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Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance
Abstract
Psilocybin and psilocin are controlled substances in many countries. These are the two main hallucinogenic compounds of the "magic mushrooms" and both act as agonists or partial agonists at 5-hydroxytryptamine (5-HT)2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic relevance but considerable physiological variability between individuals that can influence dose-response and toxicological profile has been reported. This review aims to discuss metabolism of psilocybin and psilocin, by presenting all major and minor psychoactive metabolites. Psilocybin is primarily a pro-drug that is dephosphorylated by alkaline phosphatase to active metabolite psilocin. This last is then further metabolized, psilocin-O-glucuronide being the main urinary metabolite with clinical and forensic relevance in diagnosis.
... Once ingested, psilocybin is converted to its active metabolite, psilocin, an agonist at multiple cortical serotonin receptors including 5-HT2AR [14]. The drug's characteristic acute subjective effects can range from euphoria, mysticaltype experiences, and pleasurable perceptual changes (e.g., synesthesia, sensory illusions) to negative emotional states and psychotic-like effects [15]. Though intoxication resolves within approximately six hours, studies have reported that a single psilocybin administration paired with psychotherapeutic support can yield robust improvements in mood that persist long after the drug is metabolized [10,11,16]. ...
... While the toxicity of psilocybin is relatively low [15,16], its safety for people with PD warrants careful evaluation. First, the drug's vasoactive effects lead to increases in heart rate and blood pressure [26] which could confer elevated risk given the older age and autonomic dysfunction associated with PD [27]. ...
... Key follow-up time points are shown: one week after the 10 mg session (A7), one week after the 25 mg session (B7), one month after the 25 mg session (B30), and three months after the 25 mg session (B90). B The five most common reasons for ineligibility after prescreening were using exclusionary medications (40), not having a diagnosis of PD (15), not meeting criteria for either depression or anxiety (11), not being able to commit to the study schedule (8), and significant cognitive impairment (7). E.R. Bradley et al. ...
Mood dysfunction is highly prevalent in Parkinson’s disease (PD), a main predictor of functional decline, and difficult to treat—novel interventions are critically needed. Psilocybin shows early promise for treating depression and anxiety, but its potential in PD is unknown, as safety concerns have excluded people with neurodegenerative disease from previous trials. In this open-label pilot (NCT04932434), we examined the feasibility of psilocybin therapy among people with mild to moderate stage PD plus depression and/or anxiety. 12 participants (mean age 63.2 ± 8.2 years, 5 women) received psilocybin (one 10 mg followed by one 25 mg dose) with psychotherapy. There were no serious adverse events, no medical interventions required to manage effects of psilocybin, and no exacerbation of psychosis. Ten participants experienced treatment-emergent adverse events; the most frequent were anxiety, nausea, and increased blood pressure. We observed no worsening of PD symptomology measured by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). On the contrary, non-motor (MDS-UPDRS Part I: –13.8 ± 1.3, p < 0.001, Hedges’ g = 3.0) and motor symptoms (Part II: –7.5 ± 0.9, p < 0.001, g = 1.2; Part III: –4.6 ± 1.3, p = 0.001; g = 0.3) as well as performance in select cognitive domains (Paired Associates Learning [-0.44 ± 0.14, p = .003, g = 0.4], Spatial Working Memory [–0.52 ± 0.17, p = 0.003, g = 0.7], and Probabilistic Reversal Learning [2.9 ± 0.9, p = 0.003, g = 1.3]) improved post-treatment, and improvements were sustained until the final safety assessment one month following drug exposure. Baseline Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Anxiety Rating Scale (HAM-A) scores were 21.0 ± 8.7 and 17.0 ± 3.7, respectively. Both improved to a clinically meaningful degree post-treatment; these improvements persisted to the final assessment three months following drug exposure (MADRS: -9.3 ± 2.7, p = .001, g = 1.0; HAM-A: –3.8 ± 1.7; p = 0.031, g = 0.7). This study provides the first data on psilocybin’s effects in any neurodegenerative disease. Results suggest that psilocybin therapy in PD warrants further investigation.
... Niedługo potem, bo w latach 60', rozpoczęła się "moda" na rekreacyjne używanie grzybów halu- nooksydazę (MAO) [36]. Przez to, spożywanie etanolu może wzmacniać efekty substancji, ponieważ jego główny metabolit powoduje produkcję inhibitorów MAO [35]. Sytuacja podobnie wygląda z tytoniem. ...
... W kwaśnym środowisku zachodzi szybka defosforylacja substancji. Ten sam proces może zajść w jelicie lub za pomocą fosfatazy alkalicznej[34,35]. Defosforylacja psylocybiny prowadzi do powstania psylocyny. ...
... Defosforylacja psylocybiny prowadzi do powstania psylocyny. Psylocyna z kolei jest tak strukturalnie podobna do serotoniny, że jest metabolizowana podobnie jak ona[35]. W wątrobie dochodzi do oksydacyjnej deaminacji psylocyny, która katalizowana jest przez monoami- ...
Psylocybina jest alkaloidem obecnym w ponad 200 gatunkach grzybów. Sub
stancja ta swoją strukturą przypomina serotoninę i jest klasyfikowana jako tryptamina. Jej najważniejszą cechą jest działanie jako agonista receptorów serotoninowych 5-HT2A, co stwarza potencjalne możliwości jej zastosowania w leczeniu zaburzeń psychiatrycznych. Receptory te odgrywają kluczową rolę w regulacji nastroju, funkcji poznawczych i percepcji, a także są zaangażowane w rozwój różnych zaburzeń psychicznych. W przyszłości psylocybina może znaleźć zastosowanie w terapii depresji, zaburzeń lękowych oraz uzależnień.
Zamiast jedynie maskować objawy, psylocybina wydaje się oddziaływać na pod
stawowe problemy psychiczne, promując zmiany w percepcji i zachowaniu. W badaniach klinicznych wykazano, że substancja ta zwiększa otwartość emocjonalną, zmniejsza objawy depresji oraz redukuje poziom lęku. Co więcej, psylocybina nie wydaje się wywoływać długotrwałych skutków ubocznych i nie jest klasyfikowana jako substancja uzależniająca.
Jednakże, wiele aspektów jej działania pozostaje nieznanych, co sprawia, że dalsze badania w tej dziedzinie są kluczowe. Niezbędne są dodatkowe eksperymenty w
celu pełniejszego zrozumienia terapeutycznego potencjału psylocybiny, opracowania bezpiecznych i skutecznych protokołów leczenia, jak również zrozumienia jej długoterminowego wpływu na mózg.
... Previous reviews have summarised the metabolic fate of psilocybin and psilocin (see Fig. 1) and their clinical drug disposition characteristics [11]. There is however a lack of a comprehensive and quantitative overview of all available pharmacokinetic (PK) data on psilocybin and its pharmacologically active metabolite psilocin. ...
... Psilocybin is rapidly metabolized to the pharmacologically active unconjugated psilocin (4-hydroxy-N,N-dimethyltryptamine) before reaching the systemic circulation. In summary, metabolism occurs by dephosphorylation in the stomach by alkaline phosphatases or other non-specific esterases in the intestine and kidneys [11][12][13][14]. As virtually all psilocybin is transformed to unconjugated psilocin before absorption, it is considered to be a pro-drug [11,[15][16][17]. ...
... In summary, metabolism occurs by dephosphorylation in the stomach by alkaline phosphatases or other non-specific esterases in the intestine and kidneys [11][12][13][14]. As virtually all psilocybin is transformed to unconjugated psilocin before absorption, it is considered to be a pro-drug [11,[15][16][17]. Unconjugated psilocin may also be transformed to the inactive conjugated psilocin by glucuronidation through UDPglucuronosyltransferases in the small intestine (UGT1A10) before absorption. ...
Psilocybin is currently being extensively studied as a potential therapeutic agent for multiple psychiatric disorders. Here, a systematic literature review of all published pharmacokinetic data on the pharmacologically active metabolite of psilocybin, psilocin, is presented.
The review includes clinical studies that reported pharmacokinetic data and/or parameters after psilocybin administration in humans. In addition, raw pharmacokinetic data from these studies was requested and/or extracted to further compare results across studies.
In total, 309 publications were identified, of which 19 publications were ultimately included, which covered 12 unique clinical datasets. Except for one study that investigated intravenous psilocybin, all included studies administered psilocybin orally. Psilocybin acts as a pro-drug and is rapidly absorbed and transformed to psilocin after oral administration. In the majority of studies, unconjugated psilocin was measured while some also measured conjugated and total concentrations. Psilocin’s biphasic concentration–time profiles demonstrates fast and extensive disposition with an apparent distribution volume of 505–1267 L and a terminal half-life of 1.23–4.72 h. Only 1.5–3.4% of the dose is excreted as psilocin in urine. Psilocin is mainly transformed to 4-hydroxyindole-3-acetic acid and in less amounts to conjugated psilocin, where 4-hydroxyindole-3-acetic acid formation may occur prior to systemic psilocin absorption. Information on the absolute bioavailability of psilocin was limited, and estimated at 55% in one study. No covariates nor food effects have been reported, based on four studies with known fasting status.
Overall, we found the pharmacokinetic parameters of psilocin to be consistent between studies. This review may guide the further clinical development of psilocybin-based therapies.
... The biotransformation of psilocin to 4-HIAA has long been considered to occur via monoamine oxidases (MAOs) and aldehyde dehydrogenases (ALDHs), with 4-hydroxyindole-3-acetaldehyde (4-HIA) as an intermediate (Dinis-Oliveira 2017). However, this Phase I metabolism process has not been experimentally elucidated, where it was mostly assumed based on the metabolic pathways of other structurally similar compounds, for example, serotonin (5-HT) and antimigraine triptan drugs. ...
... The NADPH-independent Phase I metabolism of psilocin was previously attributed to MAO-A based on the confirmed MAO-A-mediated metabolism of structurally similar 5-HT (Shih et al. 1999). It was also observed that psilocin users may co-consume MAO inhibitors to intensify their hallucinogenic effects (Halpern 2004;Dinis-Oliveira 2017). It was only recently that Thomann et al. identified the involvement of rhMAO-A in the metabolism of psilocin. ...
... Rights reserved. articles adopted this concept (Passie et al. 2002;Dinis-Oliveira 2017), corresponding to the metabolic pathways of 5-HT and antimigraine triptan drugs. Our preliminary assays directly analyzing the rhMAO-A incubation samples via LC-MS/MS and LC-Orbitrap MS was unable to identify 4-HIA, despite observing appreciable substrate depletion of psilocin. ...
Psilocin is a well-studied controlled substance with potential psychotherapeutic applications. However, research gaps remain regarding its metabolism. Our objective was to elucidate a comprehensive Phase I metabolic profile of psilocin to support its forensic management and clinical development. We utilized human enzymes from various sources to characterize the Phase I metabolism of psilocin and estimated its hepatic and extrahepatic clearances via in vitro to in vivo extrapolation. We identified 2-(4-hydroxy-1H-indol-3-yl)-acetaldehyde (4-HIA) as the Phase I intermediate metabolite for the first time. Psilocin was metabolized to 4-HIA by monoamine oxidase A (MAO-A), and further metabolized to the terminal metabolite 2-(4-hydroxy-1H-indol-3-yl)-acetic acid (4-HIAA) by cytosolic aldehyde oxidase (AO) and aldehyde dehydrogenases (ALDHs). MAO-A-mediated hepatic clearance of psilocin (CLH,MAO-A) was estimated to be 158.74 mL/min, accounting for 80.9% of the total hepatic metabolism of psilocin (CLH,all). MAO-A primarily contributed to the Phase I metabolism of psilocin. Total MAO-A-mediated organ clearance (CLall organs,MAO-A) was estimated to be 614.81 mL/min, with CLH,MAO-A accounting for 25.8%, indicating extensive MAO-A-mediated extrahepatic clearance of psilocin. Overall, our study sheds novel insights on Phase I metabolic pathway of psilocin and illuminated the importance of MAO-A-mediated hepatic and extrahepatic clearances of psilocin.
... Psilocybin is a naturally occurring substance found in several species of mushrooms. 42 It is a prodrug that is dephosphorylated into the pharmacologically active psilocin by alkaline phosphatases. 42,43 It is suggested that psilocin undergoes phase I metabolism by monoamine oxidase A (MAO-A) to form an intermediate metabolite 4-hydroxyindole-3-acetaldehyde (4-HIA) which is then oxidized by aldehyde dehydrogenase (ALDH) to produce 4-hydroxyindole-3-acetic acid (4-HIAA). ...
