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Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults
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.
... This is the phenomenon known as "functional selectivity". (Brown, 2017) In the brain, 5-HT2a receptors are widespread although they feature particularly prominently in the cortical regions. 5-HT2a receptors have diverse functions in the brain, including regulation of sleep, mood, appetite and social functioning. ...
... 5-HT2A and 5-HT2C receptors are located predominantly in the "higher" areas, on cortical layer". (Brown, 2017) Both Psilocybin and Psilocin are water-soluble which makes them available orally and are rapidly absorbed through the stomach wall and into the bloodstream. ...
... In healthy individuals, psilocybin/psilocin has a half-life of 3 hours. ". (Brown, 2017) Psilocin is regarded as a prototypic classical psychedelic, and thus the main psychoactive effects of psilocin are due to binding to the 5-HT2A and 5-HT2C serotonin receptor subtypes, where it acts with high specificity as a partial agonist. The stimulation of the 5-HT2A receptor is understood to be predominantly responsible for the characteristic psychoactive effects of "changes in perception, visual patterns and discrete images, euphoria, distorted sense of time, synesthesia, emotional lability, and sometimes mystical or spiritual experiences" (Brown, et al. 2017). ...
Detailed Infographic that details: Current Statistics, Brief History, Scientific trials, Molecule Structures, Safety and Toxicity, Mitigating Harms
Pharmacology (How Psychedelics Work), Benefits: How Psychedelics work to aid mental health issues, Current & Previous Research, Legality and Frameworks for the future.
... Amongst these agents, there has been an increased interest in the use of psilocybin for the treatment of numerous psychiatric disorders (2). Found in various species of fungi (3), psilocybin is a naturally occurring prodrug of the psychedelic compound psilocin (4)(5)(6). Recent clinical research has reported compelling results demonstrating psilocybin's therapeutic efficacy in addressing treatment resistant depression (TRD) (7)(8)(9)(10). Significant and meaningful improvement in depression scores were presented, with long-term benefits lasting weeks, and in some individuals up to six months post-treatment. ...
... These rapid and persistent anti-depressive and anxiolytic effects produced by psilocybin are characteristically accompanied by a potent psychedelic episode lasting up to 6 h from the time of dosing (4,7,(14)(15)(16). The long duration of this altered state is attributed to the PK profile of psilocybin (6,17). Upon ingestion, exposure to acidic conditions within the GI tract, along with intestinal and hepatic alkaline phosphatase lead to the dephosphorylation of psilocybin, producing elevated levels of systemic psilocin. ...
... Orally administered psilocybin is subject to significant first-pass metabolism, involving dephosphorylation at the 4-hydroxyl position producing the bioactive form psilocin (6,4,17,(22)(23)(24)(25)(26)(27). This dephosphorylation occurs in various compartments within the body. ...
The psychedelic compound psilocybin has shown therapeutic benefit in the treatment of numerous psychiatric diseases. A recent randomized clinical trial conducted at Johns Hopkins Bayview Medical Center demonstrated the efficacy of psilocybin-assisted therapy in the treatment of Major Depressive Disorder (MDD). Similarly, a phase IIb study evaluating psilocybin-assisted therapy for treatment-resistant depression (TRD) presented statistically meaningful and long-term reduction in depressive symptoms. Also, many studies have reported the successful treatment of severe anxiety after a single oral dose of psilocybin, especially in patients struggling with cancer-related distress (CRD). Despite these compelling clinical results, concerns regarding the duration of the psychedelic experience produced by psilocybin pose a significant barrier to its widespread therapeutic application. Psilocybin, derived from magic mushrooms is the naturally occurring prodrug of the neuroactive compound psilocin. When orally administered, exposure to the acidic gastrointestinal (GI) environment together with enzymatic processing by intestinal and hepatic alkaline phosphatase lead to the dephosphorylation of psilocybin producing elevated levels of systemic psilocin. These plasma levels are detectable up to 24 h and produce a psychoactive episode lasting as long as 6 h post-ingestion. In order to positively modify the kinetics of the acute psychedelic response, we have engineered a library of novel prodrug derivatives (NPDs) of psilocin, introducing a diversity of alternative metabolically cleavable moieties modified at the 4-carbon position of the core indole ring. This library consists of twenty-eight unique compounds represented by nine distinct prodrug classes. Each molecule was screened in vitro for metabolic stability using isolated human serum, and human cellular fractions derived from liver and intestinal tissues. This screen revealed fifteen prodrugs that produced measurable levels of psilocin in vitro, with ester and thiocarbonate-based prodrug derivatives significantly represented. These fifteen NPDs were further evaluated for pharmacokinetic (PK) profiles in mice, assessing plasma levels of both residual prodrug and resultant psilocin. PK results confirmed the efficiency of ester and thiocarbonate-based prodrug metabolism upon oral and intravenous administration, achieving levels reduced, albeit comparable to levels of psilocybin-derived psilocin. Of note, almost all NPDs tested maintained reduced overall exposure of psilocin relative to psilocybin, with no measurable levels detected at 24 h post-dose. Finally, all NPDs were screened for CNS bioavailability in healthy mice using the Head Twitch Response (HTR), a behavioural biomarker of 5-HT2A receptor stimulation and an established proxy for psychoactive potential. Interestingly, five NPDs produced peak HTR that approached or exceeded levels induced by an equivalent dose of psilocybin. Among these bioactive prodrugs, an ester-based and thiocarbonate-based molecule produced long-term anxiolytic benefit in chronically stressed mice evaluated in the marble burying psychiatric model. Overall, this screening campaign identified novel candidate prodrugs of psilocin with altered metabolic profiles and reduced pharmacological exposure, potentially attenuating the duration of the psychedelic response. These molecules still maintained the long-term psychiatric and physiological benefits characteristic of psilocybin therapy. Additionally, these modified parameters also offer the opportunity for altered routes of administration bypassing conventional oral dosing.
... After oral administration of increasing doses of psilocybin, it loses its phosphate group and is totally converted to psilocin in the acidic environment of the stomach or by alkaline phosphatase in the intestine and kidneys [182][183][184]. Therefore, evaluations of the pharmacological profile of psilocybin have been performed with its main derivative [182]. ...
... Therefore, evaluations of the pharmacological profile of psilocybin have been performed with its main derivative [182]. Psilocin is identified in plasma within half an hour of administration and reaches peak concentrations within three hours [184]. Plasma AUC increases in proportion to dose, indicating linear pharmacokinetics in doses between 0.3 and 0.6 mg/kg of psilocybin [183,184]. ...
... Psilocin is identified in plasma within half an hour of administration and reaches peak concentrations within three hours [184]. Plasma AUC increases in proportion to dose, indicating linear pharmacokinetics in doses between 0.3 and 0.6 mg/kg of psilocybin [183,184]. The average bioavailability of psilocin is around 50% and its average half-life is around three hours. ...
The need to identify effective therapies for the treatment of psychiatric disorders is a particularly important issue in modern societies. In addition, difficulties in finding new drugs have led pharmacologists to review and re-evaluate some past molecules, including psychedelics. For several years there has been growing interest among psychotherapists in psilocybin or lysergic acid diethylamide for the treatment of obsessive-compulsive disorder, of depression, or of post-traumatic stress disorder, although results are not always clear and definitive. In fact, the mechanisms of action of psychedelics are not yet fully understood and some molecular aspects have yet to be well defined. Thus, this review aims to summarize the ethnobotanical uses of the best-known psychedelic plants and the pharmacological mechanisms of the main active ingredients they contain. Furthermore, an up-to-date overview of structural and computational studies performed to evaluate the affinity and binding modes to biologically relevant receptors of ibogaine, mescaline, N,N-dimethyltryptamine, psilocin, and lysergic acid diethylamide is presented. Finally, the most recent clinical studies evaluating the efficacy of psychedelic molecules in some psychiatric disorders are discussed and compared with drugs already used in therapy.
... 12,17 Previously reported halflives of psilocin ranged between 2 and 3 hours. 12,13 Some earlier trials used weight-adjusted dosing, 6,7 but psilocybin is now mostly administered as single fixed doses of 15, 25, or 30 mg. 3,5,[18][19][20] Although psilocybin has been intensively investigated clinically for many years, very little pharmacokinetic (PK) data and no data on the PK-pharmacodynamic (PK-PD) relationship are available. Furthermore, descriptions of PKs and doseeffect relationships of the increasingly used fixed doses are lacking. ...
... Furthermore, descriptions of PKs and doseeffect relationships of the increasingly used fixed doses are lacking. The few small previous PK studies used body weight-adjusted dose administrations, 12,13 whereas therapeutic trials favor fixed doses of psilocybin. 13,21 Therefore, the present study investigated the PKs and acute effects of psilocin and the PK-PD relationship of clinically representative fixed doses of 15, 25, and 30 mg psilocybin. ...
... The few small previous PK studies used body weight-adjusted dose administrations, 12,13 whereas therapeutic trials favor fixed doses of psilocybin. 13,21 Therefore, the present study investigated the PKs and acute effects of psilocin and the PK-PD relationship of clinically representative fixed doses of 15, 25, and 30 mg psilocybin. For this purpose, data from two separate phase I studies in healthy participants were analyzed using a validated analytical method and established PK-PD modeling techniques. ...
