreted by the liver and kidney, however, enzymes involved in these reactions are unknown (Brown et al., 2017;Dinis-Oliveira, 2017). The halflife of psilocin is 3 h (±1.1 h) in healthy individuals, depending on specific characteristics and route of administration (Brown et al., 2017). ...
... These metabolites are excreted by the liver and kidney, however, enzymes involved in these reactions are unknown (Brown et al., 2017;Dinis-Oliveira, 2017). The halflife of psilocin is 3 h (±1.1 h) in healthy individuals, depending on specific characteristics and route of administration (Brown et al., 2017). ...
Article
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Classical psychedelics represent a family of psychoactive substances with structural similarities to serotonin and affinity for serotonin receptors. A growing number of studies have found that psychedelics can be effective in treating various psychiatric conditions, including post-traumatic stress disorder, major depressive disorder, anxiety, and substance use disorders. Mental health disorders are extremely prevalent in the general population constituting a major problem for the public health. There are a wide variety of interventions for mental health disorders, including pharmacological therapies and psychotherapies, however, treatment resistance still remains a particular challenge in this field, and relapse rates are also quite high. In recent years, psychedelics have become one of the promising new tools for the treatment of mental health disorders. In this review, we will discuss the three classic serotonergic naturally occurring psychedelics, psilocybin, ibogaine, and N, N-dimethyltryptamine, focusing on their pharmacological properties and clinical potential. The purpose of this article is to provide a focused review of the most relevant research into the therapeutic potential of these substances and their possible integration as alternative or adjuvant options to existing pharmacological and psychological therapies.
... According to a study by the John Hopkins University of Medicine, higher doses of psilocybin (20-30 mg/70 kg) directly correlate to positive persisting effects on behaviour, attitude, mood, and general outlook on life up to 14 months after follow-up [227]. On the same tangent, another study also suggests that an oral dose of 25 mg psilocybin (correlating to roughly 0.3 mg/kg of body weight) may be within the therapeutic window [252]. ...
... In another study, the pharmacokinetics of escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults was also investigated [252]. Though psilocin clearance varied among patients (which may be due to varying rates of psilocin glucuronide metabolite hydrolysis across patients), a linear relationship was reported between psilocin clearance and the twofold range of doses [252]. ...
... In another study, the pharmacokinetics of escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults was also investigated [252]. Though psilocin clearance varied among patients (which may be due to varying rates of psilocin glucuronide metabolite hydrolysis across patients), a linear relationship was reported between psilocin clearance and the twofold range of doses [252]. The mean elimination half-life of psilocin was 3 h with a standard deviation of 1.1 [252]. ...
Article
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The psychedelic effects of some plants and fungi have been known and deliberately exploited by humans for thousands of years. Fungi, particularly mushrooms, are the principal source of naturally occurring psychedelics. The mushroom extract, psilocybin has historically been used as a psychedelic agent for religious and spiritual ceremonies, as well as a therapeutic option for neuropsychiatric conditions. Psychedelic use was largely associated with the “hippie” counterculture movement, which, in turn, resulted in a growing, and still lingering, negative stigmatization for psychedelics. As a result, in 1970, the U.S. government rescheduled psychedelics as Schedule 1 drugs, ultimately ending scientific research on psychedelics. This prohibition on psychedelic drug research significantly delayed advances in medical knowledge on the therapeutic uses of agents such as psilocybin. A 2004 pilot study from the University of California, Los Angeles, exploring the potential of psilocybin treatment in patients with advanced-stage cancer managed to reignite interest and significantly renewed efforts in psilocybin research, heralding a new age in exploration for psychedelic therapy. Since then, significant advances have been made in characterizing the chemical properties of psilocybin as well as its therapeutic uses. This review will explore the potential of psilocybin in the treatment of neuropsychiatry-related conditions, examining recent advances as well as current research. This is not a systematic review.
... A recent review of some such studies [23] characterises low to high doses of psilocybin as involving a range from 2 mg (low) to 28 mg (high). Other studies have used doses up to 0.6 mg/kg psilocybin (i.e. 45 mg to a person who weighs 75 kg) [24,25]. ...
... Tolerance to psilocybin builds up rapidly thus further reducing the potential to be used regularly and abused [188]. The metabolites of psilocybin/psilocin exhibit low toxicity and do not accumulate in the body [20,24]. Psilocin is largely excreted after 3 hours, completely eliminated after 24 hours with a half-life of 2.5-3 hours [22,24]. ...
... The metabolites of psilocybin/psilocin exhibit low toxicity and do not accumulate in the body [20,24]. Psilocin is largely excreted after 3 hours, completely eliminated after 24 hours with a half-life of 2.5-3 hours [22,24]. ...
Article
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Anorexia Nervosa (AN) is a major health problem with one of the highest mortalities and treatment costs of any psychiatric condition. Cognitive behavioural therapy (CBT) is currently the most widely used treatment for AN in adults but provides remission rates ≤ 50%. Treatment drop-out is exceedingly high and those that persevere with treatment often relapse, causing increased risk of morbidity and mortality. There is an urgent need to find new interventions, especially as there are no approved pharmacological treatments for AN. Ideally, new treatments would target treatment-resistance and to decrease the chronicity associated with the disorder. Over the past two decades, emerging research into classic psychedelic substances (lysergic diethylamide acid (LSD), 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT), N,N-Dimethyltryptamine (DMT) and psilocybin), indicates that marked reductions in anxiety and depression-like symptoms, and lasting improvement in mental health, can follow from one or two exposures to these psychedelic substances. Anxiety and depression are the most prevalent co-morbid psychiatric symptoms in AN. Here we suggest that classic psychedelics, particularly psilocybin, have the potential to normalise dysfunctional neurobiological systems in AN and provide a novel treatment intervention that is worthy of consideration, particularly for treatment-resistant patients.
... Psilocybin is a 5HT2A agonist tryptamine alkaloid structurally similar to 5-HT and found in "magic mushrooms," especially of the genus Psilocybe (Brown et al., 2017). In clinical trials, synthetic psilocybin is administered. ...
... Once orally administered, psilocybin's phosphate group is rapidly dephosphorylated by alkaline phosphatase and esterase enzymes in the intestines to its active metabolite, psilocin (Hasler et al., 1997;Horita & Weber, 1961). Psychological effects, including euphoria, joy, disorientation, visual and temporal perceptual alterations, are observed within 20-90 min, with peak plasma psilocin concentrations occurring around 100-120 min (Brown et al., 2017;Hasler et al., 1997). Psilocin undergoes glucuronidation in the intestine to psilocin gluconoride, a process mediated by UDPglucuronosyltransferase 1A10 (UGT1A10; Manevski et al., 2010). ...
... PSYCHEDELIC-ASSISTED PSYCHOTHERAPIES one pharmacokinetic study of psilocybin (Brown et al., 2017) has included BIPOC (one Native American) limiting our ability to statistically investigate ethnoracial differences. ...
Article
Emerging evidence from randomized, double-blind, placebo-controlled clinical trials suggests psychedelic compounds such as 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, and lysergic acid diethylamide (LSD), when administered as an adjunct to psychotherapy, that is, psychedelic-assisted psychotherapy (PAP), may be beneficial for treating substance use disorders, posttraumatic stress disorder (PTSD), depression, anxiety, and other psychiatric conditions. Previous ethnopsychopharmacological research has identified ethnoracial differences in the metabolism, safety, and efficacy of psychotropic drugs, yet no studies have directly investigated the impact of ethnoracially based differences in psychedelic drug pharmacology. Although there is an extensive global history of psychedelic use among peoples of various cultures, ethnicities, and intersectional identities, psychedelic research has been conducted almost exclusively on White populations in North America and Western Europe. The failure to include Black, Indigenous, and People of Color (BIPOC) in psychedelic research trials neglects the ethnic, racial, and cultural factors that may impact individual responses to PAP and thereby prevents generalizability of findings. This article investigates the impact of biological and social factors related to culture, ethnicity, and race on pharmacological responses to PAP, as well as clinical outcomes. The limitations of ethnopsychopharmacology are discussed, and the authors present expected cultural, clinical, and public health benefits of expanding funding for this area. This work will draw attention to the unique and individualized needs of ethnoracially diverse clients in therapeutic settings and is intended to inform future PAP trials. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
... Although psilocybin has been clinically investigated for many years, pharmacokinetic data are still limited. 8,26,27 In particular, no data are available on actual psychoactive free (unconjugated) psilocin concentrations from controlled studies. 28 Therefore, we also determined the pharmacokinetics of a clinically representative dose of 25 mg of psilocybin. ...
... 8 Mean maximal plasma concentrations of unconjugated psilocin of 20 ng/mL were reached on average 2 hours after drug administration, consistent with modeled estimates for a 25 mg dose from previous studies. 26,51 The terminal half-life of unconjugated psilocin was 1.8 hours (range: 1.1-2.2 hours), consistent with the short duration of action of psilocybin. ...
... This half-life is shorter than the 3-5 hours that was previously reported. 26,27,51 However, previous studies were smaller, and unclear as to whether unconjugated or total concentrations of psilocin were measured. The effect-time curve of acute subjective effects reflected the unconjugated psilocin plasma concentration-time curve, consistent with the view that unconjugated psilocin is the psychoactive and pharmacologically active analyte that best reflects effects after psilocybin administration. ...
Article
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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, cross‐over 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 h (range 1.1‐2.2 h), 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.
... Physiological parameters including organ blood flow (Q) and organ volume (V) were obtained from published literature [13][14][15] . Pharmacokinetic parameters including bioavailability and absorption rate constant were acquired from published literature 16,17 and optimized using Berkeley Madonna Software. Physicochemical parameters including partition coefficient of each compartment were calculated using an approach from the literature 18 19 have developed a physiologically based pharmacokinetic model of a rifapentine model using the Python software (version 2.7.2) as their computational tool along with these numby, scipy and matplotlib packages [20][21][22][23] . ...
... In the selected studies, two different doses of PB (0.224 mg/kg and 0.3 mg/kg) were administered to humans via a single oral administration. Simulated results of PI concentrationtime profiles in plasma following oral administration of PB (0.224 mg/kg and 0.3 mg/kg) compared to the observed data acquired from Hasler et al. 17 and Brown et al. 16 are presented in Figure 4A and Figure 5A, respectively. Simulated brain concentration-time profiles of PI for both doses (0.224 mg/kg and 0.3 mg/kg) are also presented in Figure 4A and Figure 5A, respectively. ...