... 42 It is a prodrug that is dephosphorylated into the pharmacologically active psilocin by alkaline phosphatases. 42,43 It is suggested that psilocin undergoes phase I metabolism by monoamine oxidase A (MAO-A) to form an intermediate metabolite 4-hydroxyindole-3-acetaldehyde (4-HIA) which is then oxidized by aldehyde dehydrogenase (ALDH) to produce 4-hydroxyindole-3-acetic acid (4-HIAA). 43 The 4-HIA can be reduced to 4-hydroxytryptophol (4-HTP) by alcohol dehydrogenase (ADH), but this has been detected only in vitro and not in humans, likely due to rapid metabolism or lack of production. ...
... 43 The suggested main pathway for psilocin is phase II metabolism where it is glucuronidated into psilocin-Oglucuronide, which forms ~ 80% of psilocin metabolites. 42 In an analysis of 19 recombinant human UDP-glucuronosyltransferases (UGTs) from the 1A, 2A, and 2B subfamilies, UGT1A10 was found to have the highest activity for psilocin glucuronidation. 44 UGTs 1A8 and 1A9 also showed considerable activity in metabolizing psilocin, whereas UGTs 1A6 and 1A7 exhibited very low activity. ...
Psychedelics have recently re‐emerged as potential treatments for various psychiatric conditions that impose major public health costs and for which current treatment options have limited efficacy. At the same time, personalized medicine is increasingly being implemented in psychiatry to provide individualized drug dosing recommendations based on genetics. This review brings together these topics to explore the utility of pharmacogenomics (a key component of personalized medicine) in psychedelic‐assisted therapies. We summarized the literature and explored the potential implications of genetic variability on the pharmacodynamics and pharmacokinetics of psychedelic drugs including lysergic acid diethylamide (LSD), psilocybin, N,N‐dimethyltryptamine (DMT), 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeO‐DMT), ibogaine and 3,4‐methylenedioxymethamphetamine (MDMA). Although existing evidence is limited, particularly concerning pharmacodynamics, studies investigating pharmacokinetics indicate that genetic variants in drug‐metabolizing enzymes, such as cytochrome P450, impact the intensity of acute psychedelic effects for LSD and ibogaine, and that a dose reduction for CYP2D6 poor metabolizers may be appropriate. Furthermore, based on the preclinical evidence, it can be hypothesized that CYP2D6 metabolizer status might contribute to altered acute psychedelic experiences with 5‐MeO‐DMT and psilocybin when combined with monoamine oxidase inhibitors. In conclusion, considering early evidence that genetic factors can influence the effects of certain psychedelics, we suggest that pharmacogenomic testing should be further investigated in clinical research. This is necessary to evaluate its utility in improving the safety and therapeutic profile of psychedelic therapies and a potential future role in personalizing psychedelic‐assisted therapies, should these treatments become available.
... Disruption of the cell structure may lead to faster degradation of tryptamines due to hydrolysis to psilocin and subsequent oxidation to quinoid dyes. 55,56 This hypothesis was confirmed by the fact that almost immediately after cutting, the fresh fruiting body turned blue. The degradation of psilocybin may be due to the gradual biotransformation of the sliced specimens since psilocybin is dephosphorylated enzymatically by phosphatase to psilocin, which is unstable because of it being readily subjected to oxidation to blue quinoid dye. ...
... The degradation of psilocybin may be due to the gradual biotransformation of the sliced specimens since psilocybin is dephosphorylated enzymatically by phosphatase to psilocin, which is unstable because of it being readily subjected to oxidation to blue quinoid dye. 55,56 Significant blue staining was observed for the chopped fresh mushroom samples only a few seconds after the fruiting bodies were cut. ...
Synthetic psilocybin (PSB), but also the PSB-containing mushrooms are used for psychedelic therapy and microdosing. It is necessary to know alkaloids variability and stability in wild-grown mushrooms. Concentrations of other psychotropic (or potentially psychotropic) tryptamines such as psilocin (PS), baeocystin (BA), norbaeocystin (NB), and aeruginascin (AE) are also relevant. This study aims to determine the concentrations of PSB, PS, BA, NB and AE in a large sample set of mushroom genera previously reported to contain psychotropic tryptamines. Freshly cultivated fruit bodies of Psilocybe cubensis were used for monitoring stability (including storage and processing conditions of fruiting bodies). Mycelium and the individual parts of the fruiting bodies (caps, stipes, and basidiospores) were also examined. The concentration of tryptamines was analyzed using ultra-high-performance liquid chromatography coupled with mass spectrometry. Analytical standards were synthetized in house and UHPLC-MS/MS method was fully validate for quantification of tryptamine alkaloids in mushroom samples. Most mushroom collections were documented by fungarium specimens and/or ITS rDNA/LSU/EF1-α sequencing.The tryptamine concentrations in mushrooms are extremely variable, which could possibly influence the medicinal effect compared to therapy with chemically pure PSB. The storage conditions strongly affected the alkaloids decay and showed that the highest degradation of tryptamines was seen in fresh mushrooms stored at −80° C, and the lowest decay was seen in dried biomass stored in the dark at room temperature.
This study was funded by the Ministry of Health of the Czech Republic (NU21-04-00307).
References
GOTVALDOVA, K., BOROVICKA, J., HAJKOVA, K., CIHLAROVA, P., ROCKEFELLER, A. &KUCHAR, M. 2022. Extensive Collection of Psychotropic Mushrooms with Determination of Their Tryptamine Alkaloids. International Journal of Molecular Sciences, 23.
GOTVALDOVA, K., HAJKOVA, K., BOROVICKA, J., JUROK, R., CIHLAROVA, P. &KUCHAR, M. 2021. Stability of psilocybin and its four analogs in the biomass of the psychotropic mushroom Psilocybe cubensis. Drug Testing and Analysis, 13, 439-446.
... Psilocin is metabolized via Phase I and Phase II hepatic pathways to form O-glucuronide conjugates that undergo renal excretion. [58][59][60][61] There is evidence that psilocybin use by humans may predate recorded history, while its use in Mesoamerica for spiritual and occult rituals in the 15 th century is well documented. The Swiss chemist Albert Hofmann isolated psilocin from the Psilocybe Mexicana mushroom in 1954, and his employer Sandoz distributed this product (along with lysergic acid diethylamide, LSD) to physicians and clinics throughout the globe. ...
... During the 1960's there were serious medical investigations into the effect of psilocin on mental health disorders, but in 1971 research was curtailed when it was classified as a Schedule 1 controlled substance; ie, as having no accepted medical use and with a high potential for abuse. [58][59][60][61][62][63] Over thirty years later, the US Food and Drug Administration (FDA) again permitted research with psilocybin in the treatment of some medical conditions. The bulk of this research has been conducted in controlled settings in which an individual consumes a hallucinogenic dose of the psychedelic substance while under the supervision of a therapist/guide. ...
The incidence of mental health disorders is increasing worldwide. While there are multiple factors contributing to this problem, neuroinflammation underlies a significant subset of psychiatric conditions, particularly major depressive and anxiety disorders. Anti-inflammatory interventions have demonstrated benefit in these conditions. Psilocin, the active ingredient of mushrooms in the Psilocybe genus, is both a potent serotonin agonist and anti-inflammatory agent, increases neuroplasticity, and decreases overactivity in the default mode network. Studies using hallucinogenic doses of psilocin under the supervision of a therapist/guide have consistently demonstrated benefits to individuals with depression and end-of-life anxiety. Microdosing psilocybin in sub-hallucinogenic doses has also demonstrated benefit in mood disorders, and may offer a safe, less expensive, and more available alternative to full doses of psilocybin for mood disorders, as well as for other medical conditions in which inflammation is the principal pathophysiology.
... Briefly, nearly 80% of psilocin is metabolized into psilocin-O-glucuronide by UGT enzymes, while the residual fraction is degraded into 4-HTP and 4-HIAA through a minor pathway involving MAO-A. [121][122][123] The cytochrome P450 system has a minor role in psilocin's metabolism, and individuals with variations of CYP activity do not differ in their response to psilocin. 112 Psilocin has a dose-independent half-life of about 2-4 hours. ...
... 112 About 80-85% of metabolites are excreted in the urine (mostly psilocin-O-glucuronide), while the remainder 15-20% is excreted through the biliary system. 121,126 Renal function has a minimal impact on the drug's elimination process. Therefore, dose adjustments may be unnecessary for patients with renal impairment, although limited data is available in this population. ...
Psilocybin therapy has recently emerged as a promising new treatment for depression and other mental health disorders. This chapter summarizes the most recent data on its safety and efficacy. The delivery of psilocybin therapy and its subjective effects are also presented. Furthermore, this chapter outlines our current understanding of psilocybin’s pharmacology and neurobiological effects. Other similar psychedelic substances with encouraging therapeutic potential are briefly presented.
... Psilocybin (O-phosphoryl-4-Hydroxy-N, N-dimethyltryptamine) is a white solid indole alkaloid with the formula C 12 H 17 N 2 O 4 P. This molecule is the main psychoactive component of the so-called "magic mushrooms", a nomenclature that encompasses several fungi species, especially those from the genus Psilocybe sp.. 21 Its molecular structure is similar to serotonin (5-OH-tryptamine), which means that the consumption of psilocybin interferes with the serotonergic system of mammals, particularly humans. Indeed, psilocin, the dephosphorylated derivative of psilocybin, primarily interacts with the serotonergic receptor system in the brain. ...
... L-tryptophan decarboxylase) is the first enzyme in the psilocybin synthesis pathway and the one that has drawn the attention of researchers to the biocatalysis of tryptamines.37,43 PsiD is an L-tryptophan decarboxylase (TDC) related to the PLP-independent phosphatidylserine decarboxylase (PSD) family.21 Notably, PsiD of P. cubensis exhibits a non-classical catalytic triad E-H-S (Glu 242 -His 296 -Ser 403 ), leading to autocatalytic cleavage between G 402 /S 403 , resulting in two fragments: a 49 kDa β-chain (402 amino acids) and a 4 kDa α-chain (37 amino acids).43,44 ...
Tryptamines play diverse roles as neurotransmitters and psychoactive compounds found in various organisms. Psilocybin, a notable tryptamine, has garnered attention for its therapeutic potential in treating mental health disorders like depression and anxiety. Despite its promising applications, current extraction methods for psilocybin are labor‐intensive and economically limiting. We suggest biocatalysis as a sustainable alternative, leveraging enzymes to synthesize psilocybin and other tryptamines efficiently. By elucidating psilocybin biosynthesis pathways, researchers aim to advance synthetic methodologies and industrial applications. This review underscores the transformative potential of biocatalysis in enhancing our understanding of tryptamine biosynthesis and facilitating the production of high‐purity psilocybin and other tryptamines for therapeutic and research use.
... K a values were determined using Scatchard analysis. 99) tryptamine alkaloids present in hallucinogenic mushrooms 38,39) (Fig. 5A). Following administration, Pyb is rapidly dephosphorylated to generate Psi, which is pharmacologically active agent. ...
Immunoassays enable the sensitive determination of various compounds and have been widely utilized in pharmaceutical and medical sciences. To develop practical assays, it is essential to obtain antibodies that capture the target analytes with high specificity and affinity. To date, we have generated high-performance antibodies and developed immunoassays for determining bioactive compounds, particularly focusing on haptens, such as steroids and synthetic drugs. In previous studies, we have produced specific anti-hapten antibodies by immunizing animals with reasonably prepared hapten–carrier conjugates. However, the resulting antibodies sometimes lacked sufficient affinity for a sensitive determination. Therefore, we challenged genetic engineering to produce artificially modified antibodies with improved affinity. Therein, native antibodies with insufficient affinities were converted into single-chain Fv fragments (scFvs), to which random point mutations were introduced to generate diverse scFv libraries. Mutated scFv species with increased affinities were selected and isolated with the aid of phage-display system combined with panning. Using this strategy, we obtained scFvs specific to several haptens, such as estradiol-17β (E2) and cotinine, that show significantly improved affinity (Ka) than that of the parental scFv, enabling more sensitive enzyme-linked immunosorbent assays. However, the panning step often fails in straightforward selection and requires laborious trial-and-error work. Thus, we developed a “clonal array profiling (CAP)” system for more efficient isolation of the mutants with enhanced affinities, which successfully functioned generating multiple anti-cortisol scFvs with the Ka improved up to 63-fold and an anti-E2 scFv with 372-fold larger Ka. In this study, we identified new strategies that allow for efficient site-directed mutagenesis to improve affinity. We expect that the engineered antibodies described here will open the door to next-generation immunoassays that will enable simpler and more reliable determination of bioactive compounds.