Psilocybin is being investigated as a potential treatment for psychiatric and neurological disorders. Only a few studies have evaluated the pharmacokinetics of psilocybin and have used body weight-adjusted dosing. Data on pharmacokinetics and the pharmacokinetic-pharmacodynamic relationship of fixed doses that are commonly used are unavailable. The present study characterized the pharmacokinetics and pharmacokinetic-pharmacodynamic relationship of 15, 25, and 30 mg of orally administered psilocybin in 28, 23, and 28 healthy subjects, respectively. Plasma levels of unconjugated psilocin (the psychoactive metabolite of psilocybin) and corresponding subjective effects were repeatedly assessed up to 24 h. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modeling. Mean (95% confidence interval) maximal psilocin concentrations were 11 ng/ml (10-13), 17 ng/ml (16-19), and 21 ng/ml (19-24) after the administration of 15, 25, and 30 mg psilocybin, respectively. Maximal concentrations were reached after an average of 2 h. Elimination half-lives were 1.8 h (1.7-2.0), 1.4 h (1.2-1.7), and 1.8 h (1.6-1.9) for 15, 25, and 30 mg psilocybin, respectively. Mean (± SD) durations of subjective effects were 5.6 ± 2.2 h, 5.5 ± 1.6 h, and 6.4 ± 2.2 h, and maximal effects ("any drug" effects) were 58% ± 25%, 73% ± 27%, and 80% ± 18% after 15, 25, and 30 mg psilocybin, respectively. Psilocin exhibited dose-proportional pharmacokinetics. The duration and intensity of subjective effects were dose-dependent. Body weight did not influence pharmacokinetics or the response to psilocybin. These data may serve as a reference for future clinical trials.
... Psilocin is extensively distributed through the bloodstream to all tissues, including crossing the bloodbrain barrier to elicit central nervous system effects (23). Psilocin is detectable in plasma after 30 min (17) and displays linear pharmacokinetics (36). ...
... The dose response curve correlates to a session experience with an onset of action at 20-40 min, peak subjective effects at 60-90 min and an active duration of 4-6 h (Figure 1) (18). A dose-escalating study of oral psilocybin found an average psilocin T 1/2 of 3 h, but also found minor variability (standard deviation 1.1) between participants (Figure 1) (36). Variability was not predicted by body weight, and may instead be due to less or more hydrolysis of the psilocin glucuronide metabolite (36). ...
... A dose-escalating study of oral psilocybin found an average psilocin T 1/2 of 3 h, but also found minor variability (standard deviation 1.1) between participants (Figure 1) (36). Variability was not predicted by body weight, and may instead be due to less or more hydrolysis of the psilocin glucuronide metabolite (36). After a 25 mg fixed oral dose of psilocybin, one study reported a maximal psilocin plasma concentration at 120 min (Tmax) of 20 ng/mL (Cmax) (28) and similarly, another study reported a Cmax of 18.7 ng/mL (37). ...
The interest in psilocybin as a therapeutic approach has grown exponentially in recent years. Despite increasing access, there remains a lack of practical guidance on the topic for health care professionals. This is particularly concerning given the medical complexity and vulnerable nature of patients for whom psilocybin-assisted psychotherapy may be considered. This article aims to provide health care professionals with an overview of practical considerations for psilocybin therapy, rooted in a patient safety focus. Within this piece we will review basic psilocybin pharmacology and pharmacokinetics, indications, practical therapeutic strategies (e.g., dosing, administration, monitoring) and safety considerations (e.g., contraindications, adverse events, and drug interactions). With this information, our goal is to increase the knowledge and comfort of health care professionals to discuss and counsel their patients on psilocybin therapy, ultimately improving patient care and safety.
... Body weight-adjusted dosing is a 'gold standard' in pharmacological research, and has been widely used in research on psilocybin (Bogenschutz et al., 2015;Brown et al., 2017;Carbonaro et al., 2016;Carter et al., 2005Carter et al., , 2007Grob et al., 2011;Nicholas et al., 2018;Ross et al., 2016;Schmidt et al., 2012;Umbricht et al., 2002;Vollenweider et al., 2007). Given the PET findings above (Stenbaek et al., 2020), and an increased receptor density in those with a higher BMI, it is unclear what impact weight-adjusted dosing would have on the acute experience. ...
... Such a strategy has the important benefit of simplifying the logistics of large-scale clinical roll-out. Moreover, this approach has been supported by pharmacokinetic simulations conducted by Brown et al. (2017) who demonstrated that 25 mg would be a sufficient fixed dose to induce the therapeutically meaningful acute experiences of a dose of 0.3 mg/kg Hirschfeld and Schmidt, 2020;Nicholas et al., 2018). No studies to date have directly assessed the relationship between BMI and the acute experience after a fixed high (i.e. ...
... While body weight-adjusted dosing is currently regarded as a 'gold-standard' in research, there has been increasing recognition that body weight may not provide a sufficient measure of body composition when adjusting dosing (Green and Duffull, 2004;Morrish et al., 2011). Additionally, it adds practical and financial complexity to standardization, validation and large-scale distribution (Brown et al., 2017), which in turn significantly impacts the feasibility of large-scale rollout of psychedelic-assisted therapy. Having a fixed dose could significantly simplify the design and logistics of numerous future clinical studies, particularly in clinical trials where BMI is a feature of the target population, such as psilocybin-assisted psychotherapy in anorexia nervosa. ...
Background
Psilocybin is a serotonin type 2A (5-HT 2A ) receptor agonist and naturally occurring psychedelic. 5-HT 2A receptor density is known to be associated with body mass index (BMI), however, the impact of this on psilocybin therapy has not been explored. While body weight-adjusted dosing is widely used, this imposes a practical and financial strain on the scalability of psychedelic therapy. This gap between evidence and practice is caused by the absence of studies clarifying the relationship between BMI, the acute psychedelic experience and long-term psychological outcomes.
Method
Data were pooled across three studies using a fixed 25 mg dose of psilocybin delivered in a therapeutic context to assess whether BMI predicts characteristics of the acute experience and changes in well-being 2 weeks later. Supplementing frequentist analysis with Bayes Factors has enabled for conclusions to be drawn regarding the null hypothesis.
Results
Results support the null hypothesis that BMI does not predict overall intensity of the altered state, mystical experiences, perceptual changes or emotional breakthroughs during the acute experience. There was weak evidence for greater ‘dread of ego dissolution’ in participants with lower BMI, however, further analysis suggested BMI did not meaningfully add to the combination of the other covariates (age, sex and study). While mystical-type experiences and emotional breakthroughs were strong predictors of improvements in well-being, BMI was not.
Conclusions
These findings have important implications for our understanding of pharmacological and extra-pharmacological contributors to psychedelic-assisted therapy and for the standardization of a fixed therapeutic dose in psychedelic-assisted therapy.
... Indeed, following oral administration of ascending doses of psilocybin, no parent compound was observed in plasma or urine. 15 Few human pharmacokinetic studies have been undertaken so that detailed information of some aspects is unknown. For example, the influence of intrinsic factors on observed pharmacokinetic parameters (eg, hepatic and renal impairment, age, and gender) in addition to that of extrinsic factors are poorly studied, if at all. ...
... Following oral administration of psilocybin, psilocin appears in the plasma within 20 to 30 minutes and maximum concentrations are achieved within 2 to 3 hours of the dose. 15,16 Conversion of the parent compound to psilocin appears to be highly variable based on the dispersion of Tmax values reported in oral administration studies (see Table 1). Maximum concentrations of psilocin were linearly dependent on dose in the only oral ascending dose study conducted to date. ...
... Maximum concentrations of psilocin were linearly dependent on dose in the only oral ascending dose study conducted to date. 15 Similarly, area under the plasma concentration time curve (AUC) also increased proportionally to the dose confirming linear pharmacokinetics of psilocin in the dose range 0.3 to 0.6 mg/kg. 15 Psilocin is extensively distributed to the tissues as the apparent volume of distribution exceeds that of total body water. ...
Psilocybin is a tryptamine alkaloid found in some mushrooms, especially those of the genus Psilocybe. Psilocybin has four metabolites including the pharmacologically active primary metabolite psilocin which readily enters the systemic circulation. The psychoactive effects of psilocin are believed to arise due to the partial agonist effects at the 5HT2A receptor. Psilocin also binds to various other receptor subtypes although the actions of psilocin at other receptors is not fully explored. Psilocybin administered at doses sufficient to cause hallucinogenic experiences has been trialled for addictive disorders, anxiety and depression. This review investigates studies of psilocybin and psilocin and assesses the potential for use of psilocybin and a treatment agent in neuropsychiatry. The potential for harm is also assessed, which may limit the use of psilocybin as a pharmacotherapy. Careful evaluation of the number needed to harm versus the number needed to treat will ultimately justify the potential clinical use of psilocybin. This field needs a responsible pathway forward.
... 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). ...
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.
... Its half-life is roughly 3 h and no detectable drug is present 24 h after a single dose. 15,16 Psilocybin induces an altered state of consciousness characterised by changes in mood, thinking patterns and perceptual experience. A state of awe and other personally meaningful experiences that are often difficult to describe in words can be experienced with higher doses. ...
... The effects of psilocybin usually start at 30 min, peak at 90 min and subside after 4-6 h. 15,16 Dosing sessions are video-recorded to monitor for risk events or deviation from therapeutic protocols, unless participants withdraw consent for this. After the dosing session, participants are medically assessed for discharge, then accompanied home by a friend, partner or carer. ...