Article
Background : Psilocybin (PB) is a psychoactive compound commonly found in magic mushroom ( Psilocybe cubensis ) . PB is quickly converted by the body to psilocin (PI), which has a psychedelic effect through the activation of the 5 - HT 2A receptor in the brain. The objective of this study is to develop a physiologically based pharmacokinetic (PBPK) model of PB and PI in rats and humans for predicting concentrations of the psychoactive substance in the brain. Methods : Following a search in PubMed, three studies were retrieved and information concerning concentration - time profiles of PI were extracted from the selected studies. In the study in rats, PI was orally administered with a dose of 10.1 mg / kg. There were two studies in humans following a single intravenous dose of PB (1 mg) and oral dose of PB (0.224 mg / kg and 0.3 mg / kg). Berkeley Madonna software was used for computer coding and simulations. The developed PBPK model consisted of seven organ compartments (i.e. lung, heart, brain, fat, muscle, kidney, and liver). Results : The simulations show a good agreement between observed and simulated data, although results for oral administration in rats and humans showed under - predictions and results for intravenous administration in humans showed over - predictions. Conclusions : A PBPK model of PB and PI in rats and humans was developed and could predict concentration-time profiles of PI in plasma, particularly in the brain, following intravenous and oral administration of PB. This model may be useful for a safer dosage regimen of PB for patients with some disorders.
... Whether these differences in receptor binding profiles produce differential subjective effects in humans has not yet been studied. Recent research has investigated either psilocybin or LSD alone [7,[11][12][13][14][15]. Differences between the two substances with regard to their acute effects, similarities, and doseequivalence remain unclear. ...
... The elimination half-life values of LSD and psilocin were an average of~4 h and 2.5 h, respectively. These values are consistent with previous studies [7,13,19,37], although a slightly shorter half-life of 2 h has also been described for psilocybin [38,44]. Body weight had no influence on LSD or psilocin plasma concentrations, as described previously [7,38,45]. ...
Article
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Growing interest has been seen in using lysergic acid diethylamide (LSD) and psilocybin in psychiatric research and therapy. However, no modern studies have evaluated differences in subjective and autonomic effects of LSD and psilocybin or their similarities and dose equivalence. We used a double-blind, randomized, placebo-controlled, crossover design in 28 healthy subjects (14 women, 14 men) who underwent five 25 h sessions and received placebo, LSD (100 and 200 µg), and psilocybin (15 and 30 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales for subjective effects, autonomic effects, adverse effects, effect durations, plasma levels of brain-derived neurotrophic factor (BDNF), prolactin, cortisol, and oxytocin, and pharmacokinetics. The doses of 100 and 200 µg LSD and 30 mg psilocybin produced comparable subjective effects. The 15 mg psilocybin dose produced clearly weaker subjective effects compared with both doses of LSD and 30 mg psilocybin. The 200 µg dose of LSD induced higher ratings of ego-dissolution, impairments in control and cognition, and anxiety than the 100 µg dose. The 200 µg dose of LSD increased only ratings of ineffability significantly more than 30 mg psilocybin. LSD at both doses had clearly longer effect durations than psilocybin. Psilocybin increased blood pressure more than LSD, whereas LSD increased heart rate more than psilocybin. However, both LSD and psilocybin showed comparable cardiostimulant properties, assessed by the rate-pressure product. Both LSD and psilocybin had dose-proportional pharmacokinetics and first-order elimination. Both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration. Any differences between LSD and psilocybin are dose-dependent rather than substance-dependent. However, LSD and psilocybin differentially increased heart rate and blood pressure. These results may assist with dose finding for future psychedelic research. Trial registration: ClinicalTrials.gov identifier: NCT03604744
... To accomplish this, we collected simultaneous data of BOLD fMRI images, subjective drug intensity (SDI) ratings (i.e., real-time self-report psychedelic phenomenal experience changes in relation to psilocybin) ( Madsen et al., 2019 ) and PPL (via blood samples) at multiple time points throughout the psilocybin psychedelic experience (5-6 h). This scan strategy makes it possible to map brain function, phenomenal experience and PPL throughout psilocybin's three pharmacological and experiential phases: ascent, peak and descent ( Brown et al., 2017 ;Griffiths et al., 2011 ;Hasler et al., 2004Hasler et al., , 1997Lindenblatt et al., 1998 ;Madsen et al., 2019 ). ...
... Consistent with previous psilocybin pharmacokinetics studies employing similar peroral doses (0.2-0.3 mg/kg) ( Brown et al., 2017 ;Hasler et al., 1997 ;Lindenblatt et al., 1998 ), we observed considerable interindividual variability in maximum PPL (C max ) and time to reach C max (t max ) ( Table S9 ). Considering this pharmacological variability and the strong correlations of PPL with both phenomenal experience and FC changes, it is likely that interindividual differences in subjective effects and the clinical response, which sometimes has been ascribed to psychological factors, are at least partly explained by interindividual differences in PPL ( Carhart-Harris et al., 2016a ;Griffiths et al., 2016Griffiths et al., , 2011Ross et al., 2016 ), consistent with similar observations in LSD ( Holze et al., 2019 ). ...
Preprint
The emerging novel therapeutic psilocybin produces psychedelic effects via engagement of cerebral serotonergic targets by psilocin (active metabolite). The serotonin 2A receptor critically mediates these effects by altering distributed neural processes that manifest as increased entropy, reduced functional connectivity (FC) within discrete brain networks (i.e., reduced integrity) and increased FC between networks (i.e., reduced segregation). Reduced integrity of the default mode network (DMN) is proposed to play a particularly prominent role in psychedelic phenomenology, including perceived ego-dissolution. Here, we investigate the effects of a psychoactive oral dose of psilocybin (0.2-0.3 mg/kg) on plasma psilocin level (PPL), subjective drug intensity (SDI) and their association in fifteen healthy individuals. We further evaluate associations between these measures and resting-state FC, measured with functional magnetic resonance imaging, acquired over the course of five hours after psilocybin administration. We show that PPL and SDI correlate negatively with measures of network integrity (including DMN) and segregation, both spatially constrained and unconstrained. We also find that the executive control network and dorsal attention network desegregate, increasing connectivity with other networks and throughout the brain as a function of PPL and SDI. These findings provide direct evidence that psilocin critically shapes the time course and magnitude of changes in the cerebral functional architecture and subjective experience following psilocybin administration. Our findings provide novel insight into the neurobiological mechanisms underlying profound perceptual experiences evoked by this emerging transnosological therapeutic and implicate the expression of network integrity and segregation in the psychedelic experience and consciousness.
... Batches É-81-1 and É-97-1 (Table 2, entries 6 and 7) were both synthesized in July 2013 and were dried in a vacuum oven at 50 C for 7 and 5 h, respectively. These batches were employed in published clinical trials (Brown et al., 2017;Nicholas et al., 2018). PXRD analysis was carried out on these samples using the same conditions outlined for Sample 1. ...
... In contrast, Sample 6 was composed entirely of Hydrate A, while Sample 7 consisted of Polymorph A with an insignificant trace of Hydrate A. The QPA results for these three samples highlight the potential variability in the preferred polymorphs of bulk psilocybin produced by aqueous crystallization, followed by heated vacuum drying. Together with Sample 4, Samples 6 and 7 represented the psilocybin API that was used by research universities in support of human clinical trials and further establish precedent for the use of both psilocybin Hydrate A and Polymorph A, respectively, as early as 2017 (Brown et al., 2017;Nicholas et al., 2018). ...
Article
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Psilocybin {systematic name: 3-[2-(di­methyl­amino)­eth­yl]-1H-indol-4-yl di­hydro­gen phosphate} is a zwitterionic tryptamine natural product found in numerous species of fungi known for their psychoactive properties. Following its structural elucidation and chemical synthesis in 1959, purified synthetic psilocybin has been evaluated in clinical trials and has shown promise in the treatment of various mental health disorders. In a recent process-scale crystallization investigation, three crystalline forms of psilocybin were repeatedly observed: Hydrate A, Polymorph A, and Polymorph B. The crystal structure for Hydrate A was solved previously by single-crystal X-ray dif­fraction. This article presents new crystal structure solutions for the two anhydrates, Polymorphs A and B, based on Rietveld refinement using laboratory and synchrotron X-ray dif­fraction data, and density functional theory (DFT) calculations. Utilizing the three solved structures, an investigation was conducted via Rietveld method (RM) based qu­anti­tative phase analysis (QPA) to estimate the contribution of the three different forms in powder X-ray diffraction (PXRD) patterns provided by different sources of bulk psilocybin produced between 1963 and 2021. Over the last 57 years, each of these samples qu­anti­tatively reflect one or more of the hydrate and anhydrate polymorphs. In addition to qu­anti­tatively evaluating the com­position of each sample, this article evaluates correlations between the crystal forms present, corresponding process methods, sample age, and storage conditions. Furthermore, revision is recommended on characterizations in recently granted patents that include descriptions of crystalline psilocybin inappropriately reported as a single-phase `isostructural variant.' Rietveld refinement demonstrated that the claimed material was com­posed of approximately 81% Polymorph A and 19% Polymorph B, both of which have been identified in historical samples. In this article, we show conclusively that all published data can be explained in terms of three well-defined forms of psilocybin and that no additional forms are needed to explain the diffraction patterns.
... Peak plasma concentration of psilocin, the active metabolite of psilocybin, is reported to occur 105 ± 37 min after oral psilocybin administration (Hasler et al., 1997). The elimination half-life of psilocin is 3 h, indicating that, 48 h after oral administration of psilocybin, all but 0.0016% of psilocin will be eliminated (Brown et al., 2017;Passie et al., 2002). One study found psilocin to be undetectable in urine 24 h after oral administration (Hasler et al., 2002). ...
... As psilocybin is given as a single dose and found to be undetectable in urine by 24 h after administration, women may be advised to abstain from breastfeeding for a period of 48 h after psilocybin administration. By that stage, with an elimination half-life of 3 h, over 99.99% of psilocybin will have been eliminated from the maternal system (Brown et al., 2017). In addition, only 4% of adverse effects of breast milk drug exposure occur in infants older than 6 months (Anderson et al., 2003). ...
Article
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Background Postpartum depression (PPD) is a major public health concern and has, at its core, a sense of maternal ‘disconnection’ – from the self, the infant, and the support system. While PPD bears similarities with MDD, there is increasing evidence for its distinct nature, especially with the unique aspect of the mother-infant relationship. Current treatment modalities for PPD, largely based on those used in major depressive disorder (MDD), have low remission rates with emerging evidence for treatment resistance. It is, therefore, necessary to explore alternative avenues of treatment for PPD. Objective In this narrative review, we outline the potential therapeutic rationale for serotonergic psychedelics in the treatment of PPD, and highlight safety and pragmatic considerations for the use of psychedelics in the postpartum period. Methods We examined the available evidence for the treatment of PPD and the evidence for psychedelics in the treatment of MDD. We explored safety considerations in the use of psychedelics in the postpartum period. Results There is increasing evidence for safety, and encouraging signals for efficacy, of psilocybin in the treatment of MDD. Psilocybin has been shown to catalyse a sense of ‘reconnection’ in participants with MDD. This effect in PPD, by fostering a sense of ‘reconnection’ for the mother, may allow for improved mood and maternal sensitivity towards the infant, which can positively impact maternal role gratification and the mother-infant relationship. Conclusion Psychedelic assisted therapy in PPD may have a positive effect on the mother-infant dyad and warrants further examination.