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... A main process upon ingestion of psilocybin-producing fruiting bodies is the dephosphorylation of psilocybin by alkaline phosphatase and other nonspecific esterases in the gastrointestinal tract and the liver [69][70][71] . Even though this dephosphorylation occurs in in vivo experimental settings in which fungal extracts are administered orally, most in vitro systems lack this complexity and psilocybin is not transformed into psilocin. ...
Psilocybin-producing fungi have garnered attention due to accumulating evidence regarding the therapeutic potential of their principal component psilocybin. This diverse group of fungi harbors a wealth of less-studied metabolites, however, thus far most research has addressed them as a cohesive group. By optimizing an approach for extraction and analysis, we examined the metabolomes of 42 distinct fungi strains and show that the breadth and diversity of metabolites within and between 9 species. We integrated and validated the reproducible and reliable extraction of fruiting bodies followed by chromatographic separation, quantification and identification of their known and yet to be identified secondary metabolites. The optimal extraction of fruiting bodies for high yield of indole alkaloids was achieved using a 1:20 tissue:solvent ratio, 25:75 H2O:MeOH (pH = 9), for 1.5 h, followed by the quantification of 8 tryptophan-derived indolamines by HPLC–DAD and the identification of putative metabolite hydroxypsilocybin by HPLC–MS/MS. The metabolomic analysis revealed the diversity of metabolites within and between species. Finally, we developed and present a method that mimics the in vivo process of dephosphorylation that occurs upon ingestion for in vitro setups. Overall, our study summarizes a standardized approach for both in vitro and in vivo studies involving psilocybin-producing fungi, showcasing the unique metabolome of each strain and the rich diversity of these fungi, encompassing promising pharmaceutical potential.
... Additionally, pharmacokinetics plays a vital role in drug development, informing the design of clinical trials and ensuring that medications are used safely and efficiently in clinical practice [11]. Psilocybin is a prodrug that undergoes rapid metabolism in the body to its active form, psilocin (N,N-dimethyl-4-hydroxytryptamine), mostly through gut and hepatic dephosphorylation [12]. The pharmacokinetics of psilocybin and psilocin are influenced by various factors, including the rate of absorption, systemic distribution, and elimination via urine and feces [13]. ...
Background: Psilocybin has shown promise in therapeutic applications for mental disorders. Understanding the pharmacokinetics of psilocybin and its active metabolite psilocin is crucial for optimizing its clinical use and minimizing adverse effects. Methods: This systematic review involved a comprehensive search across MEDLINE, APA PsycINFO, and Embase databases, from inception to December 2024, identifying original studies that investigated the pharmacokinetics of psilocybin. Results: Fourteen studies met the inclusion criteria: eight laboratory-based and six clinical studies. Laboratory studies used animal models or in vitro systems, while clinical studies included 112 healthy human participants. Psilocybin is rapidly dephosphorylated to psilocin, which is absorbed with Tmax values ranging from 1.8 to 4 h following oral administration. Cmax varied dose-dependently, from 8.2 ± 2.8 ng/mL (plasma) to 871 ng/mL (urine). One study reported psilocin bioavailability at 52.7 ± 20%. The volume of distribution was extensive, ranging from 277 ± 92 L to 1016 L, suggesting significant tissue distribution. Psilocin metabolism is primarily mediated by CYP2D6 and CYP3A4, with secondary contributions from monoamine oxidase A. It undergoes further hepatic biotransformation into 4-hydroxyindole-3-acetic acid and 4-hydroxytryptophol. Elimination half-life varied across studies, ranging from 1.5 to 4 h. Conclusions: Psilocybin pharmacokinetics demonstrate significant variability based on dosage, route, and species. CYP enzymes play a critical role in its metabolism, highlighting the potential for drug–drug interactions. These findings underscore the importance of further research to elucidate psilocybin’s pharmacokinetic profile, which is assessed in vivo by its active metabolite psilocin.
... Psilocybin is the main psychedelic compound in "magic mushrooms". Psilocybin is metabolized in the liver to psilocin, which is a potent agonist of the 5-HT2A receptor [4]. Previous studies have shown that psychedelic effects are modulated by this specific receptor [5], although other effects may be modulated through separate mechanisms, such as activation of the TrkB receptor [6]. ...
Psilocybin, a psychedelic compound found in specific hallucinogenic mushrooms, is known to induce changes in visual perception and experience in humans. However, there is little knowledge of the molecular mechanisms through which psilocybin affects vision-associated regions in the brain, such as the visual cortex. The current study determined both psilocybin-induced and experience-dependent changes (exposure to light) in visual cortex gene expression in mice. Of great interest, psilocybin induced robust gene expression changes in the visual cortex that closely mirror light-induced gene expression changes, even when the mice are kept in the dark. These gene expression changes correspond to specific molecular pathways, including synaptic functioning, and represent genes expressed in specific subtypes of neurons. In addition, exposure to both psilocybin and light induced synergetic changes in genes involved in epigenetic programming. Overall, the study determined that psilocybin induces robust changes in gene expression in the visual cortex that may have functional consequences in visual perception both in the absence and in synergy with visual experience.
... Some psychedelics are prodrugs requiring conversion into psychoactive substances before exerting their effects. For example, psilocybin must be dephosphorylated to psilocin by the intestinal lining and liver, while DMT does not have oral bioavailability because it is eliminated by monoamine oxidase A (MAO) [34,35]. While MAO inhibitors are less commonly used due to their side effects, the metabolism of serotonin and serotonergic hallucinogens by MAO creates the need for careful consideration of the concurrent use of psychedelics and MAO inhibitors. ...
Purpose
To evaluate the current level of evidence for the use of psychedelics for the management of cancer pain and associated psychological distress.
Content
Pain is a common symptom of cancer and treatment. However, there are high rates of undertreatment of cancer pain due to the complex underlying biology of the condition, and potentially due to a decrease in opioid prescribing in response to the opioid epidemic. A diagnosis of cancer and cancer‐related pain can trigger high levels of psychological distress throughout cancer treatment. Cancer pain can also be exacerbated by anxiety, depression, quality of life challenges, and fear of death and dying, as well as by fear of recurrence or progression. Several pharmacologic and non‐pharmacologic approaches have been utilized to mitigate pain and symptom burden with some success. However, there remains an unmet need for better management of cancer pain and associated symptoms. Psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, mescaline, and N,N‐dimethyltryptamine (DMT), are under consideration as new pharmacologic strategies for mitigating pain and the distress associated with cancer pain and associated symptom burden. Although published studies are limited, regulatory hurdles have decreased. Many clinical trials are underway to assess further the use of psychedelics and behavioral counseling for patients with cancer and comorbidities such as anxiety or depression. These studies examine both the feasibility and efficacy of psychedelics for pain and psychological distress. Early results are promising, and additional research is needed to understand efficacy and tolerability in broader cancer populations.
Implications
There is an unmet need to improve pain management in patients with cancer and to mitigate psychological distress. Further research is required to understand the efficacy of psychedelics for the treatment of cancer pain and distress. Recent regulatory changes have paved the way for increased research on the clinical efficacy of psychedelics in cancer.
... 2016, Johnson i współaut. 2014, 2017. ...
In the past decade, there has been a surge of interest in the therapeutic use of psychedelics, especially in the treatment of depression and addiction, resulting in many new research projects on their properties. This publication outlines the history of scientific experiments conducted with psychedelics in the 1950s and 1960s, as well as their subsequent international outlawing in the 1970s and the resurgence of research into their medical potential with the onset of the 21st century. Additionally, it discusses the potential mechanisms responsible for their therapeutic impact, the dangers accompanying their use, and changes in their legal status in some countries. The text also makes predictions about the development of a new branch of medicine based on the use of classic psychedelics and their new analogs.
... Psilocybin readily dissolves in water but is too hydrophilic to cross the blood-brain barrier. Psilocybin is metabolized into psilocin through a dephosphorylation reaction either by the acidic contents of the stomach or by alkaline phosphatase, increasing its hydrophobicity and allowing it to take effect in the brain [73,74]. Psilocybin remains in the body for about five to eight hours. ...
Purpose of Review
Exploration of the potential of serotonergic psychedelic drugs, such as psilocybin and LSD, as potential treatments for headache disorders. This review addresses the need for well-informed physician guidelines and discusses mechanisms, safety, and efficacy of these treatments. Further research, including the consideration of combination with psychotherapy, is needed.
Recent Findings
Psychedelics demonstrate promising outcomes as treatments for headache disorders. Recent findings indicated that some patients who underwent brief periods of treatment with psychedelics experienced a reduction in headache attack frequency, severity, or duration.
Summary
When prescription medications are ineffective at treating headache disorders, or are habit-forming, patients often turn to alternative options. There is anecdotal evidence that psychedelic drugs like LSD and psilocybin can effectively treat and prevent pain in patients with headache disorders, such as migraine or cluster headache. It is vital that physicians treating patients who self-treat with psychedelics be well-informed about the mechanisms and their effects to best advise their patients and coordinate their care well. This is a review assessing the literature on the mechanisms, safety, and efficacy of psychedelic drugs as a headache management intervention. We believe there is evidence that may support further investigation into the clinical use of psychedelic medications to treat cluster headache and migraine, including the consideration of use in conjunction with other interventions like cognitive behavioral therapy or acceptance and commitment training.
... Consequently, alkaline phosphatase, monoamine oxidase, and UDGPT emerge as pivotal metabolites governing psilocybin clearance. 25,26 This SR focused on outcome data related to psilocin, the active metabolite of psilocybin. ...
Objectives
This scoping review aimed to synthesize the existing data about psilocybin pharmacokinetics to learn what has been described regarding body disposition and safety when psilocybin was used in controlled research settings.
Methods
We performed a scoping literature review following the framework proposed by the JBI manual for evidence synthesis. Controlled clinical trials reporting pharmacokinetic data of psilocybin were considered appropriate for inclusion. We extracted the data on psilocybin pharmacokinetics and summarized it from the available literature on this topic. We also performed an exploratory-descriptive analysis using study level data to examine the relationship between dose of psilocybin and maximum serum concentrations (Cmax).
Results
We initially identified 850 articles, of which 5 were included. These trials included 112 healthy volunteers who received psilocybin in a controlled clinical setting. The peak concentration of psilocin in plasma (Cmax) ranged from 8.2 ng/mL to 37.2 ng/mL (median = 17, IQR = 11.9 to 23.5). The maximal concentrations (Cmax) of psilocin were reached (Tmax) around 2 hours, ranging from 1.7 hours to 2.2 hours (median = 2, IQR = 1.9 to 2.1) after psilocybin oral administration. Elimination half-life was between 1.2 hours and 3.3 hours (median = 2.0, IQR = 1.6 to 2.8). A strong positive relationship between dose and Cmax ( R ² = 0.95) was found. No serious adverse events were observed. We did not find studies reporting pharmacokinetic data from patients with depression or cancer patients transitioning to palliative care.
Conclusions
In summary, this review unveils oral psilocybin pharmacokinetics in healthy adults, revealing gaps in its application to target populations like those with depression or in palliative care.
... However, this may not apply to all antidepressants, and potential interactions should be considered carefully. For instance, since psilocin is metabolized by the liver monoamine oxidase (MAO), 91 MAO inhibitors may intensify the effects, and this combination should be avoided. Conversely, a recent retrospective online survey found that psilocybin's effect was attenuated up to 3 months after discontinuing SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs). ...
The revival of psilocybin in psychopharmacological research heralds a potential paradigm shift for treating mood and anxiety disorders, and other psychiatric conditions beyond the psychotic spectrum. This critical review evaluates current evidence on psilocybin’s efficacy, juxtaposing potential benefits with the practical aspects of psychedelic-assisted psychotherapy (PAP) and the methodological constraints of existing research.