Psilocybin is a classic psychedelic drug that has attracted increasing research interest over the past 10 years as a possible treatment for mood, anxiety and related conditions. Initial phase 2 clinical trials of psilocybin given alongside psychological support for major depression and treatment-resistant depression (TRD) demonstrated encouraging signs of basic safety, further confirmed by a large study in groups of healthy volunteers. The first international multi-centre randomised controlled trial was published in 2022, with signs of efficacy for the 25 mg dose condition in people with TRD when compared with an active placebo. Phase 3 trials in TRD are scheduled to start in 2023. Early evidence suggests that single doses of psilocybin given with psychological support induce rapid improvement in depressive symptoms that endure for some weeks. We therefore provide a timely update to psychiatrists on what psilocybin therapy is, what it is not, and the current state of the evidence-base.
... For human clinical trials, 25 mg/70 kg is administered as a representative high psilocybin dose [40,41]. Using DoseCal, a virtual calculator for dosage conversion between human and different animal species [42], a 25 mg/70 kg human dose was converted to 4.4 mg/kg in mice. ...
... A further analysis of the dose-response results was conducted into a pharmacological dose-response logarithmic curve ( Figure 3E), and the data points that were included were taken from PSIL induction of maximal peak HTR ( Figure 3D). For human clinical trials, 25 mg/70 kg is administered as a representative high psilocybin dose [40,41]. Using DoseCal, a virtual calculator for dosage conversion between human and different animal species [42], a 25 mg/70 kg human dose was converted to 4.4 mg/kg in mice. ...
There is increasing interest in the therapeutic potential of psilocybin. In rodents, the serotonin precursor, 5-hydroxytryptophan (5-HTP) and psilocybin induce a characteristic 5-HT2A receptor (5-HT2AR)-mediated head twitch response (HTR), which is correlated with the human psychedelic trip. We examined the role of other serotonergic receptors and the trace amine -associated receptor 1 (TAAR1) in modulating 5-HTP- and psilocybin-induced HTR. Male C57BL/6J mice (11 weeks, ~30 g) were administered 5-HTP, 50–250 mg/kg i.p., 200 mg/kg i.p. after pretreatment with 5-HT/TAAR1 receptor modulators, psilocybin 0.1–25.6 mg/kg i.p. or 4.4 mg/kg i.p., immediately preceded by 5-HT/TAAR1 receptor modulators. HTR was assessed in a custom-built magnetometer. 5-HTP and psilocybin induced a dose-dependent increase in the frequency of HTR over 20 min with attenuation by the 5-HT2AR antagonist, M100907, and the 5-HT1AR agonist, 8-OH-DPAT. The 5-HT2CR antagonist, RS-102221, enhanced HTR at lower doses but reduced it at higher doses. The TAAR1 antagonist, EPPTB, reduced 5-HTP- but not psilocybin-induced HTR. We have confirmed the key role of 5-HT2AR in HTR, an inhibitory effect of 5-HT1AR, a bimodal contribution of 5-HT2CR and a role of TAAR1 in modulating HTR induced by 5-HTP. Compounds that modulate psychedelic-induced HTR have important potential in the emerging therapeutic use of these compounds.
... 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). ...
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.
... 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]. ...
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
... 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). ...
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.
... When psilocin plasma levels reach 4-6 μg/mL in humans, psychological effects commence, with a threshold oral dose of 3-5 mg resulting in sympathomimetic effects, while full psychedelic effects arise with 8-25 mg oral doses of psilocybin (Passie et al., 2002). Brown et al. (2017) demonstrated a linear pharmacokinetic trend of psilocin over a two-fold range of 0.3-0.6 mg/kg. Detectable amounts of psilocin in human plasma can be found within 20 to 40 min after oral administration, with maximum plasma concentrations occurring 70 to 100 minutes following oral administration (Dinis-Oliveira, 2017; Passie et al., 2002). ...
Psychedelic mushrooms containing psilocybin and related tryptamines have long been used for ethnomycological purposes, but emerging evidence points to the potential therapeutic value of these mushrooms to address modern neurological, psychiatric health, and related disorders. As a result, psilocybin containing mushrooms represent a re-emerging frontier for mycological, biochemical, neuroscience, and pharmacology research. This work presents crucial information related to traditional use of psychedelic mushrooms, as well as research trends and knowledge gaps related to their diversity and distribution, technologies for quantification of tryptamines and other tryptophan-derived metabolites, as well as biosynthetic mechanisms for their production within mushrooms. In addition, we explore the current state of knowledge for how psilocybin and related tryptamines are metabolized in humans and their pharmacological effects, including beneficial and hazardous human health implications. Finally, we describe opportunities and challenges for investigating the cultural production of psychedelic mushrooms and metabolic engineering approaches to alter secondary metabolite production through biotechnology approaches integrated with machine learning. Ultimately, this critical review of all aspects related to psychedelic mushrooms represents a roadmap for future research efforts that will pave the way to new applications and refined protocols.
... Various doses are applied in different studies but generally they can be divided into standard, high and supra-therapeutic, being 25, 35 and 50-60 mg respectively 6,7,8,9 . This concerns pure psilocybin either in the form of an extracted isolate or a synthetic substance. ...
Introduction: The word “psychedelic” derives from the Greek language and can be loosely translated as “mind manifesting” which is to convey that these substances allow the mind to unleash its hidden potential. Psilocybin is considered to be a “classic psychedelic” and is most commonly found in the form of so-called “magic mushrooms”. Due to its unique properties psilocybin has been used during religious ceremonies and rituals for centuries and more recently also explored in a medical context. Nowadays many studies are being carried out to prove the efficacy of its use in the treatment of various psychiatric disorders. Aim of study: Review of the current knowledge on the subject of psilocybin applied in the treatment of psychiatric disorders, such as major depressive disorder, treatment-resistant depression and addiction. Methods and materials: A review of chosen literature was carried out in the PubMed database and Google Scholar using the following phrases: psilocybin, psychedelics, psychedelic-assisted therapy, major depressive disorder, addiction. Results: Recent studies suggest that psilocybin may be an effective form of treatment for cancer-related psychiatric distress, treatment-resistant depression and addiction. There are some reports of psilocybin being useful when treating obsessive-compulsive disorder and cluster headaches. Conclusions: More large-scale, randomized, placebo-controlled studies are required to prove these promising findings. Psychological support is crucial during the treatment with psilocybin.
... Psilocin is structurally like the human neurotransmitter serotonin and undergoes similar metabolism. [6] Psilocybin is rarely lethal but transient adverse effects are common with intoxication. These range from mild, such as headache, relative hypertension and tachycardia and anxiety, to potentially severe including panic attacks, derealisation, seizures, confusion and renal injury. ...
Classic psychedelics such as psilocybin, ketamine and lysergic acid diethylamide (LSD) are 5HT2A serotonin receptor agonists that produce individualised subjective affects. Today, public interest in psychedelic medicine has reached a fervour but the evidence for clinical benefit still lags. Psilocybin and psilocin are tryptophan based alkaloids found worldwide in mushrooms of the genera Psilocybe, Panaeolus, Conocybe, Gymnopilus, Stropharia, Pluteus and Panaeolina. This review addresses the current evidence base for psilocybin as a clinical medicine, the general chemistry and proposed mechanism of its therapeutic effect and future research directions for psilocybin based therapies.
... Notably, our subject's self-reported Ishihara Test score improved only minimally at 12 h post-administration, but improved to a score consistent with normal color vision at 24 h post-administration before dipping slightly and peaking at day eight post-administration. This seems to indicate that optimization of newfound color processing capabilities was gradual rather than immediate, occurring non-linearly and not reaching completion until well after the five half-lives required for all psilocybin consumed to be eliminated (Brown et al., 2017). This may suggest that psilocybin served as a catalyst for a learning process around color interpretation or, alternatively, that the downstream effects of psilocybin on altering the connectivity between visual regions may take time to fully manifest. ...
Background
Recent survey data indicate that some people report long-term improvement in color vision deficiency (CVD), also known as color blindness, following use of psychedelics such as lysergic acid diethylamide (LSD) and psilocybin. However, there are no objective data reported in the medical literature quantifying the degree or duration of CVD improvement associated with psychedelic use.
Case presentation
Here we present the case of a subject with red-green CVD (mild deuteranomalia) who self-administered the Ishihara Test to quantify the degree and duration of CVD improvement following the use of 5 g of dried psilocybin mushrooms. Self-reported Ishihara Test data from the subject revealed partial improvement in CVD peaking at 8 days and persisting for at least 16 days post-psilocybin administration. This improvement may have lasted longer, though the subsequent observations are confounded by additional substance use.
Conclusion
A single use of psilocybin may produce partial improvements in CVD extending beyond the period of acute effect, despite this condition typically resulting from a genetic defect. Systematic exploration of this possible phenomenon is needed to confirm our findings, gauge their generalizability, and determine the mechanism of action.
... Psilocybin was not detected in plasma or urine because of its fast first-pass metabolism, and the elimination half-life of psilocin was 3 h with lower renal clearance (<2%). In addition, psilocybin has demonstrated a favorable safety profile without toxicity reports and no significant adverse effects even at the highest dose tested (0.6 mg/kg) [115]. Moreover, in the follow-up studies after therapeutic intervention with psilocybin, 94% of the healthy participants reported beneficial effects described as a life-changing experience, as well as improvements in mood, mindset, gratification, and social relationships [82,116]. ...