... Among the group of classic psychedelics, psilocybin is to date the most widely investigated substance in patients, with also several academic studies in healthy subjects (Hirschfeld and Schmidt 2021). Several modern Phase 1 and 2 studies have been conducted over recent years to investigate psilocybin dosing (Brown et al. 2017;Griffiths et al. 2011;Kraehenmann et al. 2017a;Madsen et al. 2019;Hasler et al. 2004;Hirschfeld and Schmidt 2021;Garcia-Romeu et al. 2021). However, despite increasing work in patients, scarce pharmacokinetic data on psilocybin are available (Kolaczynska et al. 2020;Madsen et al. 2019;Brown et al. 2017), with a lack of solid dose-finding studies using different doses of psilocybin within the same study (Hirschfeld and Schmidt 2021). ...
... Several modern Phase 1 and 2 studies have been conducted over recent years to investigate psilocybin dosing (Brown et al. 2017;Griffiths et al. 2011;Kraehenmann et al. 2017a;Madsen et al. 2019;Hasler et al. 2004;Hirschfeld and Schmidt 2021;Garcia-Romeu et al. 2021). However, despite increasing work in patients, scarce pharmacokinetic data on psilocybin are available (Kolaczynska et al. 2020;Madsen et al. 2019;Brown et al. 2017), with a lack of solid dose-finding studies using different doses of psilocybin within the same study (Hirschfeld and Schmidt 2021). The pharmacokinetics and dose-response characteristics of LSD are better defined (Holze et al. 2019(Holze et al. , 2021aDolder et al. 2017). ...
Article
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Classic psychedelics, including psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine, and mescaline, and entactogens/empathogens, especially 3,4-methylenedioxymethamphetamine, have received renewed attention in psychiatric research and may be developed into medications for such indications as anxiety, depression, cluster headache, and posttraumatic stress disorder, among others. However, identifying proper doses is crucial. Controlled study data on dosing using well-characterized pharmaceutical formulations of the substances are scarce. The dose equivalence of different substances, dose-response effects, and subjective effects of different doses are of great interest and practically important for their clinical use in psychotherapy. Furthermore, the so-called microdosing of psychedelics has recently gained popularity, and the first placebo-controlled studies of LSD have been published. This chapter discusses different aspects of psychedelic dosing, including pharmaceutical aspects, definitions and characteristics of different doses, including microdoses, aspects of personalized dosing, and non-pharmacological factors, that can influence the response to psychedelics.
... For example, given their self-report design, the results could be explained by the tendency for women to be more likely to disclose negative emotional experiences than men 61 . Moreover, research has demonstrated that there are no sex differences in 5-HT2AR distribution 62 nor the pharmacokinetic profiles of psychedelics [63][64][65] . In short, it seems that psychedelic drugs induce generally similar effects in males and females. ...
Article
Psychedelic drugs are increasingly being incorporated into therapeutic contexts for the purposes of promoting mental health. Yet, they can also induce adverse reactions in some individuals, and it is difficult to predict pre-treatment who is likely to experience positive or adverse acute effects. Although consideration of setting, dosage, and excluding individuals with psychotic predispositions has thus far led to a high degree of safety, it is imperative researchers develop a more nuanced understanding of how to predict individual reactions. To this end, the current systematic review coalesced the results of 14 studies that included baseline states or traits predictive of the acute effects of psychedelics. Individuals high in the traits of absorption, openness, and acceptance as well as a state of surrender were more likely to have positive and mystical-type experiences, whereas those low in openness and surrender, or in preoccupied, apprehensive, or confused psychological states were more likely to experience acute adverse reactions. Participant sex was not a robust predictor of drug effects, but 5-HT2AR binding potential, executive network node diversity, and rACC volume may be potential baseline biomarkers related to acute reactions. Lastly, increased age and experience with psychedelics were individual differences related to generally less intense effects, indicating users may become slightly less sensitive to the effects of the drugs after repeated usage. Although future well-powered, placebo-controlled trials directly comparing the relative importance of these predictors is needed, this review synthesizes the field's current understanding of how to predict acute reactions to psychedelic drugs.
... Hallucinogennaïve study participants reported slightly more Visionary Restructuralization, Disembodiment, and Changed Meaning of Percepts compared with experienced psilocybin users (Metzner et al., 1965;Studerus et al., 2012). Further, differences in individual pharmacokinetics were reported in terms of plasma psilocin levels and 5-HT2AR occupancy, which were found to correlate with the overall subjective experience (Brown et al., 2017;Hasler et al., 2004;Lindenblatt et al., 1998;Madsen et al., 2020). Finally, brain structure metrics have been reported to correlate with experiences, that is, a correlation of the thickness of the rostral anterior cingulate and subscales of 5D-ASC dimension Oceanic Boundlessness (Lewis et al., 2020). ...
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Background: Psilocybin is the psychoactive component in Psilocybe mushrooms ('magic mushrooms'). Whether and how the quality of the psilocybin-induced experience might mediate beneficial health outcomes is currently under investigation, for example, in therapeutic applications. However, to date, no meta-analysis has investigated the dose-dependency of subjective experiences across available studies. Aim: Establishing dose-response relationships of the subjective experiences induced by psilocybin in healthy study participants and a comparison of patient groups. Method: We applied a linear meta-regression approach, based on the robust variance estimation framework, to obtain linear dose-response relationship estimates on questionnaire ratings after oral psilocybin administration. Data were obtained from the Altered States Database, which contains data extracted from MEDLINE-listed journal articles that used standardized and validated questionnaires: the Altered States of Consciousness Rating Scale, the Mystical Experience Questionnaire and the Hallucinogen Rating Scale. Results: Psilocybin dose positively correlated with ratings on most factors and scales, mainly those referring to perceptual alterations and positively experienced ego dissolution. Measures referring to challenging experiences exhibited small effects and were barely modulated by dose. Conclusion: Psilocybin intensified almost all characteristics of altered states of consciousness assessed with the given questionnaires. Because subjective experiences are not only determined by dose, but also by individual and environmental factors, the results may only apply to controlled laboratory experiments and not to recreational use. This paper may serve as a general literature citation for the use of psilocybin in experimental and clinical research, to compare expected and observed subjective experiences.
... Evidence derived from the use of larger doses of psychedelics suggests that psychedelics with predominantly serotonergic effects are safe when www.nature.com/scientificreports/ administered in controlled settings 50 . Preliminary results suggest that microdose practices have a similar safety profile to large-dose psychedelic use 6 . ...
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The use of psychedelic substances at sub-sensorium ‘ microdoses’, has gained popular academic interest for reported positive effects on wellness and cognition. The present study describes microdosing practices, motivations and mental health among a sample of self-selected microdosers ( n = 4050) and non-microdosers ( n = 4653) via a mobile application. Psilocybin was the most commonly used microdose substances in our sample (85%) and we identified diverse microdose practices with regard to dosage, frequency, and the practice of stacking which involves combining psilocybin with non-psychedelic substances such as Lion’s Mane mushrooms, chocolate, and niacin. Microdosers were generally similar to non-microdosing controls with regard to demographics, but were more likely to report a history of mental health concerns. Among individuals reporting mental health concerns, microdosers exhibited lower levels of depression, anxiety, and stress across gender. Health and wellness-related motives were the most prominent motives across microdosers in general, and were more prominent among females and among individuals who reported mental health concerns. Our results indicate health and wellness motives and perceived mental health benefits among microdosers, and highlight the need for further research into the mental health consequences of microdosing including studies with rigorous longitudinal designs.
... The effects are dose-dependent and may include visual, cognitive, and emotional alterations that could mimic psychosis [7,23]. Psilocybin breaks down into psilocin [22,24]. Psilocin acts as 5-HT agonist and having a high affinity for the 5-HT2A receptor subtype. ...
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Introduction: Psilocybin mushroom use is well documented in spiritual and religious ceremonies globally. This drug is now the most popular in Europe and the USA. Objective: The objective of this study is to explore the experiences and effects of psilocybin on patients with depression and anxiety. Method: A qualitative study was conducted interviewing ten participants currently taking psilocybin while experiencing depression and/or anxiety. Ethical approval was obtained from the University ethics committee. Participants were recruited via social media and groups are known to have used psilocybin for the treatment of anxiety and/or depression. Participants were informed of study aims and consent was obtained before interviews commenced. Confidentiality was maintained throughout this study. Interviews began with informing participants that psilocybin may be effective in the management of depression. Initially, information around the way treatment with psilocybin was obtained was sought. This was followed by queries around the effects of the drug in terms of experiences both during and after treatment. Finally, participants were asked to outline the positive effects of psilocybin on their lives. Results: The data were thematically coded using Grounded Theory as an underpinning philosophical paradigm. Emerging themes included enhancement of smell, vision, hearing, and taste sensations. Another theme emerging was the experience of being ‘connected with the universe’ while on the drug. Additionally, participants reported a stabilization of mood, an increase in optimism and emotional control, and a healthier emotional connection with others. Most also felt an increase in comfort, peace and calmness. Another theme that emerged centered on the mechanism of action of psilocybin. Participants stated that this substance seemed to ‘make new connections in their brain,’ resulting in new perspectives. Some participants felt this resulted in a calming influence on the mind and body. This aligns with research showing that psilocybin works by changing the thinking and improving information processing. Conclusion: Psilocybin has promising effects on the patients with depression/anxiety even after a single dose. Psilocybin is safe but the administration should be guided by a health professional to yield safe and positive outcomes.
... The present results are consistent with a recent pharmacokinetic study of psilocybin, which found in a simulated model that use of a fixed oral psilocybin dose of 25 mg may result in psilocin AUC and C max exposures similar to those from a weightadjusted (0.3 mg/kg) oral dose (Brown et al., 2017). Our findings are also consistent with results showing that fixed oral doses of 25 mg psilocybin were associated with decreased treatmentresistant depression symptoms, although participant body weight or BMI data for this trial were not reported (Carhart-Harris et al., 2016, 2018. ...