An electronic literature search was conducted using PubMed/MEDLINE, selecting studies published up to December 2023 that explored the clinical use of psilocybin in mood and anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, and substance use disorder. Despite promising preliminary results suggesting psilocybin’s efficacy in alleviating depression and anxiety, as well as obsessions, compulsions, and addictive behaviors, significant evidence gaps persist. These include evaluating the efficacy of psilocybin compared to standard antidepressants or anxiolytic molecules and identifying patient subpopulations that might benefit most from PAP. Concerns about psilocybin’s safety, long-term efficacy, and optimal dosage remain unclear due to previous trials’ limitations. Real-world implementation faces challenges, including infrastructural requirements, personnel training, and unresolved legal and ethical issues. This paper argues for further research to substantiate the evidence base, emphasizing the need for larger studies that overcome current methodological limitations and explore psilocybin’s full therapeutic potential. While psilocybin holds promise for psychiatry, its successful translation from research to clinical practice demands more robust evidence on efficacy, safety, and methodological rigor. In addition, other factors, such as cultural stigma and legal/ethical issues, need to be successfully addressed to facilitate psilocybin’s implementation in healthcare systems.
... Upon ingestion, psilocybin is rapidly dephosphorylated by alkaline phosphatase enzymes in the liver and gut, converting it to psilocin, which can then cross the blood-brain barrier. The elimination half-life of psilocin is approximately 50 min, with psychoactive effects typically lasting 4-6 h, depending on the dose and metabolism (Dinis-Oliveira, 2017). The bioavailability of psilocybin is variable, but oral administration leads to rapid absorption and high conversion to psilocin. ...
Psychedelic drugs are under active consideration for clinical use and have generated significant interest for their potential as anti‐nociceptive treatments for chronic pain, and for addressing conditions like depression, frequently co‐morbid with pain. This review primarily explores the utility of preclinical animal models in investigating the potential of psilocybin as an anti‐nociceptive agent. Initial studies involving psilocybin in animal models of neuropathic and inflammatory pain are summarised, alongside areas where further research is needed. The potential mechanisms of action, including targeting serotonergic pathways through the activation of 5‐HT2A receptors at both spinal and central levels, as well as neuroplastic actions that improve functional connectivity in brain regions involved in chronic pain, are considered. Current clinical aspects and the translational potential of psilocybin from animal models to chronic pain patients are reviewed. Also discussed is psilocybin's profile as an ideal anti‐nociceptive agent, with a wide range of effects against chronic pain and its associated inflammatory or emotional components.
... Both psilocybin and psilocin affect serotonin receptors in the brain and induce hallucinogenic effects [121][122] . Recent studies have explored the therapeutic potential of psilocybin in the treatment of various mental health conditions including depression, anxiety, and addiction [123][124][125] . ...
Mushrooms are not only delicious additions to various dishes but also possess several health benefits due to their diverse nutritional composition. they are a good source of essential nutrients including protein, vitamins, minerals, and dietary fibre, and are low in fats and calories. comprehensive studies have been carried out with respect to the nutritive quality of wild and cultivated mushrooms. in recorded history, the purpose of mushroom cultivation was to meet household consumption and gradually, the combination of their nutritional quality and potential health benefits, and the growing interest in functional foods and natural remedies has led researchers to expand their focus towards nutraceutical innovation. the review highlights the utilitarian characteristics of mushrooms gaining popularity as source of nutraceuticals. it summarizes the various factors influencing secondary metabolism. it also identifies knowledge gaps and proposes potential area where more research is needed for optimal use of their potential. Understanding the significance and potential applications of mushrooms can contribute to the development of new products and formulations that can stimulate economic growth and expand the market for mushroom-based nutraceuticals. © 2025 Beijing academy of Food Sciences. Publishing services by Elsevier b.V. on behalf of Keai communications co., Ltd. this is an open access article under the cc bY-Nc-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
... It has been reported that psilocybin undergoes a series of metabolic processes in the body, ultimately transforming into psilocin, an active form with psychoactive effects (6). Psilocybin is absorbed by the stomach and intestines, entering the bloodstream. ...
Psilocybin, a psychoactive substance, has recently garnered attention for its high therapeutic potential in psychiatry. In this study, we investigated the multifaceted aspects of psilocybin, highlighting its chemical properties, mechanisms of action, and burgeoning role in psychiatric treatment. Furthermore, we examined the clinical applications and potential therapeutic benefits of psilocybin in the treatment of various mental health disorders, supported by accumulating clinical evidence. This review aims to deepen our understanding of the clinical impact of psilocybin, elucidate its therapeutic value, and propose directions for future research, thereby paving the way for its integration into mainstream psychiatric treatments. Psilocybin has been shown to be safe in clinical trials with manageable side effects. However, additional safety measures are required after this discussion, including dosing protocols, patient monitoring, and distress management strategies.
... Since their discovery, methods of synthetic production for both psilocin and psilocybin have been developed. When ingested, psilocybin undergoes rapid dephosphorylation by alkaline phosphatase in the small intestine, kidneys, and plasma to yield psilocin, which freely crosses the blood-brain barrier and exerts psychotropic activity [27]. The distinctive psychedelic effects induced by psilocin result from altered serotonin signaling, primarily due to the activation of the 5-HT 2A receptor (5-HT 2A R) isoform on frontal cortex pyramidal neurons [28,29]. ...
Neuroinflammation that is caused by microglia, the main immune cells of the brain, contributes to neurodegenerative diseases. Psychedelics, including psilocybin and lysergic acid diethylamide (LSD), possess certain anti-inflammatory properties and, therefore, should be considered as drug candidates for treating neuroinflammatory pathologies. When ingested, psilocybin is rapidly dephosphorylated to yield psilocin, which crosses the blood–brain barrier and exerts psychotropic activity by interacting with the 5-hydroxytryptamine 2A receptors (5-HT2ARs) on neurons. Since microglia express all three 5-HT2R isoforms, we hypothesized that, by interacting with these receptors, psilocin beneficially modulates select neuroimmune functions of microglia. We used microglia-like cell lines to demonstrate that psilocin, at non-toxic concentrations, did not affect the secretion of tumor necrosis factor (TNF) by immune-stimulated microglial cells, but significantly inhibited their phagocytic activity, the release of reactive oxygen species (ROS), and nitric oxide (NO) production. The inhibitory activity of psilocin on the latter two functions was similar to that of two selective 5-HT2R agonists, namely, 25I-NBOH and Ro60-0175. The role of this subfamily of receptors was further demonstrated by the application of 5-HT2R antagonists cyproheptadine and risperidone. Psilocin should be considered a novel drug candidate that might be effective in treating neuroimmune disorders, such as neurodegenerative diseases, where reactive microglia are significant contributors.
... Psilocybin is dephosphorylated to the active metabolite psilocin by systemic alkaline phosphatase after peripheral administration [11,38]. Tissue non-specific alkaline phosphatase (TNAP) is also expressed in brain endothelial cells and involves the integrity of blood-brain barrier [39]. ...
Background
Psilocybin is a psychedelic 5HT2A receptor agonist found in “magic mushrooms”. Recent studies have indicated that 5HT2A agonists, such as dimethyltryptamine, given before middle cerebral artery occlusion (MCAo), improve staircase behavior, increased BDNF expression, and reduce brain infarction in stroke rats. The objective of this study is to determine the protective effect of psilocybin in cellular and animal models of stroke.
Methods
Adult male and timed-pregnant Sprague-Dawley rats were used for this study. The neural protective effects of psilocybin were determined in primary rat cortical neurons and adult rats. Rats were subjected to a 60-min middle cerebral artery occlusion. Brain tissues were collected for histological and qRTPCR analysis.
Results
Psilocybin reduced glutamate-mediated neuronal loss in rat primary cortical neuronal cultures. Psilocybin-mediated protection in culture was antagonized by the BDNF inhibitor ANA12. Pretreatment with psilocybin reduced brain infarction and neurological deficits in stroke rats. Early post-treatment with psilocybin improved locomotor behavior, upregulated the expression of MAP2 and synaptophysin, and down-regulated the expression of IBA1 in the stroke brain. ANA12 significantly attenuated psilocybin-mediated reduction in brain infarction and improvements in locomotor behavior.
Conclusions
Psilocybin reduced brain infarction and improved locomotor behavior in stroke rats; the protective mechanisms involve regulating BDNF expression. Our data support a novel therapeutic approach of psilocybin in stroke.
... Psilocin, as a 5H-HT 2A serotonin receptor agonist, can initiate a series of downstream effects in the brain. These effects encompass changes in neurotransmitter release, notably dopamine and glutamate, and can modulate perception, emotions, thoughts, and symptoms of anxiety or elation (Dinis-Oliveira, 2017;López-Giménez and González-Maeso, 2018). It is hypothesized that these actions may be effective in minimizing symptoms of mood disorders and substance use disorders, create a synergistic effect when used with psychotherapy or when taken in combination with other psychedelics, and potentially have other medical indications. ...
Background
Psychedelic drugs have been of interest in medicine since the early 1950s. There has recently been a resurgence of interest in psychedelics.
Aims
The objective of this study is to determine the extent of the available literature on psilocybin for medical indications including the designs used, study characteristics, indications studied, doses, and authors’ conclusions. We identify areas for further study where there are research gaps.
Methods
We conducted a systematic scoping review of clinical indications for psilocybin, encompassing psychiatric and medical conditions. We systematically searched Medline and Embase using keywords related to psilocybin. We reviewed titles and texts in duplicate using Covidence software. We extracted data individually in duplicate using Covidence software and a senior reviewer resolved all author conflicts. We analyzed data descriptively.
Results
We included 193 published and 80 ongoing studies. Thirty-seven percent of included studies were systematic reviews. Only 12% of included studies were randomized controlled trials. The median number of participants was 22 with a median of 18 participants who had taken psilocybin. Thirty-eight percent of studies reported at least one potential conflict of interest. The most common indication was depression (28%). Also commonly studied were substance use (14%), mental health in life-threatening illness (9%), headaches (6%), depression and anxiety (6%), obsessive-compulsive disorder (3%), and anxiety disorders (3%).
Conclusions
Most studies involving the administration of psilocybin have small sample sizes and the most common focus has been psychiatric disorders. There is a need for high-quality randomized trials on psilocybin and to expand consideration to other promising indications, such as chronic pain.
... However, the more research on this system is performed, the more important it seems to become. Many studies now connect the microbiome and receptors in the gut to the CNS through the gut-brain axis (GBA) 52 . The first way that the gut can interact with psilocybin is that the liver and stomach are the sites of psilocybin to psilocin dephosphorylation by alkaline phosphatase 53 . ...
The global population is ageing rapidly, with the number of individuals aged 60 and older reaching 1 billion in 2019 and expected to double by 2050. As people age, neuropsychological health often deteriorates, leading to a higher prevalence of age-related depression. Symptoms may include anxiety, apathy, mood instability, sadness, and, in severe cases, suicidal thoughts. Depression in the elderly is a widespread concern, and conventional treatments such as antidepressants are often limited by side effects, reduced efficacy, and complications arising from polypharmacy. In response, novel therapeutic approaches are being explored, including psychedelic interventions. Recent clinical and preclinical studies suggest that psychedelics could offer a promising treatment for major depressive disorder (MDD) in older adults. These compounds, known for their profound neurobiological effects, have gained attention for their potential to address depression where traditional therapies fall short. This review aims to examine the therapeutic promise of psychedelic substances, focusing on those that show potential for treating MDD in the elderly. We also explore the underlying mechanisms through which psychedelics may exert their effects and highlight the preclinical models that support their use. Finally, we address safety considerations and propose strategies to enhance the effectiveness and safety of psychedelics in future clinical trials, offering new hope for treating age-related depressive disorders.
Psilocybin is an active alkaloid found in magic mushrooms (Psilocybe cubensis). It is classified as a Class I Psychoactive Substance due to its psychoactive properties. Recent research has suggested that psilocybin holds potential for treating major depressive disorder. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for psilocybin and its active metabolite, psilocin, in mice, rats, and humans. This model aims to explore the disposition of psilocin within the body, including its distribution to the target organ, the brain. Psilocybin is assumed to undergo complete conversion to psilocin before the latter enters systemic circulation. The PBPK model effectively characterizes the concentration-time profiles under various dosing scenarios and routes of administration in mice, rats, and humans. The human model has the potential for guiding therapeutic strategies and enhancing clinical trial designs for the therapeutic use of psilocybin.