Neuropsychiatric diseases such as depression, anxiety, and post-traumatic stress represent a substantial long-term challenge for the global health systems because of their rising prevalence, uncertain neuropathology, and lack of effective pharmacological treatments. The approved existing studies constitute a piece of strong evidence whereby psychiatric drugs have shown to have unpleasant side effects and reduction of sustained tolerability, impacting patients’ quality of life. Thus, the implementation of innovative strategies and alternative sources of bioactive molecules for the search for neuropsychiatric agents are required to guarantee the success of more effective drug candidates. Psychotherapeutic use of indole alkaloids derived from magic mushrooms has shown great interest and potential as an alternative to the synthetic drugs currently used on the market. The focus on indole alkaloids is linked to their rich history, their use as pharmaceuticals, and their broad range of biological properties, collectively underscoring the indole heterocycle as significant in drug discovery. In this review, we aim to report the physicochemical and pharmacological characteristics of indole alkaloids, particularly those derived from magic mushrooms, highlighting the promising application of such active ingredients as safe and effective therapeutic agents for the treatment of neuropsychiatric disorders.
... Among other medicinal treatments, psilocybin can be one of the new therapeutic methods. These, because they are metabolized into psilocin after ingestion, must be taken as a prodrug (Brown et al., 2017). Following some studies conducted, psilocybin does not present a substance with high risks of addiction or serious adverse reactions, but its consumption for therapeutic purposes is indicated to be done under the observation of a doctor (Barrett et al., 2018). ...
The therapeutic use of the substance psilocin produced by the fungi from the genus named Psilocybe has been an interesting but also controversial topic of discussion among researchers since the 1950s until now. These fungi can synthesize several alkaloids such as psilocybin, which has hallucinogenic properties, but also muscarine, which is a toxic substance that stimulates that part of the nervous system called parasympathetic. The use of psilocybin in therapy has been spreading for several decades from America, spreading all over the western world. For the first time, the substance was isolated from a species called Psilocybe mexicana mushroom, but then more than 30 such species were discovered. Psilocybin mushrooms were used by the Aztec shamans in healing, religious and divinatory rituals, but also by the Mesoamerican populations. This natural organic compound is derived from the substance dimethyltryptamine phosphate which is known to be a brain stimulant, and which is found in more than 200 species of mushrooms of the Psilocybe genus. The liver breaks down psilocybin through the phosphorylation process resulting in psilocin, the substance that causes the psychoactive effect. Because the substance is used for relaxing the nervous system, its introduction into medicine and psychotherapy has brought great controversies until now.
... However, this method is not feasible in cases of unconventional relationships between body size and pharmacokinetics. As an example, psilocin has an elimination half-life of approximately 150 minutes in rats (Chen et al., 2011), approximately 180 minutes in humans (Brown et al., 2017), while some report even shorter half-lives in humans (Passie et al., 2002). ...
Psychedelic-assisted psychotherapy holds great promise in the treatment of mental health disorders. Research into 5-hydroxytryptamine 2A receptor (5-HT2AR) agonist psychedelic compounds has increased dramatically over the past two decades. In humans, these compounds produce drastic effects on consciousness, and their therapeutic potential relates to changes in the processing of emotional, social, and self-referential information. The use of animal behavior to study psychedelics is under debate, and this review provides a critical perspective on the translational value of animal behavior studies in psychedelic research. Acute activation of 5-HT2ARs produces head twitches and unique discriminative cues, disrupts sensorimotor gating, and stimulates motor activity while inhibiting exploration in rodents. The acute treatment with psychedelics shows discrepant results in conventional rodent tests of depression-like behaviors but generally induces anxiolytic-like effects and inhibits repetitive behavior in rodents. Psychedelics impair waiting impulsivity but show discrepant effects in other tests of cognitive function. Tests of social interaction also show conflicting results. Effects on measures of time perception depend on the experimental schedule. Lasting or delayed effects of psychedelics in rodent tests related to different behavioral domains appear to be rather sensitive to changes in experimental protocols. Studying the effects of psychedelics on animal behaviors of relevance to effects on psychiatric symptoms in humans, assessing lasting effects, publishing negative findings, and relating behaviors in rodents and humans to other more translatable readouts, such as neuroplastic changes, will improve the translational value of animal behavioral studies in psychedelic research. SIGNIFICANCE STATEMENT: Psychedelics like LSD and psilocybin have received immense interest as potential new treatments of psychiatric disorders. Psychedelics change high-order consciousness in humans, and there is debate about the use of animal behavior studies to investigate these compounds. This review provides an overview of the behavioral effects of 5-HT2AR agonist psychedelics in laboratory animals and discusses the translatability of the effects in animals to effects in humans. Possible ways to improve the utility of animal behavior in psychedelic research are discussed.
... To facilitate the data classification, and tabulation, we used a label that contains information about (1) the durability (short-term or long-term assessment, see below) and, if applicable, (2) the directionality of the outcome measure, i.e., an increase or decrease of a scale that assesses the psilocybin-induced changes on a given domain and construct. Outcomes were considered short term if they were taken within 24 hours of drug administration, and long term if the assessment extended beyond this period considering the clearance of psilocybin in humans [25]. The directionality of the findings was defined on a case-by-case basis and according to the associated domain and construct. ...
Background
Preliminary results from randomized controlled studies as well as identified molecular, cellular, and circuit targets of select psychedelics (e.g., psilocybin) suggest that their effects are transdiagnostic. In this review, we exploit the Research Domain Criteria (RDoC) transdiagnostic framework, to synthesize extant literature on psilocybin.Objective
We aimed to identify RDoC-based effects of psilocybin and vistas for future mechanistic and interventional research.MethodsA systematic search in electronic databases (i.e., PubMed, Scopus, PsycINFO, and Web of Science) performed in January and February 2021 identified English articles published between 1990 and 2020 reporting the effects of psilocybin on mental health measures. Data from included articles were retrieved and organized according to the RDoC bio-behavioral matrix and its constituent six main domains, namely: positive valence systems, negative valence systems, cognitive systems, social processes, sensorimotor systems, and arousal and regulatory systems.ResultsThe preponderance of research with psilocybin has differentially reported beneficial effects on positive valence systems, negative valence system, and social process domains. The data from the included studies support both short-term (23 assessments) and long-term (15 assessments) beneficial effects of psilocybin on the positive valence systems. While 12 of the extracted outcome measures suggest that psilocybin use is associated with increases in the “fear” construct of the negative valence systems domain, 19 findings show no significant effects on this construct, and seven parameters show lowered levels of the “sustained threat” construct in the long term. Thirty-four outcome measures revealed short-term alterations in the social systems’ construct namely, “perception and understanding of self,” and “social communications” as well as enhancements in “perception and understanding of others” and “affiliation and attachment”. The majority of findings related to the cognitive systems’ domain reported dyscognitive effects. There have been relatively few studies reporting outcomes of psilocybin on the remaining RDoC domains. Moreover, seven of the included studies suggest the transdiagnostic effects of psilocybin. The dashboard characterization of RDoC outcomes with psilocybin suggests beneficial effects in the measures of reward, threat, and arousal, as well as general social systems.Conclusions
Psilocybin possesses a multi-domain effectiveness. The field would benefit from highly rigorous proof-of-mechanism research to assess the effects of psilocybin using the RDoC framework. The combined effect of psilocybin with psychosocial interventions with RDoC-based outcomes is a priority therapeutic vista.
... A pharmacokinetic study showed no significant difference in blood or urine levels of psilocyn (the active metabolite of psilocybin) whether the dose was weight adjusted or not (0.3 mg/kg or 25 mg) [23]. Using a single dosage would simplify both research protocols and routine use. ...
Purpose of the Review
We aim to provide an overview of the current state of knowledge about the efficacy of psilocybin in the treatment of depression, as well as its mechanisms of action.
Recent Findings
Psilocybin has a large, rapid, and persistent clinical effect in the treatment of resistant or end-of-life depression. Tolerance is good, with mild side effects limited to a few hours after dosing. The studies conducted to date have had small sample sizes. One clinical trial has been conducted against a reference treatment (escitalopram) without showing a significant superiority of psilocybin in the main outcome. The neurobiological mechanisms, mostly unknown, differ from those of SSRI antidepressants.
Summary
Psilocybin represents a promising alternative in the treatment of depression. Further research with larger sample sizes, particularly against reference treatments, is needed to better understand the neurobiological factors of its effects and to investigate its potential for use in everyday practice.
... 20 to 40 mg p.o. (approx. 0.3 to 0.6 mg/kg) with effects lasting about 3 to 6 h (Brown et al., 2017a). The LD 50 in mice is 280 mg/kg, and very rare overdose-related deaths in humans were mostly linked to accidents after increased risk-taking under influence of the drug (Passie et al., 2002;Schlag et al., 2022). ...
This is a narrative review about the role of classic and two atypical psychedelics in the treatment of unipolar and bipolar depression. Since the 1990s, psychedelics experience a renaissance in biomedical research. The so-called classic psychedelics include lysergic acid diethylamide (LSD), psilocybin, mescaline and ayahuasca. Characteristic effects like alterations in sensory perception, as well as emotion- and self-processing are induced by stimulation of serotonin 2A receptors in cortical areas. The new paradigm of psychedelic-assisted psychotherapy suggests a therapeutic framework in which a safely conducted psychedelic experience is integrated into a continuous psychotherapeutic process. First randomized, controlled trials with psilocybin show promising efficacy, tolerability, and adherence in the treatment of unipolar depression. On the other hand, classic psychedelics seem to be associated with the induction of mania, which is an important issue to consider for the design of research and clinical protocols. So called atypical psychedelics are a heterogeneous group with overlapping subjective effects but different neurobiological mechanisms. Two examples of therapeutic value in psychiatry are 3,4-methyl enedioxy methamphetamine (MDMA) and ketamine. Since 2020 the ketamine enantiomer esketamine has been granted international approval for treatment-resistant unipolar depression, and also first evidence exists for the therapeutic efficacy of ketamine in bipolar depression. Whether psychedelics will fulfil current expectations and find their way into broader clinical use will depend on future rigorous clinical trials with larger sample sizes. A well-considered therapeutic and legal framework will be crucial for these substances to create new treatment settings and a potential paradigm shift.