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Background Growing evidence suggests psilocybin, a naturally occurring psychedelic, is a safe and promising pharmacotherapy for treatment of mood and substance use disorders when administered as part of a structured intervention. In most trials to date, psilocybin dose has been administered on a weight-adjusted basis rather than the more convenient procedure of administering a fixed dose. Aims The present post hoc analyses sought to determine whether the subjective effects of psilocybin are affected by body weight when psilocybin is administered on a weight-adjusted basis and when psilocybin is administered as a fixed dose. Methods We analyzed acute subjective drug effects (mystical, challenging, and intensity) associated with therapeutic outcomes from ten previous studies (total N = 288) in which psilocybin was administered in the range 20 to 30 mg/70 kg (inclusive). Separate multivariate regression analyses examined the relationships between demographic variables including body weight and subjective effects in participants receiving 20 mg/70 kg ( n = 120), participants receiving 30 mg/70 kg ( n = 182), and participants whose weight-adjusted dose was about 25 mg (to approximate the fixed dose that is currently being evaluated in registration trials for major depressive disorder) ( n = 103). Results In the 20 mg/70 kg and 30 mg/70 kg weight-adjusted groups, and in the fixed dose group, no significant associations were found between subjective effects and demographic variables including body weight or sex. Across a wide range of body weights (49 to 113 kg) the present results showed no evidence that body weight affected subjective effects of psilocybin. Conclusions These results suggest that the convenience and lower cost of administering psilocybin as a fixed dose outweigh any potential advantage of weight-adjusted dosing.
... solubilization, buffer and buffer strength are not appraised in detail. In current study, we stressed on absorption and empirical (simulated) In vivo release, and the outcoming desired release and absorption outlines based on this input data [24,25]. ...
Article
Aim: This research work was aimed to evaluate Metformin hydrochloride (MH) floating dosage form by In vitro evaluation/In vivo prediction and to evaluate it’s predictability through it’s application during the R&D using Insilico technique in WINONLIN Software. MH was examined as a model drug, which is a biguanide and is an hypoglycemic agent administered orally. The study was aimed to determine the the systemic concentrations of MH using In-vivo prediction. Study Design: Fabrication and assessment of Metformin hydrochloride floating drug delivery system: In Vitro evaluation /In Vivo prediction. Biorelevant media was selected for dissolution profile of 12 units of dosage form. Software assisted program used for data feeding and results output. Methodology: The absorption window for MH is the upper portion of the small gut in which the GI absorption is complete after 6 h. Hence gastroretentive formulation was developed and validity of dissolution study was extended by In vivo pharmacokinetic prediction using WinNonlin Software. A mechanistic oral absorption model was built in Phoenix WinNonlin® software. In the presented work, significant yet crucial, gastrointestinal (GI) variables are considered for biopredictive dissolution testing to account for a valuable input for physiologically-based pharmacokinetic (PBPK) platform programs. While simulations are performed and mechanistic insights are gained from such simulations from the WinNonlin program. Results: These floating tablets were observed for In vitro release and studied for In vivo pharmacokinetic prediction. From the obtained values, a meaningful In vivo prediction was done. interestingly from the results attained floating tablets showed sustained drug release and extended drug absorbed in 24h. Fascinatingly, from the data it was proved that drug formulation resides for desired time. The absorption of MH from the developed CR tablet was 1.4 fold higher than its marketed tablet and it had higher AUC0–t values than the marketed product which indicates superior bioavailability of test product compared to marketed tablet with similar dose in Invivo pharmacokinetic prediction. The mean value of biological half-life (t1/2) and Tmax of MH from test formulation is two times more, Test product has shown higher MRT, showing that the drug is maintained longer in the body in comparison to marketed product indicates controlled absorption. Conclusion: Here we concluded that, a comparative prediction pharmacokinetic evaluation of the fabricated controlled release tablets and the marketed formulation indicates that the fabricated controlled release tablets are well absorbed and the degree of absorption is greater than that of the marketed ER formulation with larger gastric residence time.
... Psilocybin (4-oxyphospho-n, n-dimethyl-tryptamine), a form of indoleamine similar to 5-hydroxytryptamine, is a hallucinogenic agent (Brown et al., 2017) and the main component causing psychedelic action in Psilocybe (Hasler et al., 1997), one of the most commonly used hallucinogens in human studies (Johnson et al., 2008). Wasson first proposed the use of serotonergic hallucinogens for treatment of depression in 1957 (Mclaughlin et al., 1978). ...
Article
Background: Previous studies have shown that psilocybin has antidepressant effects. In the current study, we aim to explore the dose effects of psilocybin on primary (major depression patients) and secondary depression (depressed cancer patients). Methods: Published studies concerning psilocybin for depression were retrieved. In accordance with PRISMA guidelines, 6 databases (PubMed, Embase, Web of Science, Cochrane Library, Clinicaltrials.gov 2.3 and WanFang database) were searched for research studies published or still in progress from inception to 30 November, 2020, with language restricted to English and Chinese. Hedges' g of Beck Depression Inventory (BDI) score changes was calculated as the primary outcome. Results: 7 articles were finally included, with a total of 136 participants. In terms of efficacy, Hedges' g was 1.289 (95%CI=[1.020, 1.558], heterogeneity I2=50.995%, p<0.001). As psilocybin dose increases within a certain range, the antidepressive effect declines and then increases, with 30-35 mg/70 kg achieving the optimal therapeutic effect. Subgroup analysis suggested that the antidepressive effect of psilocybin was extremely significant at a relatively high dose (30-35mg/70kg: Hedges' g=3.059, 95%CI=[2.269, 3.849], p<0.001), long-term (>1month: Hedges' g=1.123, 95%CI=[0.861, 1.385], p<0.001) and when used in primary depression patients (Hedges' g=2.190, 95%CI=[1.423, 2.957], p<0.001). Limitations: Only a small number of studies can be identified of variable quality, thus our conclusions remain preliminary. Conclusions: Our preliminary results have shown that psilocybin exerts a rapid effect in reducing depressive symptom on primary and secondary depression. The optimal dose of psilocybin may be 30-35mg/70kg or higher; future clinical trials are warranted for further evaluation on its effect.
... In rats, metabolism of psilocin (8) occurs in part by oxidative deamination to 4-hydroxy-3-indoleacetic acid, but in humans, the predominant metabolite is psilocin-glucuronate [114]. As noted above, psilocybin (2) undergoes rapid dephosphorylation after oral administration, and the centrally active metabolite psilocin (8) had a plasma elimination half-life of about three hours in healthy humans [115]. ...
Article
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Hallucinogens are a loosely defined group of compounds including LSD, N,N-dimethyltryptamines, mescaline, psilocybin/psilocin, and 2,5-dimethoxy-4-methamphetamine (DOM), which can evoke intense visual and emotional experiences. We are witnessing a renaissance of research interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or single photon emission computer tomography (SPECT). In general, molecular imaging can depict the uptake and binding distribution of labelled hallucinogenic compounds or their congeners in the brain, as was shown in an early PET study with N1-([11C]-methyl)-2-bromo-LSD ([11C]-MBL); displacement with the non-radioactive competitor ketanserin confirmed that the majority of [11C]-MBL specific binding was to serotonin 5-HT2A receptors. However, interactions at serotonin 5HT1A and other classes of receptors and pleotropic effects on second messenger pathways may contribute to the particular experiential phenomenologies of LSD and other hallucinogenic compounds. Other salient aspects of hallucinogen action include permeability to the blood–brain barrier, the rates of metabolism and elimination, and the formation of active metabolites. Despite the maturation of radiochemistry and molecular imaging in recent years, there has been only a handful of PET or SPECT studies of radiolabeled hallucinogens, most recently using the 5-HT2A/2C agonist N-(2[11CH3O]-methoxybenzyl)-2,5-dimethoxy- 4-bromophenethylamine ([11C]Cimbi-36). In addition to PET studies of target engagement at neuroreceptors and transporters, there is a small number of studies on the effects of hallucinogenic compounds on cerebral perfusion ([15O]-water) or metabolism ([18F]-fluorodeoxyglucose/FDG). There remains considerable scope for basic imaging research on the sites of interaction of hallucinogens and their cerebrometabolic effects; we expect that hybrid imaging with PET in conjunction with functional magnetic resonance imaging (fMRI) should provide especially useful for the next phase of this research.
... Psychological effects start around 10-40 min after ingestion and last for 2-6 h. Linear pharmacokinetics over the 0.3-0.6 mg/kg oral dose range were demonstrated (10). LSD exhibits affinity for 5-HT1A/D, 2A/B/C, and 5-HT6, the dopamine D 1 and D 2 , and α-adrenergic receptors. ...
Article
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Clinical studies suggest the therapeutic potential of psychedelics, including ayahuasca, DMT, psilocybin, and LSD, in stress-related disorders. These substances induce cognitive, antidepressant, anxiolytic, and antiaddictive effects suggested to arise from biological changes similar to conventional antidepressants or the rapid-acting substance ketamine. The proposed route is by inducing brain neuroplasticity. This review attempts to summarize the evidence that psychedelics induce neuroplasticity by focusing on psychedelics' cellular and molecular neuroplasticity effects after single and repeated administration. When behavioral parameters are encountered in the selected studies, the biological pathways will be linked to the behavioral effects. Additionally, knowledge gaps in the underlying biology of clinical outcomes of psychedelics are highlighted. The literature searched yielded 344 results. Title and abstract screening reduced the sample to 35; eight were included from other sources, and full-text screening resulted in the final selection of 16 preclinical and four clinical studies. Studies ( n = 20) show that a single administration of a psychedelic produces rapid changes in plasticity mechanisms on a molecular, neuronal, synaptic, and dendritic level. The expression of plasticity-related genes and proteins, including Brain-Derived Neurotrophic Factor (BDNF), is changed after a single administration of psychedelics, resulting in changed neuroplasticity. The latter included more dendritic complexity, which outlasted the acute effects of the psychedelic. Repeated administration of a psychedelic directly stimulated neurogenesis and increased BDNF mRNA levels up to a month after treatment. Findings from the current review demonstrate that psychedelics induce molecular and cellular adaptations related to neuroplasticity and suggest those run parallel to the clinical effects of psychedelics, potentially underlying them. Future (pre)clinical research might focus on deciphering the specific cellular mechanism activated by different psychedelics and related to long-term clinical and biological effects to increase our understanding of the therapeutic potential of these compounds.
... Although some psilocybin-based treatment efficacy has been demonstrated in clinical settings, dose-effects and healthy human studies continue in order to better understand the pharmacokinetics of psilocybin. [19][20][21] There are only a small number of published psilocybin clinical trials to date, but the number of ongoing trials continues to grow, with > 40 currently active or recruiting trials. 22 The trials that are currently published have examined the efficacy for the treatment of mental illnesses such as major depressive disorder (MDD) and/or treatment-resistant depression (TRD), 23-25 end-of-life depression and anxiety, [26][27][28] obsessive-compulsive disorder, 29 and alcohol and tobacco-related addiction. ...