We aimed to investigate whether psilocin, the bioactive metabolite of the well-known psychedelic, psilocybin, may have antipruritic effects in mice by interfering with the kynurenine pathway and interacting with 5-HT2A receptors. Eight mice were randomly assigned to each of the study groups receiving either normal saline, compound 48/80, psilocin (0.3, 1, and 3 mg/kg), or psilocin (1 mg/kg) + 1-MT (0.3 mg/kg). The scratching bouts were documented in each group. The hallucinogenic properties of psilocin were documented using the head-twitch response (HTR) test. To confirm their involvement, we also quantified the expression levels of TNF-α, TLR-4, indoleamine-2,3-dioxygenase (IDO), and 5-HT2A receptors across various study groups. We found that psilocin (1 mg/kg) exerted the most significant antipruritic and hallucinogenic effects (P < 0.0001). The activity of 5-HT2A receptors in the skin tissue of mice was confirmed by western blot. When psilocin (1 mg/kg) was given together with 1-MT (0.3 mg/kg), the antipruritic effects became more pronounced as compared to when psilocin was given alone (P < 0.05). TLR-4 and TNF-α expression levels considerably reduced after psilocin was applied, both alone and together with 1-MT (P < 0.05, P < 0.01, respectively). We also observed significantly decreased activity of IDO in the treatment groups (P < 0.05, P < 0.01 after giving psilocin alone, and together with 1-MT, respectively). To our knowledge, this is the first study to confirm the effectiveness of psychedelics in battling pruritus. Our findings offer a novel repositioning for psilocin. This may be particularly beneficial for psychological conditions accompanied by pruritus.
Introduction:
Although long known for their psychoactive effects, psychedelic drugs have only recently been investigated for medicinal use. Psilocybin has attracted the greatest interest with studies suggesting that it may be a useful agent in psychiatry and in palliative care.
Areas covered:
Clinical trials that included psilocybin were searched in PubMed, Embase, and ClinicalTrials.gov, demonstrating that adult psychiatry and palliative care are the medical fields that show the greatest interest in psilocybin treatment.
Expert opinion:
Psilocybin is a powerful drug that needs to be used with caution but may benefit some patients, including when other options have failed. It is best evidenced in treatment resistant depression and in palliative care, where patients are usually treated in specialist care centers. It has a novel mechanism of action, targeting the 5HT2A receptor, and can show rapid onset of action. There are many questions regarding its use that remain to be clarified, including its efficacy for other indications and its role as adjunctive treatment in psychotherapy. The psychoactive, or psychedelic effects are well documented, but their clinical importance is disputed.
Objective: Psychedelics are gaining renewed attention, especially through the practice of microdosing, where low
doses are taken regularly. Microdosing lysergic acid diethylamide (LSD) and psilocybin is used by both healthy
individuals and those with mental health conditions to improve daily functioning, reduce anxiety, and enhance
mood and cognition. However, there is limited information about the side effects of this practice. This review
aimed to collect and characterize the side effects of psychedelic microdosing.
Methods: We conducted a systematic review of original papers from PubMed, Web of Science, and Scopus
(accessed August 03, 2024) that reported side effects of microdosing LSD and psilocybin. Non-English papers,
non-original studies, studies without typical microdosing doses, or those lacking descriptions of side effects were
excluded. Our methodology has been developed in accordance with PRISMA guidelines. Because side effects
were assessed heterogeneously in these papers, we did not perform a bias evaluation.
Results: We included 31 studies, 15 of which we classified as laboratory studies with higher quality evidence, and
14 studies with lower quality evidence, as well as 2 clinical cases. Side effects were typically dose-dependent,
mild, and short-lived. Common adverse effects included increased blood pressure, anxiety, and cognitive
impairment.
Discussion: This review is limited by the heterogeneity in reporting side effects and the short duration of many
studies. Future studies should transparently and systematically present a description of side effects.
Background
Psilocybin, a serotonin 2A receptor agonist with psychedelic properties, shows promise as a novel treatment for alcohol use disorder (AUD). While current studies involve two dosing sessions, the effects of a single dose have not been investigated.
Aims
To investigate the pharmacokinetics, feasibility, safety and efficacy of single-dose psilocybin therapy in AUD.
Methods
This open-label, single-group study investigated single-dose psilocybin therapy in 10 treatment-seeking adults (8 men and 2 women; median age 44 years) with severe AUD. The treatment involved two preparation sessions, a high-dose psilocybin session (25 mg) and two integration sessions. Pharmacokinetics were determined by noncompartmental analysis, and changes in alcohol consumption, craving and self-efficacy, were assessed using a linear mixed model.
Results
Notable between-participant pharmacokinetic variations were observed, with peak plasma psilocin concentrations ranging from 14 to 59 µg/L. Alcohol consumption significantly decreased over the 12 weeks following psilocybin administration. Heavy drinking days were reduced by 37.5 percentage points (95% CI: −61.1 to −13.9, p = 0.005), and drinks per day decreased by 3.4 drinks (95% CI: −6.5 to −0.3, p = 0.03). This was corroborated by reports of rapid and sustained reductions in craving and increases in self-efficacy.
Conclusions
Despite pharmacokinetic variations, a single 25 mg psilocybin dose was safe and effective in reducing alcohol consumption in AUD patients. Larger randomised, placebo-controlled, single-dose AUD trials are warranted.
Clinical trial registration
https://clinicaltrials.gov/study/NCT04718792
Introduction:
A substantial number of patients exhibit treatment-resistant depression (TRD), posing significant challenges to clinicians. The discovery of novel molecules or mechanisms that may underlie TRD pathogenesis and antidepressant actions is highly needed.
Areas covered:
Using the PubMed database, the authors searched for emerging evidence of novel approaches for TRD based on experimental and human studies. Herein, the authors discuss the mechanisms underlying glutamatergic antagonists, modulators of the opioid system, and tryptamine-derivate psychedelics as well as the emerging platforms to investigate novel pharmacological targets for TRD. A search for clinical trials investigating novel agents and interventions for TRD was also conducted.
Expert opinion:
The understanding of the multiple pathophysiological mechanisms involved in TRD may add further value to the effective treatment, contributing to a more personalized approach. Esketamine was approved for the treatment of TRD and novel drugs with rapid antidepressant actions such as psilocybin and buprenorphine have also been investigated as potential therapeutic strategies. Over the past decades, technological advances such as omics approaches have broadened our knowledge regarding molecular and genetic underpinnings of complex conditions like TRD. Omics approaches could open new avenues for investigating glial-mediated mechanisms, including their crosstalk with neurons, as therapeutic targets in TRD.
Objective:
The authors critically examine the evidence base for psilocybin administered with psychological support/therapy (PST) in the treatment of psychiatric disorders and offer practical recommendations to guide future research endeavors.
Methods:
PubMed was searched for English-language articles from January 1998 to November 2023, using the search term "psilocybin." A total of 1,449 articles were identified and screened through titles and abstracts. Of these, 21 unique open-label or randomized controlled trials (RCTs) were identified that examine psilocybin for the treatment of obsessive-compulsive and related disorders (N=2), anxiety/depression associated with a cancer diagnosis (N=5), major depressive disorder (MDD; N=8), substance use disorders (N=4), anorexia (N=1), and demoralization (i.e., hopelessness, helplessness, and poor coping) in AIDS survivors (N=1).
Results:
The most developed evidence base is for the treatment of MDD (three double-blind RCTs with positive signals spanning a range of severities). However, the evidence is tempered by threats to internal and external validity, including unsuccessful blinding, small samples, large variability in dosing and PST procedures, limited sample diversity, and possibly large expectancy effects. Knowledge of mechanisms of action and predictors of response is currently limited.
Conclusions:
The evidence is currently insufficient to recommend psilocybin with PST as a psychiatric treatment. Additional rigorously designed clinical trials are needed to definitively establish efficacy in larger and more diverse samples, address dosing considerations, improve blinding, and provide information on mechanisms of action and moderators of clinical response. Head-to-head comparisons with other evidence-based treatments will better inform the potential future role of psilocybin with PST in the treatment of major psychiatric disorders.
Psychotropic substances may interfere in different aspects of life, routine and functionality of its users. Among the affected fields, sleep is one of the most prominent. Currently, a wide array of different substances is available in the market, acting on sleep and behavior by a multitude of mechanisms and pathways. The impact on sleep must not be treated as an isolated phenomenon in such cases, as it may be directly associated with the reinforcing properties and capability of causing dependence of these drugs. Three great classes of psychotropic substances can be defined: stimulants, depressants, and hallucinogens. Each of these has particularities that need to be considered when assessing sleep in recreational substance users. Furthermore, each substance in these classes warrants a closer look, as they may present specific traits that are crucial to the treatment of individuals with substance use disorder, such as the occult insomnia observed in cocaine users or the severe psychiatric symptoms accompanied by insomnia frequently reported during benzodiazepine abstinence. In this sense, this chapter aims to carefully evaluate each of the main classes of substances, focusing on the more recent findings regarding the relationship between their use and sleep. This body of evidence will serve as a guide to physicians and personnel from health agencies, calling attention to the decisive role sleep has in the treatment of patients with substance use disorder.
The synthetic utility of tetrabenzyl pyrophosphate for achieving chemoselective phosphorylation of phenols, as well as primary, secondary, and tertiary alcohols, is reported here. Additionally, we introduce a rapid, mild, and chemoselective debenzylation procedure, enabling access to phosphates in the presence of redox sensitive groups. Finally, stoichiometrically controlled monodebenzylation provides a versatile platform for late-stage divergent synthesis of phosphodiester and phosphoramidate chemical libraries.
In post-mortem (PM) investigations, forensic toxicologists attempt to identify legal or illegal substances present before death and determine how they contributed to the cause of death. A critical challenge is ensuring that PM sample concentrations accurately reflect those at the time of death, as postmortem redistribution (PMR) can alter these levels due to anatomical and physiological changes. The PMR phenomenon is called a ‘toxicological nightmare’. PMR significantly affects post-mortem drug concentrations, particularly for lipophilic drugs and those with a high volume of distribution. The emergence of new psychoactive substances (NPSs) has led to a growing recognition of their role as a significant public health concern, frequently associated with fatalities related to polydrug use. These substances are renowned for their ability to induce intoxication at low doses, which has led to the continuous updating of toxicological and forensic methods to improve detection and adopt new analytical standards. The comprehensive detection of NPS metabolites, some of which are still undiscovered, presents an additional analytical challenge, as do their metabolic pathways. This complicates their identification in fatal cases using standard analytical methods, potentially leading to an underestimation of their actual prevalence in toxicological results. Furthermore, the interpretation of analytical results is hindered by the absence of data on PM blood levels and the specific contributions of NPS to causes of death, exacerbated by the lack of knowledge of whether the PMR phenomenon influences them. This paper presents a comprehensive review of the literature on post-mortem cases involving various NPS, categorized according to classifications by the United Nations Office on Drugs and Crime (UNODC) and the European Union Drugs Agency (EUDA). These categories include cathinones, phenylethylamines, arylalkylamines, phencyclidine-type substances, phenmetrazines, piperazines, phenidates, aminoindanes, LSD-like NPSs, tryptamines, fentanyl analogs, designer benzodiazepines, synthetic cannabinoids, and nitazenes. This review covers not only postmortem blood levels but also the stability of the substances studied, the methods of analysis, and attempts to shed some light on the PMR phenomenon. This review used various key terms, such as PMR, NPS, and the names of previously categorized substances and drug analyses across multiple peer-reviewed journals and databases, including Scopus, Google Schoolar, Springer, PubMed, and Wiley Online Library. In addition, references from retrieved articles were examined to identify additional relevant research. Interpreting post-mortem toxicological results is complex and lacks definitive guidelines, requiring a nuanced understanding of its challenges and potential pitfalls. As a result, post-mortem toxicology is often regarded as an art. The primary aim of this review is to provide forensic toxicologists with a comprehensive framework to assist in the evaluation and interpretation of NPS analysis. This guide is intended to complement the existing knowledge and practices applied in forensic laboratories within the toxicological analysis of post-mortem cases.
Fenomen konzumiranja psihoaktivnih sredstava prisutan je od davnina i opisivan kroz brojne povijesne zapise. Konzumiranje ilegalnih psihoaktivnih tvari i stvaranje ovisnosti o njima jedan je od najznačajnijih javnozdravstvenih problema. U ovom će radu biti prikazane psihoaktivne tvari, psihodelici, koje se koriste u liječenju psihičkih poremećaja. Potrebno je naglasiti važnost razlikovanja zloupotrebe droge i njihove uporabe u terapijske svrhe, u kontroliranim uvjetima. Psihodelici su psihoaktivne tvari koje uzrokuju promjenu u percepciji, stanju svijesti te utječu na razinu energije i raspoloženje. Dijele se na sintetičke i prirodne. Najpoznatiji su psihodelici dietilamid lizerginske kiseline (LSD), dimetiltriptamin (DMT), psilocibin i meskalin. Brojni halucinogeni lijekovi prirodnog podrijetla, dobiveni iz gljiva i biljaka, tisućama se godina koriste u vjerskim ili tradicionalnim ritualima. Sredinom 20. stoljeća pobudio se interes za upotrebom psihodelika u psihijatriji i psihologiji kao sredstvima za skraćivanje psihoterapije. Zbog političkog pritiska, ali i potencijalne opasnosti nekontrolirane upotrebe, zabranjeni su sedamdesetih godina prošlog stoljeća. U suvremenoj psihijatrijskoj praksi ponovno se primjenjuju u kontroliranim uvjetima, prema pisanom protokolu i uz detaljnu pripremu bolesnika.