... Each resting-state scan was acquired with eyes closed using echo planar imaging (axial acquisition, 3 mm isotropic voxel size, 1 mm slice gap, 37 ascending slices, 210 volumes retained for analysis, TR of 2.2s, TE of 30 ms, sense acceleration factor of 2, and four initial TRs discarded for magnetization equilibrium; total analyzed scan time was 7 min and 42 sec). The timing of scanning procedures coincided with peak subjective effects ( Griffiths et al., 2011 ) and expected peak plasma concentration of this dose of psilocybin ( Brown et al., 2017 ). Immediately before each resting-state scan in both Phase 1 and Phase 2, participants were instructed to relax with their eyes closed, allow their mind to wander naturally, and avoid engaging in any type of meditation. ...
Background:
Classic psychedelics, such as psilocybin and LSD, and other serotonin 2A receptor (5-HT2AR) agonists evoke acute alterations in perception and cognition. Altered thalamocortical connectivity has been hypothesized to underlie these effects, which is supported by some functional MRI (fMRI) studies. These studies have treated the thalamus as a unitary structure, despite known differential 5-HT2AR expression and functional specificity of different intrathalamic nuclei. Independent Component Analysis (ICA) has been previously used to identify reliable group-level functional subdivisions of the thalamus from resting-state fMRI (rsfMRI) data. We build on these efforts with a novel data-maximizing ICA-based approach to examine psilocybin-induced changes in intrathalamic functional organization and thalamocortical connectivity in individual participants.
Methods:
Baseline rsfMRI data (n=38) from healthy individuals with a long-term meditation practice was utilized to generate a statistical template of thalamic functional subdivisions. This template was then applied in a novel ICA-based analysis of the acute effects of psilocybin on intra- and extra-thalamic functional organization and connectivity in follow-up scans from a subset of the same individuals (n=18). We examined correlations with subjective reports of drug effect and compared with a previously reported analytic approach (treating the thalamus as a single functional unit).
Results:
Several intrathalamic components showed significant psilocybin-induced alterations in spatial organization, with effects of psilocybin largely localized to the mediodorsal and pulvinar nuclei. The magnitude of changes in individual participants correlated with reported subjective effects. These components demonstrated predominant decreases in thalamocortical connectivity, largely with visual and default mode networks. Analysis in which the thalamus is treated as a singular unitary structure showed an overall numerical increase in thalamocortical connectivity, consistent with previous literature using this approach, but this increase did not reach statistical significance.
Conclusions:
We utilized a novel analytic approach to discover psilocybin-induced changes in intra- and extra-thalamic functional organization and connectivity of intrathalamic nuclei and cortical networks known to express the 5-HT2AR. These changes were not observed using whole-thalamus analyses, suggesting that psilocybin may cause widespread but modest increases in thalamocortical connectivity that are offset by strong focal decreases in functionally relevant intrathalamic nuclei.
... 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). ...
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. ...
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.
... Psilocybin is rapidly dephosphorylated to psilocin, an unspeci c serotonin agonist 11,12 , where signaling through the 5-hydroxytryptamine (5-HT) 2A receptor is believed to be responsible for hallucinogenesis 13 . Psilocybin has, in line with the other psychedelic substances, a favorable safety pro le, including non-addictive properties and a large margin of exposure, compared to most central nervous system (CNS)-active drugs [13][14][15][16] . ...
Psilocybin is a psychedelic substance approaching clinical use. The drug has long-lasting effects after single or multiple administrations and enhances structural plasticity in the brain. Little is known if the plasticity inducing effects of psilocybin could be timed to other treatments and promote a larger effect. We investigated the effect of psilocybin on cultured mouse hippocampal neurons, examining the plasticity promoting effects from 5 min to 72 h post-treatment. We found robust effects on pre- and postsynaptic (Piccolo and Homer1) protein expression 1-3 h following treatment. Presynaptic Synapsin-1 expression mirrored these findings, with peak expression 72 h post-treatment. Our studies suggest psilocybin opens a window of plasticity that rapidly normalizes. As psilocybin has been shown to have an effect treating diseases (e.g. depression and cluster headache) linked with inflammation, we used an immortalized microglia cell line (IMG) to demonstrate its anti-inflammatory effects against a lipopolysaccharide (LPS) challenge (we show reduced tumor necrosis factor-alpha (TNF-α) secretion). Altogether, our studies show discrete and acute cell type specific effects of psilocybin that provides insight into its mechanisms of action and potential therapeutic value.
... 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). ...
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.
... Each resting-state scan was acquired with eyes closed using echo planar imaging (axial acquisition, 3 mm isotropic voxel size, 1 mm slice gap, 37 ascending slices, 210 volumes retained for analysis, TR of 2.2s, TE of 30 ms, sense acceleration factor of 2, and four initial TRs dis-carded for magnetization equilibrium; total analyzed scan time was 7 min and 42s). The timing of scanning procedures coincided with peak subjective effects (Griffiths et al., 2006(Griffiths et al., , 2011Carbonaro et al., 2018) and expected peak plasma concentration of this dose of psilocybin (Brown et al., 2017). Participants were instructed to not meditate during task-free scans, and had experience completing resting-state scans following this instruction on at least one previous occasion. ...
Background
Serotonin 2A receptor (5-HT 2AR ) agonist psychedelics including psilocybin and LSD (“classic” psychedelics) evoke acute alterations in perception and cognition. Altered thalamocortical connectivity has been proposed to underlie these effects, which is supported by some functional MRI (fMRI) studies. Likely due to sample size limitations, these studies have treated the thalamus as a unitary structure, despite known differential 5-HT 2AR expression and functional specificity of different intrathalamic nuclei. Independent Component Analysis (ICA) has been employed to generate functional subdivisions of the thalamus from resting state fMRI (rsfMRI) data. This report utilizes a novel data-sparing ICA approach in order to examine psilocybin-induced changes in intrathalamic functional organization and thalamocortical connectivity.
Methods
Baseline rsfMRI data (n=38) was utilized to generate a template, which was then applied in a novel ICA-based analysis of the acute effects of psilocybin on intra- and extra-thalamic functional organization and connectivity in a smaller sample (n=18). Correlations with subjective reports of drug effect and comparisons with a previously reported analytic approach (treating the thalamus as a single functional unit) were conducted.
Results
Several intrathalamic components showed significant psilocybin-induced alterations in intrathalamic spatial organization, largely localized to the mediodorsal and pulvinar nuclei, and correlated with reported subjective effects. These same components demonstrated alterations in thalamocortical connectivity, largely with visual and default mode networks. Analysis in which the thalamus is treated as a singular unitary structure showed an overall numerical increase in thalamocortical connectivity, consistent with previous literature using this approach, but this increase did not reach statistical significance.
Conclusions
Utilization of a novel analytic approach demonstrated changes in intra- and extra-thalamic functional organization and connectivity of intrathalamic nuclei and cortical networks known to express the 5-HT 2AR . Given that these changes were not observed using whole-thalamus analyses, it seems that psilocybin may cause widespread but modest increases in thalamocortical connectivity that are offset by strong focal decreases in functionally relevant intrathalamic nuclei.
... 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. ...
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.
... 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]. ...
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). ...
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 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). ...
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.
... 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. ...
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.
... 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]. ...
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.
Psilocybin, a psychoactive alkaloid with hallucinogenic properties, exists in a variety of hallucinogenic mushrooms. As a study tool to imitate psychosis, psilocybin has aroused a lot of interest in the biological community due to its various possible therapeutic benefits. It is also a very popular and widely misused natural hallucinogens with distinct metabolism pathways and toxicity. In this paper, the metabolism and mechanism of psilocybin were summarized, and the toxicology and pharmacology of psilocybin were discussed in detail, and the positive effects of psilocybin on psychological illnesses like depression, addiction, anxiety, and obsessive-compulsive disorder were gathered and sorted out, and the drug's therapeutic potential for mental and psychological illnesses was systematically clarified. Understanding the mechanism and therapeutic ability of psilocybin is of great significance to its potential development. As a hallucinogenic agent with low toxicity and no side effects, its effective application in the treatment of psychological and mental diseases can provide new ideas for the treatment of various diseases.
Hallucinogenic mushrooms have been used in religious and cultural ceremonies for centuries. Of late, psilocybin, the psychoactive compound in hallucinogenic mushrooms, has received increased public interest as a novel drug for treating mood and substance use disorders (SUDs). In addition, in recent years, some states in the United States have legalized psilocybin for medical and recreational use. Given this, clinicians need to understand the potential benefits and risks related to using psilocybin for therapeutic purposes so that they can accurately advise patients. This expert narrative review summarizes the scientific basis and clinical evidence on the safety and efficacy of psilocybin-assisted therapy for treating psychiatric disorders and SUDs. The results of this review are structured as a more extensive discussion about psilocybin’s history, putative mechanisms of action, and recent legislative changes to its legal status. There is modest evidence of psilocybin-assisted therapy for treating depression and anxiety disorders. In addition, early data suggest that psilocybin-assisted therapy may effectively reduce harmful drinking in patients with alcohol use disorders. The evidence further suggests psilocybin, when administered under supervision (psilocybin-assisted therapy), the side effects experienced are mild and transient. The occurrence of severe adverse events following psilocybin administration is uncommon. Still, a recent clinical trial found that individuals in the psilocybin arm had increased suicidal ideations and non-suicidal self-injurious behaviors. Given this, further investigation into the safety and efficacy of psilocybin-assisted therapy is warranted to determine which patient subgroups are most likely to benefit and which are most likely to experience adverse outcomes related to its use.