Article
Psilocybin is a psychoactive alkaloid that is produced naturally by approximately 200 species of mush- rooms. The potential medical use of this molecule for the treatment of mental illness is gaining renewed momentum. As demand grows and clinical trials progress, appropriate methods for producing a quality pharmaceutical product are needed. This review highlights the methods currently available, such as the prominent synthetic method and its biosyn- thetic alternatives, as well as others on the near horizon. This article further seeks to discuss the rapid and evolving nature of the psilocybin industry in the 21st century.
... A dose-finding study in healthy participants found correlations between dose and probability of having a "complete" mystical-type experience as measured by the MEQ (i.e., greater than 60% on each mystical experience subscale), with 0, 5.6, 11.1, 44.4, and 55.6% experiencing complete mystical-type experiences at 0, 0.07, 0.14, 0.29, and 0.43 mg/kg doses, respectively (Griffiths et al. 2011), and another study finding 0%, 20%, and 40% rates of complete mystical-type experiences at 0.14, 0.29, and 0.43 mg/kg in a population experienced with psychedelic use (Carbonaro et al. 2018). However, another study found no relationship between dose and rate of mystical-type experience at 0.3 mg/ kg, 0.45 mg/kg, and 0.6 mg/kg, suggesting a potential ceiling effect at higher doses (Brown et al. 2017). Intensity of dysphoric effects is also correlated with dose (Griffiths et al. 2011;Studerus et al. 2011). ...
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Rationale A broad reassessment of the potential benefits of psychedelic drugs has led to the initiation of multiple major clinical trials in an effort to advance their status to become FDA-approved medications, as well as local legislative efforts to legalize or decriminalize their use. Objectives To use recently published data to assess potential risks and benefits of psychedelic drugs as therapeutics, as well as to synthesize what is currently known in order to generate fruitful future research directions. Methods A review of studies conducted since 1991 identified 14 clinical trials of classical psychedelics, including 11 of psilocybin (N = 257 participants), 1 of lysergic acid diethylamide (N = 12 participants), and 2 of ayahuasca (N = 46 participants). Other published studies (e.g., of healthy volunteers, survey studies, case reports, neuroimaging) were also considered for review. Results Published studies since 1991 largely support the hypothesis that small numbers of treatments with psychedelic-assisted psychotherapy can offer significant and sustained alleviation to symptoms of multiple psychiatric conditions. No serious adverse events attributed to psychedelic therapy have been reported. Existing studies have several limitations, including small sample sizes, inherent difficulty in blinding, relatively limited follow-up, and highly screened treatment populations. Conclusions Substantial data have been gathered in the past 30 years suggesting that psychedelics are a potent treatment for a variety of common psychiatric conditions, though the ideal means of employing these substances to minimize adverse events and maximize therapeutic effects remains controversial. Unique factors related to study design are vital for clinical researchers in the field to address.
... Noticeable subjective effects occur at plasma concentrations of about 4-6 μg/mL (Passie et al., 2002). Laboratory studies have demonstrated that doses of up to 0.6 mg/kg have been well tolerated in healthy adults (Brown et al., 2017). The LD 50 of psilocybin is estimated to be on the order of grams per kilogram in humans, indicating a very large therapeutic index (Passie et al., 2002). ...
... Both drugs are agonists of 5-HT2 receptors (Rickli et al., 2016;Sard et al., 2005), and studies in humans suggest that 5HT2A receptor occupancy may be critical for the psychedelic experience of psilocybin (Madsen et al., 2019), although actions at other receptors could also be involved. Psilocin has a halflife of about 3 hours and its kinetics appears to be dose linear (Brown et al., 2017). ...
Article
Objectives There is an increasing interest in combining psilocybin or methylenedioxymethamphetamine with psychological support in treating psychiatric disorders. Although there have been several recent systematic reviews, study and participant numbers have been limited, and the field is rapidly evolving with the publication of more studies. We therefore conducted a systematic review of PubMed, MEDLINE, PsycINFO, the Cochrane Central Register of Controlled Trials, Embase, and CINAHL for randomised controlled trials of methylenedioxymethamphetamine and psilocybin with either inactive or active controls. Methods Outcomes were psychiatric symptoms measured by standardised, validated and internationally recognised instruments at least 2 weeks following drug administration, Quality was independently assessed using the Cochrane risk of bias assessment tool and Grading of Recommendations Assessment, Development and Evaluation framework. Results There were eight studies on methylenedioxymethamphetamine and six on psilocybin. Diagnoses included post-traumatic stress disorder, long-standing/treatment-resistant depression, obsessive-compulsive disorder, social anxiety in adults with autism, and anxiety or depression in life-threatening disease. The most information and strongest association was for the change in methylenedioxymethamphetamine scores compared to active controls in post-traumatic stress disorder ( k = 4; standardised mean difference = −0.86; 95% confidence interval = [−1.23, −0.50]; p < 0.0001). There were also small benefits for social anxiety in adults with autism. Psilocybin was superior to wait-list but not niacin (active control) in life-threatening disease anxiety or depression. It was equally as effective as escitalopram in long-standing depression for the primary study outcome and superior for most of the secondary outcomes in analyses uncorrected for multiple comparisons. Both agents were well tolerated in supervised trials. Trial quality varied with only small proportions of potential participants included in the randomised phase. Overall certainty of evidence was low or very low using the Grading of Recommendations Assessment, Development and Evaluation framework. Conclusion Methylenedioxymethamphetamine and psilocybin may show promise in highly selected populations when administered in closely supervised settings and with intensive support.
... LSD which is more potent than psilocybin induced some dose dependent physical and psychological symptoms including derealization, depersonalization and dissociation [106]. Psilocybin has pharmacodynamic effect lasting between 4-6 h with LSD lasting up to 12 h, an elimination half-life of 3.5 h and 3 h for LSD [129] and psilocybin [130] respectively, has been established. Route of administration is an important formulation consideration for psychotherapy as tryptamine and its derivates are prone to first pass metabolism. ...
Article
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Mushrooms have been used as traditional medicine for millennia, fungi are the main natural source of psychedelic compounds. There is now increasing interest in using fungal active compounds such as psychedelics for alleviating symptoms of mental health disorders including major depressive disorder, anxiety, and addiction. The anxiolytic, antidepressant and anti-addictive effect of these compounds has raised awareness stimulating neuropharmacological investigations. Micro-dosing or acute dosing with psychedelics including Lysergic acid diethylamide (LSD )and psilocybin may offer patients treatment options which are unmet by current therapeutic options. Studies suggest that either dosing regimen produces a rapid and long-lasting effect on the patient post administration with a good safety profile. Psychedelics can also modulate immune systems including pro-inflammatory cytokines suggesting a potential in the treatment of auto-immune and other chronic pain conditions. This literature review aims to explore recent evidence relating to the application of fungal bioactives in treating chronic mental health and chronic pain morbidities.
... There are few pharmacologic agents that influence UGT1A9 and UGT1A10 (Liu et al. 2011). Furthermore, the pharmacokinetics of psilocin, the active metabolite of psilocybin, is linear and is minimally affected by renal clearance (Brown et al. 2017). ...
Article
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Rationale & objectives ± 3,4-Methylenedioxymethamphetamine (MDMA) and psilocybin are currently moving through the US Food and Drug Administration’s phased drug development process for psychiatric treatment indications: posttraumatic stress disorder and depression, respectively. The current standard of care for these disorders involves treatment with psychiatric medications (e.g., selective serotonin reuptake inhibitors), so it will be important to understand drug-drug interactions between MDMA or psilocybin and psychiatric medications. Methods In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we queried the MEDLINE database via PubMed for publications of human studies in English spanning between the first synthesis of psilocybin (1958) and December 2020. We used 163 search terms containing 22 psychiatric medication classes, 135 specific psychiatric medications, and 6 terms describing MDMA or psilocybin. Results Forty publications were included in our systematic review: 26 reporting outcomes from randomized controlled studies with healthy adults, 3 epidemiologic studies, and 11 case reports. Publications of studies describe interactions between MDMA (N = 24) or psilocybin (N = 5) and medications from several psychiatric drug classes: adrenergic agents, antipsychotics, anxiolytics, mood stabilizers, NMDA antagonists, psychostimulants, and several classes of antidepressants. We focus our results on pharmacodynamic, physiological, and subjective outcomes of drug-drug interactions. Conclusions As MDMA and psilocybin continue to move through the FDA drug development process, this systematic review offers a compilation of existing research on psychiatric drug-drug interactions with MDMA or psilocybin.
... This confirmed that psilocybin is dephosphorylated to psilocin. Although doses of 0.6 mg/kg are higher than the dose that is generally used in clinical trial settings, no serious side effect was reported in the month following administration [50]. The differences between the oral and intravenous administration of psilocybin are the speed of onset and the intensity of the subjective effects. ...
Article
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The available interventions for people who are at risk of suicide have limited efficacy. Recently, research on new mental health treatments has started to consider psychedelic compounds, particularly psilocybin, a molecule with a few thousand years of history of use in human societies. The possible effects of psilocybin on suicidal ideation and behaviors have not been specifically studied yet; however, the current knowledge on the suicidal process and the available data on es/ketamine suggest that psylocibin could be used to modulate the thoughts and behavioral patterns in individu- als who are at risk of suicidal behaviors. Here, we summarize the available evidence on the possible mechanisms underlying psilocybin positive effects on suicide risk. Major pathways related to suicidal behaviors that might be modulated by psylocibin include serotonin receptors. Specifically, psylocibin directly stimulates the serotonin 2A receptor (5HT2A), targeting the inflammatory and oxidative stress pathways and leading to a rapid increase in brain plasticity and inflammation suppression and increases in cognitive flexibility, spirituality, and empathy. We also present preliminary epidemio- logical data and provide a rationale for studying psilocybin in individuals with suicidal ideation or who are at risk of suicidal behaviors. This review presents a framework to understand the basis for psilocybin use in individuals who are at risk of suicidal behaviors and calls for clinical studies.
... However, signs of physical dependence on psilocybin and withdrawal have not been documented [7]. Second, the half-life of psilocin, the active metabolite, is three hours [14]. The peak effect typically occurs within 60-90 minutes of oral ingestion, which subsides over the following six hours after ingestion [15]. ...