Psychedelics are currently undergoing a scientific renaissance, with modern studies investigating therapeutic efficacy of psychedelic-assisted therapy in a range of psychiatric conditions. In particular, psilocybin-assisted therapy (PAT) has been suggested to have positive effects on patients suffering from depression and psychiatric distress associated with life-threatening disease - contexts with growing needs for alternative treatments - in a therapeutic setting involving fewer doses and less important adverse effect compared to that of classic psychotrope administration. Psychedelics are partial agonists of the serotonin 2A (5-HT2A) G protein-coupled receptors, whose activation likely mediates the acute psychoactive effects. Furthermore, psychedelics seem to induce a hyper-plastic state which allows for adaptation of inflexible pathological thinking patterns. Post-acutely, they are suggested to induce rapid, robust and sustained neuroplasticity. Eight clinical PAT trials have been conducted between January 1st 2001 and March 31st 2023 and are reviewed here. Five of them evaluate the effect on depressive symptomatology in an otherwise general population. The other three evaluate effect on depression and anxiety in patients suffering from somatic life-threatening disease. The studies reviewed here show that PAT is safe and feasible to administer in current clinical models. Preliminary efficacy shows significant improvements in depressive and anxious symptomatology which are immediate and partially sustained. One study comparing PAT to selective serotonergic reuptake inhibitors showed no significant difference of efficacy between the two treatments. Preliminary results regarding efficacy of PAT on mood disorders are promising, but further research is warranted for stronger inferences, with a particular focus on larger, multicentric studies, more diverse populations and a stronger control for expectancy and unblinding.
Interest in psychedelic research in the West is surging, however, clinical trials have almost exclusively studied synthetic compounds such as MDMA, ketamine, DMT, LSD, ibogaine, and psilocybin. To date, few clinical trials have utilized whole mushroom/plant material like Psilocybe mushrooms, Iboga, or Ayahuasca. Individuals participating in the Roots To Thrive Psilocybin-Assisted Therapy for End of Life Distress program were administered synthetic psilocybin, whole Psilocybe cubensis, and mycological extract on separate occasions and post-treatment interview transcripts were qualitatively analyzed to discern themes and patterns. There was broad consensus that all three forms were helpful and similar, all generating visual and perceptual distortions, emotional and cognitive insight, and mystical experiences. However, synthetic psilocybin was said to feel less natural compared to organic forms, and the overall quality of experience of synthetic psilocybin was inferior to the organic forms. Research should be conducted with whole psychedelic mushrooms and extract in addition to synthetic psilocybin given this preliminary data, especially when considering that medicine keepers around the world have utilized whole mushrooms and plant material for millennia.
As psychedelics are being investigated for more medical indications, it has become important to characterize the adverse effects and pharmacological interactions with these medications. This chapter will summarize what is known about the toxicology and drug–drug interactions for classic psychedelics, such as LSD, psilocybin, DMT, 5-MeO-DMT, mescaline, 2C-B, Bromo-DragonFLY, and 25X-NBOMe.
Introduction:
Evidence based treatment for Substance use disorders (SUD) includes psychotherapy and pharmacotherapy. However, these are only partially effective. Hallucinogens, such as psilocybin, may represent potential new treatment options for SUD. This review provides a summary of (human) studies on the putative therapeutic effects of psilocybin, and discusses the receptor systems, brain regions and cognitive and emotional processes mediating psilocybin's effects. Psilocybin's chemical structure is similar to that of serotonin. Dysregulations in the serotonin system are associated with alterations in stress hormones, such as cortisol, and mood disorders. After psilocybin administration cortisol levels spike and activate the executive control network, with subsequent increased control over emotional processes, and relief of negative thinking and persistent negative emotions. Preliminary data of ongoing alcohol and smoking addiction studies in humans shows promising effects of psilocybin administration on substance use. Importantly, psilocybin has a low risk of toxicity and dependence and can be used safely under controlled clinical conditions.
Areas covered:
This paper is a narrative review based on the search terms: psilocybin, substance use disorder, addiction, depression, serotonin. Literature on potential efficacy and mechanisms of action of psilocybin in SUD is discussed. Expert commentary: Recent positive findings with psilocybin need confirmation in well-designed placebo controlled randomized trials employing a large sample size.
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.
The definition New psychoactive substances (NPS) refers to emerging drugs whose chemical structures are similar to other psychoactive compounds but not identical, representing a “legal” alternative to internationally controlled drugs. There are many categories of NPS, such as synthetic cannabinoids, synthetic cathinones, phenylethylamines, piperazines, ketamine derivatives and tryptamines. Tryptamines are naturally occurring compounds, which can derive from the amino acid tryptophan by several biosynthetic pathways: their structure is a combination of a benzene ring and a pyrrole ring, with the addition of a 2-carbon side chain. Tryptamines include serotonin and melatonin as well as other compounds known for their hallucinogenic properties, such as psilocybin in ‘Magic mushrooms’ and dimethyltryptamine (DMT) in Ayahuasca brews.
Aim: To review the scientific literature regarding tryptamines and their derivatives, providing a summary of all the available information about the structure of these compounds, their effects in relationship with the routes of administration, their pharmacology and toxicity, including articles reporting cases of death related to intake of these substances.
Methods: A comprehensive review of the published scientific literature was performed, using also non peer-reviewed information sources, such as books, government publications and drug user web fora.
Conclusions: Information from Internet and from published scientific literature, organized in the way we proposed in this review, provides an effective tool for specialists facing the emerging NPS threat to public health and public security, including the personnel working in Emergency Department.
Psilocybin, a psychoactive alkaloid contained in hallucinogenic mushrooms, is nowadays given a lot of attention in the scientific community as a research tool for modeling psychosis as well as due to its potential therapeutic effects. However, it is also a very popular and frequently abused natural hallucinogen. This review summarizes all the past and recent knowledge on psilocybin. It briefly deals with its history, discusses the pharmacokinetics and pharmacodynamics, and compares its action in humans and animals. It attempts to describe the mechanism of psychedelic effects and objectify its action using modern imaging and psychometric methods. Finally, it describes its therapeutic and abuse potential.
Fungi, in particular, are able in common with the higher plants and bacteria, to produce metabolites, including alkaloids. Alkaloids, along with other metabolites are the most important fungal metabolites from pharmaceutical and industrial point of view. Based on this observation, the authors of this review article have tried to provide an information on the alkaloids produced by the species of genera: Boletus, Fusarium and Psilocybef from 1981-2009. Thus the review would be helpful and provides valuable information for the researchers of the same field.
In order to investigate the pharmacokinetic properties of psilocybin (PY), the main psychoactive compound of Psilocybe mushrooms, high performance liquid chromatographic procedures with column-switching coupled with electrochemical detection (HPLC-ECD) for reliable quantitative determination of the PY metabolites psilocin (PI) and 4-hydroxyindole-3-acetic acid (4HIAA) in human plasma were established. Sample work-up includes protection of the highly unstable phenolic analytes with ascorbic acid, freeze-drying and in-vitro microdialysis. The data of two controlled clinical studies with healthy volunteers are presented. The subjects (N = 6 for both studies) received single oral PY doses of 0.224 +/- 0.02 mg/kg b.wt. (10-20 mg) and intravenous doses of 1 mg PY, respectively. Peak plasma levels of PI after oral administration of PY were measured after 105 +/- 37 min showing an average concentration of 8.2 +/- 2.8 ng PI/ml plasma. 4HIAA peak concentrations of 150 +/- 61 ng/ml plasma were found 113 +/- 41 min after ingestion of PY. After intravenous administration, a mean PI maximum plasma concentration of 12.9 +/- 5.6 ng/ml plasma was found 1.9 +/- 1.0 min after injection. The maximum plasma levels appearing within a very short period indicate a rapid dephosphorylation of PY also when administered systemically. 4HIAA was not detected after 1 mg of intravenous PY. Estimates for the absolute bioavailability of PI after oral administration of PY were 52.7 +/- 20% (N = 3).
Tramadol and tapentadol are centrally acting, synthetic opioid analgesics used in the treatment of moderate to severe pain. Main metabolic patterns for these drugs in humans are well characterized. Tramadol is mainly metabolized by cytochrome P450 CYP2D6 to O-desmethyltramadol (M1), its main active metabolite. M1 and tapentadol undergo mainly glucuronidation reactions. On the other hand, the pharmacokinetics of tramadol and tapentadol are dependent on multiple factors, such as the route of administration, genetic variability in pharmacokinetic components and concurrent consumption of other drugs. This review aims to comparatively discuss the metabolomics of tramadol and tapentadol, namely by presenting all their known metabolites. An exhaustive literature search was performed using textual and structural queries for tramadol and tapentadol and associated known metabolizing enzymes and metabolites. A thorough knowledge about tramadol and tapentadol metabolomics is expected to provide additional insights to better understand the interindividual variability in their pharmacokinetics and dose-responsiveness, and contribute to the establishment of personalized therapeutic approaches, minimizing side effects and optimizing analgesic efficacy.
Methadone is a full μ-opioid receptor agonist used in the treatment of heroin addiction. It is commercialized as a racemic mixture with considerable variability in the pharmacokinetics and pharmacodynamics between individuals that can affect dose-response and toxicological profile. This review aims to discuss metabolomics of methadone, namely by presenting all major and minor metabolites and pharmacokinetic drug interactions. The main mechanism for methadone metabolism is hepatic through the cytochrome P450, specifically isoenzymes 2B6, 3A4 and 2D6. Firstly, methadone is N-demethylated and cyclize to form its major 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP) metabolites. Several alternate minor pathways have been described namely various methadol metabolites, which proved to be active.It is expected that knowing the metabolomics of methadone may provide further insights, attempting a personalized therapy aiming to attain effective blood concentrations. The historical record is therefore especially important when investigating clinical and forensic cases related to methadone administration, since interindividual responses are known to vary considerably.
Cannabis sativa is the most commonly used recreational drug, Δ9-tetrahydrocannabinol (Δ9-THC) being the main addictive compound. Biotransformation of cannabinoids is an important field of xenobiochemistry and toxicology and the study of the metabolism can lead to the discovery of new compounds, unknown metabolites with unique structures and new therapeutic effects. The pharmacokinetics of Δ9-THC is dependent on multiple factors such as physical/chemical form, route of administration, genetics, and concurrent consumption of alcohol. This review aims to discuss metabolomics of Δ9-THC, namely by presenting all known metabolites of Δ9-THC described both in vitro and in vivo, and their roles in the Δ9-THC-mediated toxic effects. Since medicinal use is increasing, metabolomics of Δ9-THC will also be discussed in order to uncover potential active metabolites that can be made available for this purpose.
Background:
It is well known that ethanol can cause significant morbidity and mortality, and much of the related toxic effects can be explained by its metabolic profile.
Objective:
This work performs a complete review of the metabolism of ethanol focusing on both major and minor metabolites.
Method:
An exhaustive literature search was carried out using textual and structural queries for ethanol and related known metabolizing enzymes and metabolites.
Results:
The main pathway of metabolism is catalyzed by cytosolic alcohol dehydrogenase, which exhibits multiple isoenzymes and genetic polymorphisms with clinical and forensic implications. Another two oxidative routes, the highly inducible CYP2E1 system and peroxisomal catalase may acquire relevance under specific circumstances. In addition to oxidative metabolism, ethanol also originates minor metabolites such as ethyl glucuronide, ethyl sulfate, ethyl phosphate, ethyl nitrite, phosphatidylethanol and fatty acid ethyl esters. These metabolites represent alternative biomarkers since they can be detected several hours or days after ethanol exposure.
Conclusion:
It is expected that knowing the metabolomics of ethanol may provide additional insights to better understand the toxicological effects and the variability of dose response.