Psychedelic microdosing is the practice of taking very low doses of psychedelic substances, typically over a longer period of time. The long-term safety of chronic microdosing is relatively uncharacterized, but valvular heart disease (VHD) has been proposed as a potential risk due to activation of the serotonin 5-HT 2B receptor. However, this risk has not yet been comprehensively assessed. This analysis searched for all relevant in vitro, animal, and clinical studies related to the VHD risk of lysergic acid diethylamide (LSD), psilocybin, mescaline, N,N-dimethyltryptamine (DMT), and the non-psychedelic 3,4-methylenedioxymethamphetamine (MDMA). All five compounds and some metabolites could bind to the 5-HT 2B receptor with potency equal to or greater than that of the 5-HT 2A receptor, the primary target of psychedelics. All compounds were partial agonists at the 5-HT 2B receptor with the exception of mescaline, which could not be adequately assessed due to low potency. Safety margins relative to the maximum plasma concentrations from typical microdoses were greater than known valvulopathogens, but not without potential risk. No animal or clinical studies appropriately designed to evaluate VHD risk were found for the four psychedelics. However, there is some clinical evidence that chronic ingestion of full doses of MDMA is associated with VHD. We conclude that VHD is a potential risk with chronic psychedelic microdosing, but further studies are necessary to better define this risk.
The human uses of mushrooms and cultured mycelium products for nutrition and medicine are detailed and supported by available human studies, which in many cases are clinical trials published in peer-reviewed journals. The major medically active immunomodulating compounds in the cell walls-chitin, beta-glucans, and glycoproteins, as well as lower weight molecules-nitrogen-containing compounds, phenolics, and terpenes-are discussed in relation to their current clinical uses. The nutritional content and foods derived from mushrooms, particularly related to their medical benefits, are discussed. High-quality major nutrients such as the high amounts of complete protein and prebiotic fibers found in edible and medicinal fungi and their products are presented. Mushrooms contain the highest amount of valuable medicinal fiber, while dried fruiting bodies of some fungi have up to 80% prebiotic fiber. These fibers are particularly complex and are not broken down in the upper gut, so they can diversify the microbiome and increase the most beneficial species, leading to better immune regulation and increasing normalizing levels of crucial neurotransmitters like serotonin and dopamine. Since the growth of medicinal mushroom products is expanding rapidly worldwide, attention is placed on reviewing important aspects of mushroom and mycelium cultivation and quality issues relating to adulteration, substitution, and purity and for maximizing medicinal potency. Common questions surrounding medicinal mushroom products in the marketplace, particularly the healing potential of fungal mycelium compared with fruiting bodies, extraction methods, and the use of fillers in products, are all explored, and many points are supported by the literature.
Psilocybin is the psychoactive substance contained in the psilocybe (hallucinogenic) mushroom, which has received considerable attention among the scientific community in recent years. Human studies have demonstrated that even a single-dose of psilocybin can improve debilitating physical and psychological symptoms with durable long-term effects. >136 clinical studies with psilocybin have been completed or are ongoing for various indications, including psychiatric, neurodegenerative, chronic pain, and more. However, despite considerable clinical evidence for the therapeutic effects, the underlying molecular mechanisms responsible for its beneficial actions remain enigmatic. Studies with psilocybin have overwhelmingly focused on neurological impacts and/or behavioral outcomes; however, few studies have evaluated other mechanisms by which it exerts beneficial effects. It has recently been hypothesized that psilocybin may exert beneficial effects on aging; however, no studies have experimentally investigated the impact of psilocybin on senescence/aging. Using a previously validated human cell model of replicative senescence in vitro , cells were treated with psilocybin continuously throughout their replicative cellular lifecycle. Psilocybin treatment led to a dose-dependent decrease in cell-cycle arrest markers, increased markers of DNA replication and proliferation, reduced senescence-associated secretory phenotype (SASP), and reduced oxidative stress levels. Further, psilocybin did not demonstrate senolytic activity. Overall, these data are the first experimental evidence suggesting that psilocybin may decelerate the process of cellular senescence. Given that senescence and inflammation contribute to the pathogenesis of numerous age-related diseases, these studies could lay the foundation for the use of psilocybin as a therapeutic strategy for many age-related disease indications and/or as a geroprotective agent.
2,5-dimethoxy-4-bromophenethylamine (2C-B) is a hallucinogenic phenethylamine derived from mescaline. Observational and preclinical data have suggested it to be capable of producing both subjective and emotional effects on par with other classical psychedelics and entactogens. Whereas it is the most prevalently used novel serotonergic hallucinogen to date, it′s acute effects and distinctions from classical progenitors have yet to be characterised in a controlled study. We assessed for the first time the immediate acute subjective, cognitive, and cardiovascular effects of 2C-B (20 mg) in comparison to psilocybin (15mg) and placebo in a within-subjects, double-blind, placebo-controlled study of 22 healthy psychedelic-experienced participants. 2C-B elicited alterations of waking consciousness of a psychedelic nature, with dysphoria, subjective impairment, auditory alterations, and affective elements of ego dissolution largest under psilocybin. Participants demonstrated equivalent psychomotor slowing and spatial memory impairments under either compound compared to placebo, as indexed by the Digit Symbol Substitution Test (DSST), Tower of London (TOL) and Spatial Memory Task (SMT). Neither compound produced empathogenic effects on the Multifaceted Empathy Test (MET). 2C-B induced transient pressor effects to a similar degree as psilocybin. The duration of self-reported effects of 2C-B was shorter than that of psilocybin, largely resolving within 6 hours. Present findings support the categorisation of 2C-B as a subjectively ″lighter″ psychedelic. Tailored dose-effect studies are needed to discern the pharmacokinetic dependency of 2C-B′s experiential overlaps.
The classical psychedelic psilocybin is of interest as a treatment for alcohol use disorder (AUD). This study investigated the effects of psilocybin on voluntary ethanol consumption in adult male and female C57BL/6J mice administered saline or psilocybin intraperitoneally as a single dose of 0.1, 0.5, 1.0 or 2.0 mg/kg and provided 20% ethanol utilizing a two-bottle choice alcohol drinking paradigm. Ethanol was provided continuously for 3 days immediately following the administration of psilocybin, then withheld for 2 days, and then provided continuously for two subsequent additional days. A multilevel model (MLM) for repeated measures was used to compare ethanol consumption and preference in psilocybin-treated groups versus controls. Ethanol consumption and preference were reduced in male mice during the 3-day interval that immediately followed psilocybin administration. The effect of psilocybin on ethanol consumption was dose-related and was consistent across the 3-day interval at dosages of 0.5 mg/kg or greater. Psilocybin had no effect on consumption or preference when ethanol was subsequently reintroduced after 2 days of withdrawal. In contrast to males, psilocybin had no significant effect on ethanol consumption or preference in female mice at any dosage or time point. The lack of an effect of psilocybin on quinine preference, and its limited interaction with locomotor activity indicated that the observed reduction in voluntary ethanol consumption was not attributable to altered taste perception or motor effects. Total fluid consumption was increased in males at some time points and psilocybin dosages and unchanged in females, and the absence of any decrease in either group at any time point indicated that the observed reduction in ethanol consumption was not mediated by nonspecific effects on consummatory behavior. The finding of a sex-dependent effect of psilocybin on ethanol consumption suggests that the C57BL/6J mouse may provide a useful experimental approach to modeling sex differences in vulnerability to AUD in addition to investigation of the neurobiological basis of the effect of classical psychedelics on alcohol drinking behavior.
Hallucinogens have a long history as therapeutic agents. After the synthesis of lysergic acid diethylamide (LSD) in 1938 by Albert Hofmann, the popularity of classical hallucinogens with psychedelic properties increased among scientists, psychiatrists, neurologists, and psychotherapists. Research in the 1950s and 1960s showed great promise for the use of psychedelics in medical research and treatment. Psychedelics are characterized by their mind revealing effects, which are valuable in the treatment of major depressive disorder (MDD) and of stress- and trauma-related mental disorders (PTSD). However, research into the therapeutic uses of psychedelics became restricted, in part due to their classification as drugs with abuse potential in the mid-1960s. In the past decade, psychedelic research has been reestablished among several groups around the world (Nutt, Erritzoe, and Carhart-Harris, Cell181 (1):24–28, 2020). There is growing anticipation, awareness, and hope for the potential of these substances to become medically approved as psychoactive treatments (Belouin and Henningfield, Neuropharmacology 142:7–19, 2018). In this chapter, we offer a historical overview of psychedelic drugs and their uses and a discussion of chemical and pharmacological properties, mechanisms of action, clinical studies, adverse effects, and psychotherapeutic combination therapies with hallucinogens.