Article
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Psilocybin-containing mushrooms have been consumed by various cultures in many different parts of the world for thousands of years. Psilocybin, a classic psychedelic, contains unique psychoactive properties and has been incorporated into religious ceremonies and investigated for its medicinal value. In the mid-20th century, psilocybin, along with most other classic psychedelics (5HT-2A agonists), was classified as a Schedule I substance, bringing a halt to research on its medicinal utility. The resurgence of clinical trials involving psilocybin in the 21st century has produced promising results concerning the treatment of addiction, depression, and end-of-life mood disorders. Results from these trials have shown significant reductions in depression and anxiety when compared with a placebo, and one trial found no significant difference when compared to a routinely prescribed selective serotonin reuptake inhibitor (SSRI). Studies conducted with patients with advanced-stage cancer have demonstrated that psilocybin may also be beneficial at reducing depression and anxiety associated with psychological crises due to a terminal diagnosis. Psilocybin therapy in the treatment of addiction, which is notoriously difficult to treat, has shown encouraging results. Due to its low toxicity and low risk of overuse, psilocybin has the potential to have a significant influence in the field of addiction medicine. Psilocybin addiction research has been primarily focused on nicotine and alcohol and, in a few small, open-label trials, has shown superiority over traditional therapies. Psilocybin has a relatively unique and incompletely understood mechanism of action, which allows it to be given at several isolated periods. This infrequent dosing regimen has been shown to produce durable effects with minimal toxicity. This review analyzes the potential of psilocybin in the treatment of addiction, depression, and end-of-life mood disorders. In addition, it will discuss the difficulties involved with conducting scientific research on psychedelic compounds, adverse effects, and the therapeutic measures that are necessary to accompany the safe and effective administration of these psychoactive chemicals.
... During PET scans, participants were in continuous contact with study staff, including a monitor from their experimental sessions in the parent study. Participants were administered a 10 mg/70 kg body weight oral dose of psilocybin 80 min before radiotracer injection for the blocking scan, in order to assess psilocybin binding proximate in time to the estimated C max (Passie et al., 2002;Brown et al., 2017). ...
Article
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Psilocybin (a serotonin 2A, or 5-HT 2A , receptor agonist) has shown preliminary efficacy as a treatment for mood and substance use disorders. The current report utilized positron emission tomography (PET) with the selective 5-HT 2A receptor inverse agonist radioligand [ ¹¹ C]MDL 100,907 (a.k.a. M100,907) and cortical regions of interest (ROIs) derived from resting-state functional connectivity-based brain parcellations in 4 healthy volunteers (2 females) to determine regional occupancy/target engagement of 5-HT 2A receptors after oral administration of a psychoactive dose of psilocybin (10 mg/70 kg). Average 5-HT 2A receptor occupancy across all ROIs was 39.5% (± 10.9% SD). Three of the ROIs with greatest occupancy (between 63.12 and 74.72% occupancy) were within the default mode network (subgenual anterior cingulate and bilateral angular gyri). However, marked individual variability in regional occupancy was observed across individuals. These data support further investigation of the relationship between individual differences in the acute and enduring effects of psilocybin and the degree of regional 5-HT 2A receptor occupancy.
... A study found that the peak psilocin (the active metabolite of psilocybin) concentration was more gradually attained in some subjects than in others, suggesting metabolism rates can vary between individuals. 71 Some studies indicated the potential of psychedelicassisted therapies for pain relief. 17,18,[41][42][43]47,46 However, Pahnke et al. 40 state that, in the case of LSD, for example, although greater pain tolerance was achieved, the effect of the psychedelic did not seem to be long-lasting or predictable enough to justify the large expenditure of time and energy involved in carrying out the intervention if pain relief is the primary goal. ...
Article
Context People affected by serious illness usually experience suffering in its various dimensions, not only in the physical but also in the psychosocial and spiritual aspects. The interest in psychedelic-assisted therapies as a potential new therapeutic modality has increased since evidence suggests a significant impact of their use on the outcomes of patients with serious illness. Objectives To systematically review the available evidence on the effects of psychedelic-assisted therapies for symptom control in patients diagnosed with serious illness. Methods The protocol of this systematic review has been prepared according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines. This review included randomized and non-randomized controlled trials published in peer-reviewed scientific journals. A comprehensive search for studies was carried out in the main scientific databases, including Web of Science, Scopus, Cochrane Library, PsycINFO, PubMed, CINAHL, and EMBASE. There were no limitations regarding the year or language of publication. Results The sample was composed of 20 studies. The results suggest positive effects of psychedelic-assisted therapies for symptom control in patients diagnosed with serious illness, with considerable safety of use. Most studies have been conducted with lysergic acid diethylamide (LSD), psilocybin, and N,N-dipropyltryptamine (DPT) in cancer patients. The adverse effects reported were of physical and/or psychological nature and of mild to moderate intensity, transient, and self-resolutive. Conclusion The evaluated evidence suggests positive effects of psychedelic-assisted therapies for symptom control in patients diagnosed with serious illness, especially regarding symptoms of psychological and spiritual nature.
... The psilocin metabolite 4-hydroxyindole-3-acetic acid (4-HIAA), applied at a 100 µM concentration, did not affect hERG currents. The average peak plasma concentration of the non-glucuronidated psychoactive psilocin is 20 ng/mL or 0.1 µM after administration of a typical psilocin dose for humans of 25 mg (Brown et al., 2017;Becker et al., 2021;Dahmane et al., 2021;Davis et al., 2021;Kolaczynska et al., 2021). Hence, a 500-fold higher psilocin concentration than that actually reached in human plasma was needed to cause relevant hERG channel inhibition. ...
Article
Psilocybin, a hallucinogen contained in “magic” mushrooms, holds great promise for the treatment of various psychiatric disorders, and early clinical trials are encouraging. Adverse cardiac events after intake of high doses of psilocybin and a trial reporting QT interval prolongation in the electrocardiogram attributed to the drug’s main metabolite, psilocin, gave rise to safety concerns. Here we show that clinical concentrations of psilocin do not cause significant human ether-a-go-go-related gene (hERG) potassium channel inhibition, a major risk factor for adverse cardiac events. We conclude that hERG channel blockage by psilocin is not liable for psilocybin- associated cardiotoxic effects.
... These database searches we carried out as part of this review were not able to find any publications of this nature. The application of MS and chromatography techniques are primarily used to analyse biofluids for concentrations of psychoactive substances (145)(146)(147)(148). However, this should not infer that NMR has no place in this research field. ...
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While psychedelics may have therapeutic potential for treating mental health disorders such as depression, further research is needed to better understand their biological effects and mechanisms of action when considering the development of future novel therapy approaches. Psychedelic research could potentially benefit from the integration of metabonomics by proton nuclear magnetic resonance ( ¹ H NMR) spectroscopy which is an analytical chemistry-based approach that can measure the breakdown of drugs into their metabolites and their metabolic consequences from various biofluids. We have performed a systematic review with the primary aim of exploring published literature where ¹ H NMR analysed psychedelic substances including psilocin, lysergic acid diethylamide (LSD), LSD derivatives, N,N -dimethyltryptamine (DMT), 5-methoxy- N,N -dimethyltryptamine (5-MeO-DMT) and bufotenin. The second aim was to assess the benefits and limitations of ¹ H NMR spectroscopy-based metabolomics as a tool in psychedelic research and the final aim was to explore potential future directions. We found that the most current use of ¹ H NMR in psychedelic research has been for the structural elucidation and analytical characterisation of psychedelic molecules and that no papers used ¹ H NMR in the metabolic profiling of biofluids, thus exposing a current research gap and the underuse of ¹ H NMR. The efficacy of ¹ H NMR spectroscopy was also compared to mass spectrometry, where both metabonomics techniques have previously shown to be appropriate for biofluid analysis in other applications. Additionally, potential future directions for psychedelic research were identified as real-time NMR, in vivo ¹ H nuclear magnetic resonance spectroscopy (MRS) and ¹ H NMR studies of the gut microbiome. Further psychedelic studies need to be conducted that incorporate the use of ¹ H NMR spectroscopy in the analysis of metabolites both in the peripheral biofluids and in vivo to determine whether it will be an effective future approach for clinical and naturalistic research.
... 14 In a resurgence of clinical interest, government licensed clinical trials using psilocybin in phase 1 and 2 designs have been published since 2000. [14][15][16][17][18][19][20][21][22][23] We completed a phase 1 randomised, placebo-controlled safety study in which 89 healthy volunteers were randomised 1:1:1 to receive a single dose of placebo, 10 mg of psilocybin or 25 mg psilocybin in a clinical research facility, with 3 months of clinical follow-up. In this trial, there were no serious adverse events (AEs), no AEs that led to withdrawal and data from cognitive tasks indicated no negative effects of psilocybin when compared with placebo. ...
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Introduction Psilocybin-assisted therapy may be a new treatment for major depressive disorder (MDD), with encouraging data from pilot trials. In this trial (short name: PsiDeR) we aimed to test the feasibility of a parallel-group, randomised, placebo-controlled design. The primary outcomes in this trial are measures of feasibility: recruitment rates, dropout rates and the variance of the primary outcome measure of depression. Methods and analysis We are recruiting up to 60 participants at a single centre in London, UK who are unresponsive to, or intolerant of, at least two evidence-based treatments for MDD. Participants are randomised to receive a single dosing session of 25 mg psilocybin or a placebo. All participants receive a package of psychological therapy. The primary outcome measure for depression is the Montgomery Asberg Depression Rating Scale collected by blinded, independent raters. The primary endpoint is at 3 weeks, and the total follow-up is 6 weeks. With further informed consent, this study collects neuroimaging and omics data for mechanism and biomarker analyses and offers participants an open label extension consisting of a further, open label dose of 25 mg of psilocybin. Ethics and dissemination All participants will be required to provide written informed consent. The trial has been authorised by the National Research Ethics Committee (20-LO/0206), Health Research Authority (252750) and Medicine’s and Healthcare Products Regulatory Agency (CTA 14523/0284/001-0001) in the UK. Dissemination of results will occur via a peer-reviewed publication and other relevant media. Trial registration numbers EUDRACT2018-003573-97; NCT04959253 .
... However, signs of physical dependence on psilocybin and withdrawal have not been documented [7]. Second, the half-life of psilocin, the active metabolite, is three hours [14]. The peak effect typically occurs within 60-90 minutes of oral ingestion, which subsides over the following six hours after ingestion [15]. ...
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Acute ischemic strokes (AIS) and hemorrhagic strokes lead to disabling neuropsychiatric and cognitive deficits. A serious and fatal complication of AIS is the occurrence of hemorrhagic transformation (HT). HT is cerebral bleeding that occurs after an ischemic event in the infarcted areas. This review summarises how specific risk factors such as demographic factors like age, gender, and race/ethnicity, comorbidities including essential hypertension, atrial fibrillation, diabetes mellitus, congestive heart failure, and ischemic heart disease along with predictors like higher NIHSS score, larger infarction size, cardioembolic strokes, systolic blood pressure/pulse pressure variability, higher plasma glucose levels, and higher body temperature during ischemic event, lower low-density lipoprotein and total cholesterol, early ischemic changes on imaging modalities, and some rare causes make an individual more susceptible to developing HT. We also discuss few other risk factors such as the role of blood-brain barrier, increased arterial stiffness, and globulin levels in patients postreperfusion using thrombolysis and mechanical thrombectomy. In addition, we discuss the implications of dual antiplatelet therapy and the length of treatment in reference to the incidence of developing HT. Current research into inflammatory mediators and biomarkers such as Cyclooxygenase-2, matrix metalloproteinases, and soluble ST2 and their potential role as treatment options for HT is also briefly discussed. Finally, this review calls for more research into use of dual antiplatelet and the timing of antiplatelet and anticoagulant use in reference to hemorrhagic transformation.