Hallucinogens are drugs that alter consciousness by distorting primarily auditory and visual perception but can affect any sensory system. Hallucinogens also affect judgment, orientation, memory, and emotions. Despite profound alterations in perception, adverse effects are minimal and hallucinogens are not addictive. Hallucinogen use has its roots in shamanic practices of indigenous cultures and is even incorporated in today's religions like the Native American church. By putting a person in an altered state of consciousness, many religions believed that the user was able to see beyond the boundaries of reality and reach out to mythical beings. Hallucinogen use in scientific research was not popular until the 1950s when Albert Hoffman discovered lysergic acid diethylamide (LSD). The discovery of the drug encouraged further research into understanding its mechanisms and its relationship with mental diseases like schizophrenia. Unfortunately, the Comprehensive Drug Abuse Prevention and Control Act of 1970 significantly limited hallucinogenic research and human research for 42 years before 2012. However, animal research between 1990 and 2010 has determined the importance of serotonergic mechanisms and more specifically the 5-HT2A receptors in mediating LSD's hallucinogenic effects. Researchers continue to identify mechanisms of LSD action through additional receptors such as dopaminergic and metabotropic glutamate receptors. Positron emission tomography scans and functional magnetic resonance imaging have also revealed the importance of the prefrontal cortical region and its interaction with other areas during a hallucinogenic state. Although human clinical research is limited, recent research sees a much deeper relationship by linking LSD brain activity and neurotransmitter levels to psychotic behaviors. The relationship between LSD and acute psychosis is being explored via animal models. Further understanding of hallucinogens on a physiological and psychological level has led to possible psychotherapeutic areas of research in anxiety and substance abuse. This chapter describes a brief history of hallucinogenic research, the pharmacology and neuroanatomy of serotonergic hallucinogens, the acute and chronic adverse effects of serotonergic hallucinogens, the possible treatments for complications with hallucinogenic use, the epidemiology, the relationship between hallucinogens and schizophrenia, and possible therapeutic uses of serotonergic hallucinogens.
Cocaine is the most commonly used illicit drug among those seeking care in Emergency Departments or drug detoxification centers. Cocaine, chemically known as benzoylmethylecgonine, is a naturally occurring substance found in the leaves of the Erythroxylum coca plant. The pharmacokinetics of cocaine is dependent on multiple factors, such as physical/chemical form, route of administration, genetics and concurrent consumption of alcohol. This review aims to discuss metabolomics of cocaine, namely by presenting all known metabolites of cocaine and their roles in the cocaine-mediated toxic effects.
A two-step synthesis of psilocin glucuronide (PCG), the main metabolite of psilocin, with methyl 2,3,4-tri-O-isobutyryl-1-O-trichloroacetimidoyl-α-d-glucopyranuronate is reported. With the synthesized PCG, hydrolysis conditions in serum and urine were optimized. Escherichia coli proved to be a better enzyme source for β-glucuronidase than Helix pomatia. It was essential to add ascorbic acid to serum samples to protect psilocin during incubation. Furthermore the stability of PCG and psilocin was compared as stability data are the basis for forensic interpretation of measurements. PCG showed a greater long-term stability after six months in deep frozen serum and urine samples than psilocin. The short-term stability of PCG for one week in whole blood at room temperature and in deep frozen samples was also better than that of psilocin. Therefore, PCG can be considered to be more stable than the labile psilocin and should always be included if psilocin is analyzed in samples.
Introduction:
alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. In particular berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids with anti-lipogenic and hypoglycemic effects. On the other hand, mate plant has reported to have high antioxidant potential, including an inhibitory ability against plasma and LDL oxidation.
Areas covered:
Most of the studies reported in literature about alkaloids are pre-clinical trials, and we have already discussed them in a previous review we conducted. This time we want to focus our attention on clinical studies about berberine, and mate plant, so the aim of this review is to evaluate berberine and mate plant efficacy and safety in humans.
Conclusion:
Berberine is a potent oral hypoglycemic agent with a good effect on lipid metabolism. It is safe and the cost of treatment is very low. Also mate plant seems to have antioxidant and hypolipidemic actions, even if further studies are necessary.
Psilocybin/psilocin from so-called psychoactive mushrooms causes hallucinogenic effects. Especially for people with mental or psychiatric disorders ingestion of magic mushrooms may result in horror trips combined with the intention of self-destruction and suicidal thoughts. Automutilation after consumption of hallucinogenic mushrooms has already been described. Our case report demonstrates the suicide of a man by self-inflicted cut and stab injuries. A causal connection between suicidal behaviour and previous ingestion of psychoactive mushrooms is discussed.
Hallucinogen is a term used to describe compounds that alter a person's perception of reality. Typically, a hallucinogen causes the user to have a heightened state of awareness of sensory input (audio, visual, etc.) and diminished control over the experience. Hallucinogens are divided into several categories. One method of characterization of hallucinogens is as nitrogen containing or non-nitrogen containing. Other classification schemes classify them as indolylalkylamines and phenylalkylamines. Regardless of the classification scheme, most of the compounds are plant alkaloids or derivatives. This chapter discusses the most common examples, including lysergic acid diethylamide (LSD), mescaline, psilocybin and phencyclidine (PCP). LSD, mescaline and psilocybin are chemically different structures, yet, they have similar pharmacological activities. These drugs have a long history and their popularity comes and goes with time, but they remain a constant presence in the drug community. LSD in particular has risen in popularity in recent years, and it appears that LSD use is continuing to rise. The use of low doses of this drug made its isolation and identification a significant analytical challenge.
The psychotropically active principles of the Mexican hallucinogenic fungus Psilocybe maxicana HEIM have been isolated and obtained in crystalline form. The two new substances, which have been called psilocybin and psilocin, are present in the fruit bodies, the artificially cultivated mycelium and in the sclerotia. The dried mushroom contains 0.2 to 0.4 per cent psilocybin. Psilocin is present, at the most, in trace amounts only.
A validated method for the simultaneous determination of psilocin, bufotenine, lysergic acid diethylamide and its metabolites in serum, plasma and urine using liquid chromatography-electrospray ionization/tandem mass spectrometry was developed. During the solid-phase extraction procedure with polymeric mixed-mode cation exchange columns, the unstable analytes were protected by ascorbic acid, drying with nitrogen and exclusion of light. The limits of detection and quantitation for all analytes were low. Recovery was ≥86 % for all analytes and no significant matrix effects were observed. Interday and intraday imprecisions at different concentrations ranged from 1.1 to 8.2 % relative standard deviation, bias was within ±5.3 %. Processed samples were stable in the autosampler for at least 2 days. Furthermore, freeze/thaw and long-term stability were investigated. The method was successfully applied to authentic serum and urine samples.
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is the major psychoactive alkaloid of some species of mushrooms distributed worldwide. These mushrooms represent a growing problem regarding hallucinogenic drug abuse. Despite its experimental medical use in the 1960s, only very few pharmacological data about psilocybin were known until recently. Because of its still growing capacity for abuse and the widely dispersed data this review presents all the available pharmacological data about psilocybin.
The active principle ofPsilocybe mexicana Heim, a mexican mushroom with hallucinogenic properties, has been isolated in crystalline form. The compound has been given the namePsilocybin; it possesses indole characteristics and contains phosphorus. A second substance, closely related toPsilocybin but found only in traces, has been calledPsilocin.
1.
The reaction induced by oral administration of 57 to 114 mcgm/kg of 0-Phosphoryl-4-hydroxy-N-dimethyltryptamine (psilocybin) has been compared with that induced by a placebo and LSD-25 (1.0 to 1.5 mcgm/kg) in 9 subjects.
2.
Both LSD and psilocybin caused elevations in body temperature, pulse and respiratory rates, and systolic blood pressure. Threshold for elicitation of the kneejerk was decreased by both drugs.
3.
After both drugs, abnormal mental states characterized by feelings of strangeness, difficulty in thinking, anxiety, altered sensory perception (particularly visual), elementary and true visual hallucinations, and alterations of body image were reported by the subjects.
4.
The effects of psilocybin did not persist as long as those of LSD.
5.
LSD is 100 to 150 times as potent as psilocybin.
Hallucinogenic Mushrooms in Mexico: An Overview.
Psilocybe, with 53 known hallucinogenic species in Mexico, is the most important and diverse group of sacred mushrooms used by Mexican indigenous cultures. Psilocybe caerulescens, known by the present-day Nahuatl Indians as teotlaquilnanácatl, is hypothesized to be the ceremonially-used teonanácatl mushroom cited by Sahagún in the 16th century, the true identity of which has remained obscure for centuries. Correcting a widely disseminated error derived from early published information on Mexican hallucinogenic mushrooms, emphasis is placed on the fact that Panaeolus species have never been used traditionally in Mexico. Reports of the use of species of Amanita, Clavaria, Conocybe, Cordyceps, Dictyophora, Elaphomyces, Gomphus, Lycoperdon, Psathyrella, and Stropharia as sacred or narcotic mushrooms are discussed. A brief history of the discovery of hallucinogenic mushrooms in Mexico is presented, as well as notes on their taxonomy, distribution, and traditional use in Mexico.
The effects of indolealkylamine and phenylethylamine psychotomimetic drugs on brain 5-hydroxytryptamine (5-HT) metabolism have been studied. Indolealkylamines (psilocybin, psilocin, N,N-dimethyltryptamine or DMT) have a lysergic acid diethylamide (LSD)-like effect (increased 5-HT with concomitant decrease in 5-hydroxyindoleacetic acid. 5-HIAA). A degree of inhibition of monoamine oxidase can be demonstrated with psilocybin and psilocin, but not with LSD. The data suggest that other factors are operative in producing decreased levels of 5-HIAA. Phenylethylamines (mescaline, 2,5-dimethoxy-α,4-dimethylphenylethylamine or DOM) not only increase 5-HT but also, at higher doses, 5-HIAA; at lower doses, there is some indication of an LSD-like effect on 5-HIAA. Both categories of drug influence 5-HT metabolism, and the noted differences with respect to 5-HIAA cannot as yet be accounted for.
A liquid chromatography-electrospray ionization/tandem mass spectrometry method for the quantitation of psilocin in plasma is presented. Sample workup was performed with mixed-mode solid-phase extraction using ascorbic acid and nitrogen for drying to protect the unstable analyte. Calibration curves were linear from 2 to 100 ng/mL, and no selectivity problems occurred. The limit of detection was 0.1 ng/mL, and the limit of quantitation was 0.34 ng/mL. Recovery was >86% and matrix effects were <110%. Both were reproducible. Interday and intraday precisions at different concentrations were 1.5-4.3% relative standard deviation, bias within ±9%. Processed samples were stable in the autosampler for at least 26 h. Furthermore, the stability of psilocin in blood stored at different temperatures over various periods of time was investigated. Samples stored at room temperature showed a continuous decrease of analyte leading to a loss of about 90% after 1 week. Storage in the fridge improved sample stability significantly. Freezing of blood samples led to a not reproducible loss of psilocin.
In 2007, the Minister of Health of the Netherlands requested the CAM (Coordination point Assessment and Monitoring new drugs) to assess the overall risk of magic mushrooms. The present paper is an updated redraft of the review, written to support the assessment by CAM experts. It summarizes the literature on physical or psychological dependence, acute and chronic toxicity, risk for public health and criminal aspects related to the consumption of magic mushrooms. In the Netherlands, the prevalence of magic mushroom use was declining since 2000 (last year prevalence of 6.3% in 2000 to 2.9% in 2005), and further declined after possession and use became illegal in December 2008. The CAM concluded that the physical and psychological dependence potential of magic mushrooms was low, that acute toxicity was moderate, chronic toxicity low and public health and criminal aspects negligible. The combined use of mushrooms and alcohol and the quality of the setting in which magic mushrooms are used deserve, however, attention. In conclusion, the use of magic mushrooms is relatively safe as only few and relatively mild adverse effects have been reported. The low prevalent but unpredictable provocation of panic attacks and flash-backs remain, however, a point of concern.
Serotonergic hallucinogens produce profound changes in perception, mood, and cognition. These drugs include phenylalkylamines such as mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM), and indoleamines such as (+)-lysergic acid diethylamide (LSD) and psilocybin. Despite their differences in chemical structure, the two classes of hallucinogens produce remarkably similar subjective effects in humans, and induce cross-tolerance. The phenylalkylamine hallucinogens are selective 5-HT(2) receptor agonists, whereas the indoleamines are relatively non-selective for serotonin (5-HT) receptors. There is extensive evidence, from both animal and human studies, that the characteristic effects of hallucinogens are mediated by interactions with the 5-HT(2A) receptor. Nevertheless, there is also evidence that interactions with other receptor sites contribute to the psychopharmacological and behavioral effects of the indoleamine hallucinogens. This article reviews the evidence demonstrating that the effects of indoleamine hallucinogens in a variety of animal behavioral paradigms are mediated by both 5-HT(2) and non-5-HT(2) receptors.