Several lines of evidence suggest that classic psychedelics (5-HT2A receptor agonists or partial agonists) such as psilocybin might facilitate behavior change in individuals with substance use disorders. We conducted a multi-site, double-blind, randomized controlled trial (RCT) to assess the effects of psilocybin-assisted psychotherapy in alcohol-dependent volunteers. In addition to a structured 12-week psychotherapy platform, participants (n = 96) were randomly assigned (1:1) to receive either oral psilocybin or an active placebo (oral diphenhydramine) in each of two dosing sessions (at weeks 4 and 8). Initial doses were 25 mg/70 kg psilocybin or 50 mg diphenhydramine, which could be increased in the second session depending on initial response. The psychotherapy platform combined evidence-based, manualized therapy for alcohol dependence with a supportive context for the dosing sessions. All participants were followed in the RCT through week 36. At the end of the RCT, participants who still met safety criteria were offered an open-label psilocybin session. Data collected at screening, baseline and throughout the study included: demographics, measures of alcohol use, subjective response to psilocybin and diphenhydramine, and safety measures. The primary outcome was the proportion of heavy drinking days during the 32 weeks after the first dosing session (i.e., between week 4 and week 36). Secondary outcomes included safety, additional measures of drinking (e.g., abstinence, drinking days, etc.), craving, self-efficacy, and acute effects. We will also explore moderators and mediators of the primary outcome. The primary outcomes will be published elsewhere. In this paper, we describe the protocol and rationale for our design decisions.
To date, the clinical and scientific literature has best documented the effects of classical psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, and dimethyltryptamine (DMT), in typical quantities most often associated with macrodosing. More recently, however, microdosing with psychedelics has emerged as a social trend and nascent therapeutic intervention. This variation in psychedelic practice refers to repeat, intermittent ingestion of less-than-macrodose amounts that do not cause the effects associated with full-blown “trips”. Microdosing paves the road to incorporating psychedelic drugs into a daily routine while maintaining, or even improving, cognitive and mental function. Unlike macrodosing with psychedelics, the influence of microdosing remains mostly unexplored. And yet, despite the paucity of formal studies, many informal accounts propose that microdosing plays an important role as both a therapeutic intervention (e.g., in mental disorders) and enhancement tool (e.g., recreationally—to boost creativity, improve cognition, and drive personal growth). In response to this relatively new practice, we provide an integrative synthesis of the clinical, social, and cultural dimensions of microdosing. We describe some of the overarching context that explains why this practice is increasingly in vogue, unpack potential benefits and risks, and comment on sociocultural implications. In addition, this article considers the effects that macro- and microdoses have on behavior and psychopathology in light of their dosage characteristics and contexts of use.
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.
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.
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.
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
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.
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
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.
RationaleLysergic acid diethylamide (LSD) is used recreationally and in clinical research. Acute mystical-type experiences that are acutely induced by hallucinogens are thought to contribute to their potential therapeutic effects. However, no data have been reported on LSD-induced mystical experiences and their relationship to alterations of consciousness. Additionally, LSD dose- and concentration-response functions with regard to alterations of consciousness are lacking. Methods
We conducted two placebo-controlled, double-blind, cross-over studies using oral administration of 100 and 200 μg LSD in 24 and 16 subjects, respectively. Acute effects of LSD were assessed using the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale after both doses and the Mystical Experience Questionnaire (MEQ) after 200 μg. ResultsOn the MEQ, 200 μg LSD induced mystical experiences that were comparable to those in patients who underwent LSD-assisted psychotherapy but were fewer than those reported for psilocybin in healthy subjects or patients. On the 5D-ASC scale, LSD produced higher ratings of blissful state, insightfulness, and changed meaning of percepts after 200 μg compared with 100 μg. Plasma levels of LSD were not positively correlated with its effects, with the exception of ego dissolution at 100 μg. Conclusions
Mystical-type experiences were infrequent after LSD, possibly because of the set and setting used in the present study. LSD may produce greater or different alterations of consciousness at 200 μg (i.e., a dose that is currently used in psychotherapy in Switzerland) compared with 100 μg (i.e., a dose used in imaging studies). Ego dissolution may reflect plasma levels of LSD, whereas more robustly induced effects of LSD may not result in such associations.
Acute and enduring adverse effects of psilocybin have been reported anecdotally, but have not been well characterized. For this study, 1993 individuals (mean age 30 yrs; 78% male) completed an online survey about their single most psychologically difficult or challenging experience (worst “bad trip”) after consuming psilocybin mushrooms. Thirty-nine percent rated it among the top five most challenging experiences of his/her lifetime. Eleven percent put self or others at risk of physical harm; factors increasing the likelihood of risk included estimated dose, duration and difficulty of the experience, and absence of physical comfort and social support. Of the respondents, 2.6% behaved in a physically aggressive or violent manner and 2.7% received medical help. Of those whose experience occurred >1 year before, 7.6% sought treatment for enduring psychological symptoms. Three cases appeared associated with onset of enduring psychotic symptoms and three cases with attempted suicide. Multiple regression analysis showed degree of difficulty was positively associated, and duration was negatively associated, with enduring increases in well-being. Difficulty of experience was positively associated with dose. Despite difficulties, 84% endorsed benefiting from the experience. The incidence of risky behavior or enduring psychological distress is extremely low when psilocybin is given in laboratory studies to screened, prepared, and supported participants.
Background:
Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression.
Methods:
In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797.
Findings:
Psilocybin's acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0-1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS difference -11·8, 95% CI -9·15 to -14·35, p=0·002, Hedges' g=3·1) and 3 months (-9·2, 95% CI -5·69 to -12·71, p=0·003, Hedges' g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted.
Interpretation:
This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach.
Funding:
Medical Research Council.
Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. Two small pilot studies of psilocybinassisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen level–dependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain’s default mode network. © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
Least-squares means are predictions from a linear model, or averages thereof. They are useful in the analysis of experimental data for summarizing the effects of factors, and for testing linear contrasts among predictions. The lsmeans package (Lenth 2016) provides a simple way of obtaining least-squares means and contrasts thereof. It supports many models fitted by R (R Core Team 2015) core packages (as well as a few key contributed ones) that fit linear or mixed models, and provides a simple way of extending it to cover more model classes.
Lack of a general matrix formula hampers implementation of the semi-partial correlation, also known as part correlation, to the higher-order coefficient. This is because the higher-order semi-partial correlation calculation using a recursive formula requires an enormous number of recursive calculations to obtain the correlation coefficients. To resolve this difficulty, we derive a general matrix formula of the semi-partial correlation for fast computation. The semi-partial correlations are then implemented on an R package ppcor along with the partial correlation. Owing to the general matrix formulas, users can readily calculate the coefficients of both partial and semi-partial correlations without computational burden. The package ppcor further provides users with the level of the statistical significance with its test statistic.
The 30-item revised Mystical Experience Questionnaire (MEQ30) was previously developed within an online survey of mystical-type experiences occasioned by psilocybin-containing mushrooms. The rated experiences occurred on average eight years before completion of the questionnaire. The current paper validates the MEQ30 using data from experimental studies with controlled doses of psilocybin. Data were pooled and analyzed from five laboratory experiments in which participants (n=184) received a moderate to high oral dose of psilocybin (at least 20 mg/70 kg). Results of confirmatory factor analysis demonstrate the reliability and internal validity of the MEQ30. Structural equation models demonstrate the external and convergent validity of the MEQ30 by showing that latent variable scores on the MEQ30 positively predict persisting change in attitudes, behavior, and well-being attributed to experiences with psilocybin while controlling for the contribution of the participant-rated intensity of drug effects. These findings support the use of the MEQ30 as an efficient measure of individual mystical experiences. A method to score a "complete mystical experience" that was used in previous versions of the mystical experience questionnaire is validated in the MEQ30, and a stand-alone version of the MEQ30 is provided for use in future research.
Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms.
NCT02061293.
© The Author(s) 2015.
After no research in humans for >40 years, there is renewed interest in using lysergic acid diethylamide (LSD) in clinical psychiatric research and practice. There are no modern studies on the subjective and autonomic effects of LSD, and its endocrine effects are unknown. In animals, LSD disrupts prepulse inhibition (PPI) of the acoustic startle response, and patients with schizophrenia exhibit similar impairments in PPI. However, no data are available on the effects of LSD on PPI in humans.
In a double-blind, randomized, placebo-controlled, crossover study, LSD (200 μg) and placebo were administered to 16 healthy subjects (8 women, 8 men). Outcome measures included psychometric scales; investigator ratings; PPI of the acoustic startle response; and autonomic, endocrine, and adverse effects.
Administration of LSD to healthy subjects produced pronounced alterations in waking consciousness that lasted 12 hours. The predominant effects induced by LSD included visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization phenomena. Subjective well-being, happiness, closeness to others, openness, and trust were increased by LSD. Compared with placebo, LSD decreased PPI. LSD significantly increased blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine. Adverse effects produced by LSD completely subsided within 72 hours. No severe acute adverse effects were observed.
In addition to marked hallucinogenic effects, LSD exerts methylenedioxymethamphetamine-like empathogenic mood effects that may be useful in psychotherapy. LSD altered sensorimotor gating in a human model of psychosis, supporting the use of LSD in translational psychiatric research. In a controlled clinical setting, LSD can be used safely, but it produces significant sympathomimetic stimulation.
Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Despite suggestive early findings on the therapeutic use of hallucinogens in the treatment of substance use disorders, rigorous follow-up has not been conducted. To determine the safety and feasibility of psilocybin as an adjunct to tobacco smoking cessation treatment we conducted an open-label pilot study administering moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin within a structured 15-week smoking cessation treatment protocol. Participants were 15 psychiatrically healthy nicotine-dependent smokers (10 males; mean age of 51 years), with a mean of six previous lifetime quit attempts, and smoking a mean of 19 cigarettes per day for a mean of 31 years at intake. Biomarkers assessing smoking status, and self-report measures of smoking behavior demonstrated that 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up. The observed smoking cessation rate substantially exceeds rates commonly reported for other behavioral and/or pharmacological therapies (typically <35%). Although the open-label design does not allow for definitive conclusions regarding the efficacy of psilocybin, these findings suggest psilocybin may be a potentially efficacious adjunct to current smoking cessation treatment models. The present study illustrates a framework for future research on the efficacy and mechanisms of hallucinogen-facilitated treatment of addiction.