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Psychotropic fungi of the genus Psilocybe , colloquially referred to as “magic mushrooms,” are best known for their L‐tryptophan‐derived major natural product, psilocybin. Yet, recent research has revealed a more diverse secondary metabolism that originates from this amino acid. In this minireview, we move L‐tryptophan to the center and highlight the various Psilocybe natural products and their metabolic routes. We present psilocybin and its congeners, the heterogeneous blue‐colored psilocyl oligomers, alongside β‐carbolines and N , N ‐dimethyl‐L‐tryptophan, and current knowledge on their biosyntheses. We demonstrate the multidisciplinary character of natural product research and include pharmacological, medicinal, ecological, biochemical, and evolutionary aspects.
Article
Objective To conduct a systematic review of modern‐era (post‐millennium) clinical studies assessing the therapeutic effects of serotonergic psychedelics drugs for mental health conditions. Although the main focus was on efficacy and safety, study characteristics, duration of antidepressants effects across studies, and the role of the subjective drug experiences were also reviewed and presented. Method A systematic literature search (1st Jan 2000 to 1st May 2020) was conducted in Pubmed and Psychinfo for studies of patients undergoing treatment with a serotonergic psychedelic. Results Data from 16 papers, representing 10 independent psychedelic‐assisted therapy trials (psilocybin=7, ayahuasca = 2, LSD=1) were extracted, presented in figures and tables, and narratively synthesized and discussed. Across these studies, a total of 188 patients suffering either anxiety and/or depressive symptoms associated with cancer (C‐RPD), major depressive disorder (MDD), obsessive compulsive disorder (OCD) or substance use disorder (SUD) were included. The reviewed studies established feasibility and evidence of safety, alongside promising early data of efficacy in the treatment of depression, anxiety, OCD, and tobacco and alcohol use disorders. For a majority of patients, the therapeutic effects appeared to be long‐lasting (weeks‐months) after only 1 to 3 treatment session(s). All studies were conducted in line with guidelines for the safe conduct of psychedelic therapy and no severe adverse events were reported. Conclusion The resurrection of clinical psychedelic research provides early evidence for treatment efficacy and safety for a range of psychiatric conditions, and constitutes an exciting new treatment avenue in a health area with major unmet needs.
Article
Background Psilocybin is a serotonergic psychedelic with psychoactive effects mediated by serotonin 2A receptor (5-HT2AR) activation. It produces an acute psychedelic altered state of consciousness with a unique phenomenology that can be temporally characterized by three intensity phases: onset of psychoactive effect, a peak plateau and return to normal consciousness. Aims We evaluated whether pre-drug brain 5-HT2AR binding predicted the three phases of psilocybin subjective drug intensity (SDI) and retrospective self-report of mystical type experiences in healthy individuals. Method Sixteen participants completed a pre-drug [ ¹¹ C]Cimbi-36 positron emission tomography scan to assess 5-HT2AR binding. On a separate day, participants completed a single psilocybin session (oral dose range 0.2–0.3 mg/kg), during which SDI was assessed every 20 min. The Mystical Experience Questionnaire (MEQ) was completed at the end of the session. The three SDI phases were modelled using segmented linear regressions. We evaluated the associations between neocortex 5-HT2AR binding and SDI/MEQ outcomes using linear regression models. Results Neocortex 5-HT2AR was statistically significantly negatively associated with peak plateau duration and positively with time to return to normal waking consciousness. It was also statistically significantly negatively associated with MEQ total score. Conclusion This is the first study to investigate how individual brain 5-HT2AR binding predicts subjective effects of a single dose of psilocybin. Our findings reinforce the role of cerebral 5-HT2AR in shaping the temporal and mystical features of the psychedelic experience. Future studies should examine whether individual brain levels of 5-HT2AR have an impact on therapeutic outcomes in clinical studies.
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Mounting evidence suggests safety and efficacy of psychedelic compounds as potential novel therapeutics in psychiatry. Ketamine has been approved by the Food and Drug Administration in a new class of antidepressants, and 3,4-methylenedioxymethamphetamine (MDMA) is undergoing phase III clinical trials for post-traumatic stress disorder. Psilocybin and lysergic acid diethylamide (LSD) are being investigated in several phase II and phase I clinical trials. Hence, the concept of psychedelics as therapeutics may be incorporated into modern society. Here, we discuss the main known neurobiological therapeutic mechanisms of psychedelics, which are thought to be mediated by the effects of these compounds on the serotonergic (via 5-HT2A and 5-HT1A receptors) and glutamatergic [via N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] systems. We focus on 1) neuroplasticity mediated by the modulation of mammalian target of rapamycin–, brain-derived neurotrophic factor–, and early growth response–related pathways; 2) immunomodulation via effects on the hypothalamic-pituitary-adrenal axis, nuclear factor ĸB, and cytokines such as tumor necrosis factor-α and interleukin 1, 6, and 10 production and release; and 3) modulation of serotonergic, dopaminergic, glutamatergic, GABAergic, and norepinephrinergic receptors, transporters, and turnover systems. We discuss arising concerns and ways to assess potential neurobiological changes, dependence, and immunosuppression. Although larger cohorts are required to corroborate preliminary findings, the results obtained so far are promising and represent a critical opportunity for improvement of pharmacotherapies in psychiatry, an area that has seen limited therapeutic advancement in the last 20 years. Studies are underway that are trying to decouple the psychedelic effects from the therapeutic effects of these compounds. Significance Statement Psychedelic compounds are emerging as potential novel therapeutics in psychiatry. However, understanding of molecular mechanisms mediating improvement remains limited. This paper reviews the available evidence concerning the effects of psychedelic compounds on pathways that modulate neuroplasticity, immunity, and neurotransmitter systems. This work aims to be a reference for psychiatrists who may soon be faced with the possibility of prescribing psychedelic compounds as medications, helping them assess which compound(s) and regimen could be most useful for decreasing specific psychiatric symptoms.
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Psilocin is the active metabolite of psilocybin, a serotonergic psychedelic substance. It is used recreationally and investigated in substance-assisted psychotherapy. The pharmacokinetic properties of psilocin are only partially characterized. Therefore, we developed and validated a rapid LC-MS/MS method to quantify psilocin and its metabolite 4-hydroxyindole-3-acetic acid (4-HIAA) in human plasma. Plasma samples were processed by protein precipitation using methanol. The injected sample was mixed with water in front of the C18 analytical column to increase retention of the analytes. Psilocin and 4-HIAA were detected by multiple reaction monitoring (MRM) in positive and negative electrospray ionisation mode, respectively. An inter-assay accuracy of 100−109% and precision of ≤8.7% was recorded over three validation runs. The recovery was near to complete (≥94.7%) and importantly, consistent over different concentration levels and plasma batches (CV%: ≤4.1%). The plasma matrix caused negligible ion suppression and endogenous interferences could be separated from the analytes. Psilocin and 4-HIAA plasma samples could be thawed and re-frozen for three cycles, kept at room temperature for 8 h or 1 month at -20°C without showing degradation (≤10%). The linear range (R ≥0.998) of the method covered plasma concentrations observed in humans following a common therapeutic oral dose of 25 mg psilocybin and was therefore able to assess the pharmacokinetics of psilocin and 4-HIAA. The LC-MS/MS method was convenient and reliable for measuring psilocin and 4-HIAA in plasma and will facilitate the clinical development of psilocybin.
Chapter
The attrition rate of new chemical entities (NCEs) for central nervous system (CNS) drugs is relatively high, making the development of new CNS drugs a challenge. A significant cause of this is related to safety issues arising either during animal toxicity testing or in the human clinical test phases. To reduce these, and increase approval rates by regulatory agencies, including sophisticated human-cell-based experimental models, e.g. organoids or stem-cells based models, in safety testing strategy of potential candidate drugs will result in an improved understanding and prevent safety issues in humans. Especially when these approaches are combined with omics tools in order to better understand the biological mechanisms involved, discovery of additional adverse health effects of existing and newly developed CNS drugs in the clinical test phase will be lowered.
Article
This systematic review investigates whether clinical trials of psilocybin support criterion number three of the drug's schedule I designation: There is a lack of accepted safety for use of the drug or other substance under medical supervision. Data were collected by using the PubMed database and conducting a search on November 24, 2021, with the search term psilocybin and applying the clinical trial filter. Only primary reports on the sole administration of psilocybin by a medical professional were included for analysis, excluding trials wherein psilocybin was not administered, trials wherein psilocybin was exclusively co-administered with other drugs, articles that were not clinical trials, and articles that were repeat analyses of already included trials. 52 included publications were closely examined for reports of adverse events, drug tolerability, and drug safety. Zero of these articles reported psilocybin to be unsafe, while 27 of the included trials suggested that psilocybin is safe to administer under proper medical supervision.
Article
The salification and prodrug approaches modulate the physicochemical properties and absorption, distribution, metabolism, excretion, and toxicity parameters of drugs and lead candidates. The “phosphate” is one of the key counterions/promoiety used in the salt formation and prodrug synthesis. Salification with phosphoric acid enhances the aqueous solubility and thereby facilitates the administration of a drug by the parenteral route. Phosphate moiety in prodrug synthesis mainly improves permeability by lipophilic substitution. Histamine phosphate is the first phosphate salt, and hydrocortisone phosphate was the first prodrug approved by FDA in 1939 and 1952, respectively. The orange book enlists 12 phosphate salts and 17 phosphate prodrugs. Phosphate prodrugs, namely combretastatin A‐4 diphosphate, combretastatin A‐4 phosphate, lufotrelvir, TP‐1287, pyridoxal phosphate, riboflavin phosphate, and psilocybin are clinical candidates. This review focuses on the FDA‐approved phosphate salts and prodrugs from 1939 to 2021. The biopharmaceutical advantage of phosphate salts and prodrugs over the parent molecule is also deliberated.