Life-review interventions (LRI) are psychotherapeutic techniques originally derived from gerontology, which can be distinguished from other biographical and reminiscing techniques. They have been systematically implemented and investigated not only in elderly clients with depression, cognitive decline, in oncology units and in hospices but also in adolescents with various mental problems. LRI are mainly based on the elaboration of the autobiographical memory as well as on personal identity consolidation. This bears the potential for the systematic introduction, use, and evaluation of LRI within the field of psychotraumatology.
This article gives a general overview and outlines a structured LRI by means of a case example of a World War II-traumatised patient. Other applications and implementations of LRI in psychotraumatology and other related areas are presented.
So far, only uncontrolled or controlled LRI case studies have been investigated with traumatized samples.
The importance of further randomized controlled studies is emphasized.
Although psilocybin has been used for centuries for religious purposes, little is known scientifically about its acute and persisting effects.
This double-blind study evaluated the acute and longer-term psychological effects of a high dose of psilocybin relative to a comparison compound administered under comfortable, supportive conditions.
The participants were hallucinogen-naïve adults reporting regular participation in religious or spiritual activities. Two or three sessions were conducted at 2-month intervals. Thirty volunteers received orally administered psilocybin (30 mg/70 kg) and methylphenidate hydrochloride (40 mg/70 kg) in counterbalanced order. To obscure the study design, six additional volunteers received methylphenidate in the first two sessions and unblinded psilocybin in a third session. The 8-h sessions were conducted individually. Volunteers were encouraged to close their eyes and direct their attention inward. Study monitors rated volunteers' behavior during sessions. Volunteers completed questionnaires assessing drug effects and mystical experience immediately after and 2 months after sessions. Community observers rated changes in the volunteer's attitudes and behavior.
Psilocybin produced a range of acute perceptual changes, subjective experiences, and labile moods including anxiety. Psilocybin also increased measures of mystical experience. At 2 months, the volunteers rated the psilocybin experience as having substantial personal meaning and spiritual significance and attributed to the experience sustained positive changes in attitudes and behavior consistent with changes rated by community observers.
When administered under supportive conditions, psilocybin occasioned experiences similar to spontaneously occurring mystical experiences. The ability to occasion such experiences prospectively will allow rigorous scientific investigations of their causes and consequences.
Studied the effectiveness of having a "peak experience" in the process of psychotherapy with 34 terminal cancer patients. The peak experience, a radically altered form of consciousness involving profoundly positive feelings, was produced by administering 75–227.5 mg of dipropyltryptamine (DPT). Assessment with 2 sets of questionnaires indicated that the peak experience occurred in 15 patients (peakers). Retrospective examination of the patients' records indicated that the peakers had been more distressed than nonpeakers prior to the therapy. After having the experience, the patients showed marked relief from distress, as indicated by a number of tests, questionnaires, and interviews with the therapists. However, ratings before and after the therapy made by 2 social workers, who had not been informed about the purpose and method of the therapy, did not indicate any significant effect of the therapy, either in the peakers or nonpeakers. (28 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Responses to hallucinogenic drugs, such as psilocybin, are believed to be critically dependent on the user's personality, current mood state, drug pre-experiences, expectancies, and social and environmental variables. However, little is known about the order of importance of these variables and their effect sizes in comparison to drug dose. Hence, this study investigated the effects of 24 predictor variables, including age, sex, education, personality traits, drug pre-experience, mental state before drug intake, experimental setting, and drug dose on the acute response to psilocybin. The analysis was based on the pooled data of 23 controlled experimental studies involving 409 psilocybin administrations to 261 healthy volunteers. Multiple linear mixed effects models were fitted for each of 15 response variables. Although drug dose was clearly the most important predictor for all measured response variables, several non-pharmacological variables significantly contributed to the effects of psilocybin. Specifically, having a high score in the personality trait of Absorption, being in an emotionally excitable and active state immediately before drug intake, and having experienced few psychological problems in past weeks were most strongly associated with pleasant and mystical-type experiences, whereas high Emotional Excitability, low age, and an experimental setting involving positron emission tomography most strongly predicted unpleasant and/or anxious reactions to psilocybin. The results confirm that non-pharmacological variables play an important role in the effects of psilocybin.
A large body of evidence, including longitudinal analyses of personality change, suggests that core personality traits are predominantly stable after age 30. To our knowledge, no study has demonstrated changes in personality in healthy adults after an experimentally manipulated discrete event. Intriguingly, double-blind controlled studies have shown that the classic hallucinogen psilocybin occasions personally and spiritually significant mystical experiences that predict long-term changes in behaviors, attitudes and values. In the present report we assessed the effect of psilocybin on changes in the five broad domains of personality - Neuroticism, Extroversion, Openness, Agreeableness, and Conscientiousness. Consistent with participant claims of hallucinogen-occasioned increases in aesthetic appreciation, imagination, and creativity, we found significant increases in Openness following a high-dose psilocybin session. In participants who had mystical experiences during their psilocybin session, Openness remained significantly higher than baseline more than 1 year after the session. The findings suggest a specific role for psilocybin and mystical-type experiences in adult personality change.
This dose-effect study extends previous observations showing that psilocybin can occasion mystical-type experiences having persisting positive effects on attitudes, mood, and behavior.
This double-blind study evaluated psilocybin (0, 5, 10, 20, 30 mg/70 kg, p.o.) administered under supportive conditions.
Participants were 18 adults (17 hallucinogen-naïve). Five 8-h sessions were conducted individually for each participant at 1-month intervals. Participants were randomized to receive the four active doses in either ascending or descending order (nine participants each). Placebo was scheduled quasi-randomly. During sessions, volunteers used eyeshades and were instructed to direct their attention inward. Volunteers completed questionnaires assessing effects immediately after and 1 month after each session, and at 14 months follow-up.
Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers) and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin experience as having substantial personal and spiritual significance, and attributed to the experience sustained positive changes in attitudes, mood, and behavior, with the ascending dose sequence showing greater positive effects. At 14 months, ratings were undiminished and were consistent with changes rated by community observers. Both the acute and persisting effects of psilocybin were generally a monotonically increasing function of dose, with the lowest dose showing significant effects.
Under supportive conditions, 20 and 30 mg/70 kg psilocybin occasioned mystical-type experiences having persisting positive effects on attitudes, mood, and behavior. Implications for therapeutic trials are discussed.
Psilocybin and related hallucinogenic compounds are increasingly used in human research. However, due to limited information about potential subjective side effects, the controlled medical use of these compounds has remained controversial. We therefore analysed acute, short- and long-term subjective effects of psilocybin in healthy humans by pooling raw data from eight double-blind placebo-controlled experimental studies conducted between 1999 and 2008. The analysis included 110 healthy subjects who had received 1-4 oral doses of psilocybin (45-315 µg/kg body weight). Although psilocybin dose-dependently induced profound changes in mood, perception, thought and self-experience, most subjects described the experience as pleasurable, enriching and non-threatening. Acute adverse drug reactions, characterized by strong dysphoria and/or anxiety/panic, occurred only in the two highest dose conditions in a relatively small proportion of subjects. All acute adverse drug reactions were successfully managed by providing interpersonal support and did not need psychopharmacological intervention. Follow-up questionnaires indicated no subsequent drug abuse, persisting perception disorders, prolonged psychosis or other long-term impairment of functioning in any of our subjects. The results suggest that the administration of moderate doses of psilocybin to healthy, high-functioning and well-prepared subjects in the context of a carefully monitored research environment is associated with an acceptable level of risk.
We currently understand the mental effects of psychedelics to be caused by agonism or partial agonism of 5-HT(2A) (and possibly 5-HT(2C)) receptors, and we understand that psychedelic drugs, especially phenylalkylamines, are fairly selective for these two receptors. This manuscript is a reference work on the receptor affinity pharmacology of psychedelic drugs. New data is presented on the affinity of twenty-five psychedelic drugs at fifty-one receptors, transporters, and ion channels, assayed by the National Institute of Mental Health-Psychoactive Drug Screening Program (NIMH-PDSP). In addition, comparable data gathered from the literature on ten additional drugs is also presented (mostly assayed by the NIMH-PDSP). A new method is introduced for normalizing affinity (K(i)) data that factors out potency so that the multi-receptor affinity profiles of different drugs can be directly compared and contrasted. The method is then used to compare the thirty-five drugs in graphical and tabular form. It is shown that psychedelic drugs, especially phenylalkylamines, are not as selective as generally believed, interacting with forty-two of forty-nine broadly assayed sites. The thirty-five drugs of the study have very diverse patterns of interaction with different classes of receptors, emphasizing eighteen different receptors. This diversity of receptor interaction may underlie the qualitative diversity of these drugs. It should be possible to use this diverse set of drugs as probes into the roles played by the various receptor systems in the human mind.
A test-retest reliability study of the Structured Clinical Interview for DSM-III-R was conducted on 592 subjects in four patient and two nonpatient sites in this country as well as one patient site in Germany. For most of the major categories, kappa s for current and lifetime diagnoses in the patient samples were above .60, with an overall weighted kappa of .61 for current and .68 for lifetime diagnoses. For the nonpatients, however, agreement was considerably lower, with a mean kappa of .37 for current and .51 for lifetime diagnoses. These values for the patient and nonpatient samples are roughly comparable to those obtained with other structured diagnostic instruments. Sources of diagnostic disagreement, such as inadequate training of interviewers, inf