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Objective: Given the treatment limitations of depression in bipolar disorder, we evaluated the known risks of using psilocybin (and similar substances) in this population, including a systematic assessment of published case histories, to assess the risk of psilocybin as a treatment of depression in bipolar disorder. Data Sources: A comprehensive search of case studies published through December 31, 2020 was conducted using the following electronic databases: PubMed, Web of Science, and PsychInfo, focusing on classic psychedelics and case studies or case histories. Study Selection: Our search terms resulted in 541 hits, of which 43 were non-duplicates of case studies with individuals having an adverse reaction to a psychedelic substance. Of those, 15 case studies indicated some form of adverse event involving mania or manic like behavior that persisted beyond the acute intoxication of the substance. Data Extraction: Two independent evaluators assessed all possible cases, focusing on manic behavior based on DSM criteria. Two separate evaluators convened to evaluate cases where the case information was unclear. Results: Of the 15 cases, four involved psilocybin, two cases involved individuals with a likely pre-existing diagnosis of bipolar disorder, and three involved individuals without a history of polysubstance abuse or concurrent polysubstance use. Conclusions: We conclude that there is some evidence of risk of activating mania with these substances, but that the risk does not appear to be strong or overwhelming. Instead a careful prospective study, such as an open-label treatment protocol with careful controls, appears warranted in this population.
Thesis
It is widely acknowledged that an open character or attitude is vital for having a meaningful and transformative psychedelic experience. Studies further indicate that a mindful and open state of mind paves way for so-called mystical experiences which in turn are predicting positive outcomes regarding mental health. This study further examined the role of openness as a state and trait variable in predicting the degree of experienced mystical states and the levels of acute well-being, using pooled data from 3 trials studying the acute effects of the substances lysergic acid diethylamide (LSD) and psilocybin in two distinct doses each (n = 60). Correlational and regression analyses have shown that the personality trait of openness (NEO-FFI) and its subscales or facets were significantly associated with experienced openness during the psychedelic peak phases in all examined substances and doses (r = 0.35 − 0.62). They also show that an early state of openness between ingestion and onset of substance effects leads to higher levels of mystical states (r = 0.37 − 0.54). Multiple regression analyses show that these mystical experiences have a significant effect on well-being 24 hours after ingestion, in all but the high-dose psilocybin condition. Also, the personality trait of openness to experience has been identified to moderate this relationship significantly and positively (p = 0.034 − 0.025). Further coincidental findings revolve around the timepoint and amplitude of the peak psychedelic phase, which both seem to correlate with certain personality facets of openness to experience. Findings from this thesis can provide information that may have implications for the integration of mindfulness-based therapy models, such as the psychological flexibility model, into psychedelic experiences and their research. Future use cases may also include the prediction of the course and nature of acute psychedelic experiences by means of personality screening.
Chapter
The drugs of abuse market has been steadily increasing, and new classes of psychoactive substances appear every year, with potential addictive properties and side effects. Healthcare providers need to be aware of the toxicodynamic and toxicokinetic properties of these drugs for prevention, diagnosis and treatment of emergency cases. Serotonergic hallucinogens or psychedelics are strong psychoactive substances that act on the psychological state and influence the mood and several other processes in the brain. Among these, the use of the psychoactive natural substances has a long history in many cultures in sacred and religious rituals. Starting from the 1960s and 1970s, their popularity increased also as drugs of abuse. Serotoninergic hallucinogens include the classical psychedelic natural products containing N,N-dimethyltryptamine, psilocybin and psilocin, bufotenine, mescaline, lysergic acid amide, the synthetic hallucinogens as lysergic acid diethylamide, and the new hallucinogenic substances as tryptamine and phenethylamines derivatives, for which little is known regarding the toxicological properties and acute and chronic effects. This chapter provides a comprehensive update on serotoninergic hallucinogens, starting from their history and focusing on their classification, toxicokinetics, toxicodynamics, acute and chronic effects. https://www.sciencedirect.com/science/article/pii/B9780323852159000222 Preface Toxicology is a multidisciplinary science where a vast interdisciplinary field of applications is continuously evolving and developing, aiming to maintain and enhance the safety of global health and to assist and strengthen ongoing policy regulatory frameworks. Thinking outside the box, the concept of toxicology has successfully evolved throughout the years, as new research techniques have been developed on preexisting methods and new data became available, resulting in a continuous update of our current knowledge on many different toxicological aspects. The development, improvement, and validation of such steps significantly improve our ability to further understand the hazards and risks posed by chemicals and toxic stimuli that are detrimental to human health. In modern life today, simultaneously or sequentially, we are all exposed to chemicals from diverse sources where a toxicological risk assessment has played a pivotal role in clarifying the mechanistic reasons and resulting outcomes. This book focuses on crucial modern toxicology issues highlighting aspects such as toxicity methods and models, testing tools and concepts, risk-assessment insights, pharmaceuticals and nutraceuticals, biomaterials and nanomaterials, special topics in toxicology, epidemiology, and public health, and clinical biomarkers, among others, providing an “in-depth” review of today’s scientific stance, equally benefiting toxicological scientific communities and respective regulatory bodies. Written by renowned and leading experts in these scientific fields with whom I have been closely collaborating over the past decade, this resource is dedicated to all toxicological risk assessments and multihealth impacts from different exposures. I am immensely proud of this collection of excellent studies and strongly believe that it will be a valuable asset to all scientists working on risk assessment and a substantial contribution to modern toxicology. The book’s success belongs to the authors of the chapters. The design of the book is based on the expertise and knowledge of many collaborations and partners in research. Of course, there will always be room for improvement, but the book provides an attempt at a holistic approach. The central philosophy is, “we know less than we think we know” (Socrates).
Article
The emerging novel therapeutic psilocybin produces psychedelic effects via engagement of cerebral serotonergic targets by psilocin (active metabolite). The serotonin 2A receptor critically mediates these effects by altering distributed neural processes that manifest as increased entropy, reduced functional connectivity (FC) within discrete brain networks (i.e., reduced integrity) and increased FC between networks (i.e., reduced segregation). Reduced integrity of the default mode network (DMN) is proposed to play a particularly prominent role in psychedelic phenomenology, including perceived ego-dissolution. Here, we investigate the effects of a psychoactive peroral dose of psilocybin (0.2–0.3 mg/kg) on plasma psilocin level (PPL), subjective drug intensity (SDI) and their association in fifteen healthy individuals. We further evaluate associations between these measures and resting-state FC, measured with functional magnetic resonance imaging, acquired over the course of five hours after psilocybin administration. We show that PPL and SDI correlate negatively with measures of network integrity (including DMN) and segregation, both spatially constrained and unconstrained. We also find that the executive control network and dorsal attention network desegregate, increasing connectivity with other networks and throughout the brain as a function of PPL and SDI. These findings provide direct evidence that psilocin critically shapes the time course and magnitude of changes in the cerebral functional architecture and subjective experience following psilocybin administration. Our findings provide novel insight into the neurobiological mechanisms underlying profound perceptual experiences evoked by this emerging transnosological therapeutic and implicate the expression of network integrity and segregation in the psychedelic experience and consciousness.
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The resurgence of interest in the therapeutic potential of psychedelics for treating psychiatric disorders has rekindled efforts to elucidate their mechanism of action. In this Perspective, we focus on the ability of psychedelics to promote neural plasticity, postulated to be central to their therapeutic activity. We begin with a brief overview of the history and behavioral effects of the classical psychedelics. We then summarize our current understanding of the cellular and subcellular mechanisms underlying these drugs’ behavioral effects, their effects on neural plasticity, and the roles of stress and inflammation in the acute and long-term effects of psychedelics. The signaling pathways activated by psychedelics couple to numerous potential mechanisms for producing long-term structural changes in the brain, a complexity that has barely begun to be disentangled. This complexity is mirrored by that of the neural mechanisms underlying psychiatric disorders and the transformations of consciousness, mood, and behavior that psychedelics promote in health and disease. Thus, beyond changes in the brain, psychedelics catalyze changes in our understanding of the neural basis of psychiatric disorders, as well as consciousness and human behavior.
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Because undesirable pharmacokinetics and toxicity are significant reasons for the failure of drug development in the costly late stage, it has been widely recognized that drug ADMET properties should be considered as early as possible to reduce failure rates in the clinical phase of drug discovery. Concurrently, drug recalls have become increasingly common in recent years, prompting pharmaceutical companies to increase attention toward the safety evaluation of preclinical drugs. In vitro and in vivo drug evaluation techniques are currently more mature in preclinical applications, but these technologies are costly. In recent years, with the rapid development of computer science, in silico technology has been widely used to evaluate the relevant properties of drugs in the preclinical stage and has produced many software programs and in silico models, further promoting the study of ADMET in vitro. In this review, we first introduce the two ADMET prediction categories (molecular modeling and data modeling). Then, we perform a systematic classification and description of the databases and software commonly used for ADMET prediction. We focus on some widely studied ADMT properties as well as PBPK simulation, and we list some applications that are related to the prediction categories and web tools. Finally, we discuss challenges and limitations in the preclinical area and propose some suggestions and prospects for the future.
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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
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RationaleLysergic acid diethylamide (LSD) and other serotonergic hallucinogens can induce profound alterations of consciousness and mystical-type experiences, with reportedly long-lasting effects on subjective well-being and personality. Methods We investigated the lasting effects of a single dose of LSD (200 μg) that was administered in a laboratory setting in 16 healthy participants. The following outcome measures were assessed before and 1 and 12 months after LSD administration: Persisting Effects Questionnaire (PEQ), Mysticism Scale (MS), Death Transcendence Scale (DTS), NEO-Five Factor Inventory (NEO-FFI), and State-Trait Anxiety Inventory (STAI). ResultsOn the PEQ, positive attitudes about life and/or self, positive mood changes, altruistic/positive social effects, positive behavioral changes, and well-being/life satisfaction significantly increased at 1 and 12 months and were subjectively attributed by the subjects to the LSD experience. Five-Dimensions of Altered States of Consciousness (5D-ASC) total scores, reflecting acutely induced alterations in consciousness, and Mystical Experience Questionnaire (MEQ30) total scores correlated with changes in well-being/life satisfaction 12 months after LSD administration. No changes in negative attitudes, negative mood, antisocial/negative social effects, or negative behavior were attributed to the LSD experience. After 12 months, 10 of 14 participants rated their LSD experience as among the top 10 most meaningful experiences in their lives. Five participants rated the LSD experience among the five most spiritually meaningful experiences in their lives. On the MS and DTS, ratings of mystical experiences significantly increased 1 and 12 months after LSD administration compared with the pre-LSD screening. No relevant changes in personality measures were found. Conclusions In healthy research subjects, the administration of a single dose of LSD (200 μg) in a safe setting was subjectively considered a personally meaningful experience that had long-lasting subjective positive effects. Trial registrationRegistration identification number: NCT01878942.
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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
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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. Trial registration: ClinicalTrials.gov Identifier: NCT00957359.
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