We have examined the glucuronidation of psilocin, a hallucinogenic indole alkaloid, by the 19 recombinant human UDP-glucuronosyltransferases (UGTs) of subfamilies 1A, 2A, and 2B. The glucuronidation of 4-hydroxyindole, a related indole that lacks the N,N-dimethylaminoethyl side chain, was studied as well. UGT1A10 exhibited the highest psilocin glucuronidation activity, whereas the activities of UGTs 1A9, 1A8, 1A7, and 1A6 were significantly lower. On the other hand, UGT1A6 was by far the most active enzyme mediating 4-hydroxyindole glucuronidation, whereas the activities of UGTs 1A7-1A10 toward 4-hydroxyindole resembled their respective psilocin glucuronidation rates. Psilocin glucuronidation by UGT1A10 followed Michaelis-Menten kinetics in which psilocin is a low-affinity high-turnover substrate (K(m) = 3.8 mM; V(max) = 2.5 nmol/min/mg). The kinetics of psilocin glucuronidation by UGT1A9 was more complex and may be best described by biphasic kinetics with both intermediate (K(m1) = 1.0 mM) and very low affinity components. The glucuronidation of 4-hydroxyindole by UGT1A6 exhibited higher affinity (K(m) = 178 microM) and strong substrate inhibition. Experiments with human liver and intestinal microsomes (HLM and HIM, respectively) revealed similar psilocin glucuronidation activity in both samples, but a much higher 4-hydroxyindole glucuronidation rate was found in HLM versus HIM. The expression levels of UGTs 1A6-1A10 in different tissues were studied by quantitative real-time-PCR, and the results, together with the activity assays findings, suggest that whereas psilocin may be subjected to extensive glucuronidation by UGT1A10 in the small intestine, UGT1A9 is likely the main contributor to its glucuronidation once it has been absorbed into the circulation.
Dopamine receptor binding is calf striatal membranes of 3H-dopamine and 3H-haloperidol appears to differentiate agonist and antagonist states of the receptor. Agonists and antagonists have selective affinities for dopamine and haloperidol sites respectively. In evaluating relative affinities for dopamine and haloperidol binding sites, we have observed that d-LSD interacts with considerable affinity at the dopamine receptor. Its similar competition petition for binding of the two tritiated ligands suggests that it is a mixed agonist-antagonist, which is consistent with its interactions with the dopamine-sensitive adenylate cyclase. The effects of LSD on dopamine receptor binding are stereospecific, with d-LSD being 1,000 times more potent than d-LSD. 2-Bromo-LSD has more of an antagonist profile than d-LSD for the dopamine receptor. In binding experiments methiothepin behaves like a potent and relatively pure antagonist at dopamine receptors.
Affinities of drugs for 21 indolealkylamine derivatives, some with putative hallucinogenic activity, were determined at 5-HT1A, 5-HT2A and 5-HT2B recognition sites, using radioligand competition studies. Nearly all of the derivatives displayed greatest potency for the 5-HT2A receptor, labelled by [125I]R-(-)DOI in the cortex of the rat. Most derivatives displayed 2-10 times lower affinity at the HT2B receptor labelled by [3H]ketanserin in bovine cortex. Derivatives lacking ring substituents displayed lower affinities for all of the recognition sites, compared to derivatives substituted in the 4- or 5-position of the indole ring. The 4-hydroxylated derivatives displayed 25-380-fold selectivity for the 5-HT2A site, vs the 5-HT1A site, while the 5-substituted derivatives displayed approximately equal potency at the 5-HT1A and 5-HT2A sites. Affinity of all the compounds at the 5-HT2B site was greater than 300 nM. The 6-substituted derivatives displayed greater than micromolar affinities for all of the 5-HT recognition sites examined. The size of the N,N-dialkyl substituent was a secondary determinant of affinity, with groups larger than N,N-diisopropyl resulting in a marked reduction in affinity at both the 5-HT2A and 5-HT1A recognition sites. This study demonstrated that hallucinogenic 4-hydroxy-indolealkylamines, like psychotomimetic phenylisopropylamines, bind potently and selectively to the 5-HT2A recognition site, labelled by [125I]R-(-)DOI. This provides further evidence indicating that this recently described subtype of the 5-HT2 receptor may partially mediate the action of hallucinogenic agents.
Psilocybin and psilocin at luminal concentrations of about 20 nmol/ml were incubated aerobically with everted sacs from rat jejunum and colon. When incubation was terminated, samples of the lumen and blood side solutions and of the intestinal tissue were analyzed for parent drug and metabolites by HPLC using a multidetector system. Both sacs caused hydrolysis of psilocybin to psilocin, but the rate was much faster in the jejunum than in the colon. Tissue uptake of intact psilocybin was negligible or absent, and no transfer to the contraside of the parent drug could be demonstrated. In contrast, psilocin, whether formed by hydrolysis or added as a substrate, was well taken up by both intestinal segments and transferred to the blood side. In the colonic psilocybin experiments, this uptake and transfer was limited by a low hydrolytic rate. The results indicate that psilocybin under in vivo conditions is absorbed predominantly as psilocin. No further metabolism of either drug was observed, as opposed to the complex metabolism pattern that has been reported for serotonin, a close chemical relative to psilocin.
Chemical properties, biochemistry and pharmacology of psilocybin are briefly surveyed as well as its legal status.
The massive health problem associated with cigarette smoking is exacerbated by the addictive properties of tobacco smoke and the limited success of current approaches to cessation of smoking. Yet little is known about the neuropharmacological actions of cigarette smoke that contribute to smoking behaviour, or why smoking is so prevalent in psychiatric disorders and is associated with a decreased risk of Parkinson's disease. Here we report that brains of living smokers show a 40% decrease in the level of monoamine oxidase B (MAO B; EC 1.4.3.4) relative to non-smokers or former smokers. MAO B is involved in the breakdown of dopamine, a neurotransmitter implicated in reinforcing and motivating behaviours as well as movement. MAO B inhibition is therefore associated with enhanced activity of dopamine, as well as with decreased production of hydrogen peroxide, a source of reactive oxygen species. We propose that reduction of MAO B activity may synergize with nicotine to produce the diverse behavioural and epidemiological effects of smoking.
A capillary zone electrophoretic (CZE) method was developed for the rapid determination of psilocybin in Psilocybe semilanceata. Following a simple two step extraction with 3.0+2.0 ml methanol, the hallucinogenic compound was effectively separated from matrix components by CZE utilizing a 10 mM borate-phosphate running buffer adjusted to pH 11.5. The identity of psilocybin was confirmed by migration time information and by UV spectra, while quantitation was accomplished utilizing barbital as internal standard. The calibration curve for psilocybin was linear within 0.01-1 mg/ml, while intra-day and inter-day variations of quantitative data were 0.5 and 2.5% R.S.D., respectively. In addition to psilocybin, the method was also suitable for the determination of the structurally related compound baeocystin.
Two modifications of the HPLC-ED method with respect to extraction procedure used have been developed for psilocin, the active metabolite of psilocybin, in human plasma using either liquid-liquid extraction (LLE) or automated on-line solid-phase extraction (on-line SPE). Each type of the sample preparation required a different HPLC system followed by electrochemical detection at 650 to 675 mV. The limit of quantitation of both modifications was 10 ng/ml psilocin. There was no significant difference observable between the LLE and the on-line SPE in terms of method standard deviation (LLE 1.82%, on-line SPE 1.13%) and the analytical results. However, the advantages of on-line SPE in addition to different selectivity were less manual effort, smaller plasma volumes of 400 microl (LLE 2 ml) and a recovery of psilocin in human plasma of nearly 100% (LLE 88%). In contrast to a previous procedure both methods were rapid, simple and reliable and yielded high plasma recoveries. They were used successfully in the quantitation of psilocin in plasma samples obtained from healthy volunteers after p.o. administration of 0.2 mg psilocybin per kg body mass. Plasma concentration curves and pharmacokinetic parameters were calculated.
1. A series of N-substituted tryptamines was compared with a series of beta-carbolines in rats trained to discriminate LSD (0.1 mg/kg) from saline. 2. Intermediate levels of substitution were elicited by MDMT (76.4%), DMT (77.9%), and DET (48.7%). 6-F-DET produced 41.3% LSD-appropriate responding at a dose of 6.0 mg/kg but only 4 of 8 subjects completed the test session thus precluding statistical analysis. Bufotenine (25.8%) also failed to substitute. Although none of the tryptamines substituted completely for LSD, the pattern of substitution is consonant with what is known of their activity in humans. MDMT, DMT, and DET are well established in the literature as hallucinogens but the same cannot be said for 6-F-DET and bufotenine. 3. Of the beta-carbolines tested, none substituted for LSD completely and only harmane elicited intermediate substitution (49.5%). No significant generalization of the LSD stimulus to 6-methoxyharmalan, harmaline, or THBC was observed. Thus, in contrast to the tryptamines, scant ability to substitute for LSD was observed in the beta-carbolines tested. 4. Taken together, the present data indicate that the representative tryptamines employed in the present study exhibit greater similarity to the LSD stimulus than do representative beta-carbolines. The receptor interactions responsible for these differences remain to be determined.
The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [11C]raclopride to D2-dopamine receptors in the striatum in healthy volunteers after placebo and a psychotomimetic dose of psilocybin (n = 7). Psilocybin is a potent indoleamine hallucinogen and a mixed 5-HT2A and 5-HT1A receptor agonist. Psilocybin administration (0.25 mg/kg p.o.) produced changes in mood, disturbances in thinking, illusions, elementary and complex visual hallucinations and impaired ego-functioning. Psilocybin significantly decreased [11C]raclopride receptor binding potential (BP) bilaterally in the caudate nucleus (19%) and putamen (20%) consistent with an increase in endogenous dopamine. Changes in [11C]raclopride BP in the ventral striatum correlated with depersonalization associated with euphoria. Together with previous reports of 5-HT receptor involvement in striatal dopamine release, it is concluded that stimulation of both 5-HT2A and 5-HT1A receptors may be important for the modulation of striatal dopamine release in acute psychoses. The present results indirectly support the hypothesis of a serotonin-dopamine dysbalance in schizophrenia and suggest that psilocybin is a valuable tool in the analysis of serotonin-dopamine interactions in acute psychotic states.
Active compounds of some mushrooms e.g. Psilocybe cubensis, Paneolus subalteatus or Stropharia coronilla, the psychotropic agents psilocybin and psilocin, have hallucinogenic effects. In one case of 'magic mushroom' intake, we had to analyse blood and urine. Psilocin was detected in the urine with REMEDi HS. Most of the psilocin was excreted as the glucuronide. Therefore an enzymatic hydrolysis should be the first step in analysis. Free psilocin was determined at a concentration of 0.23 mg/l while the total amount was 1.76 mg/l urine. The concentration of psilocin in serum was too low for detection with REMEDi HS. We proved a GC-MS-method with d(3)-morphine as internal standard and silylation with MSTFA. Similarly to urine, most of the psilocin in serum was found in the conjugated form. The concentration of free psilocin was 0.018 mg/l, that of total psilocin, 0.052 mg/l serum.
Pharmacokinetic studies of psilocybin in humans have shown the rapid dephosphorylation of psilocybin to psilocin with further conversion to 4-hydroxy-tryptophole (4HT) and 4-hydroxyindole-3-acetic acid (4HIAA) in plasma. Our study shows that psilocin also undergoes conjugation and can be found in the urine as the psilocin-glucuronide conjugate. Recoveries after enzymatic hydrolysis of the urine with beta-glucuronidase (Helix Pomatia or E. Coli) when compared to non-hydrolyzed urine confirmed the presence of the glucuronide. Detection of psilocin from hydrolyzed and extracted samples was optimized for GC/MS by derivatization with MSTFA. The method developed allows for the detection of psilocin in urine with a limit of quantitation of 10 ng/mL, based on 5 mL of spiked urine. Using this method, our laboratory has confirmed the presence of psilocin in 6 out of 8 urine samples, with concentrations ranging from 10 ng/mL to greater than 200 ng/mL. Before implementation of the hydrolysis and derivatization steps, our limit of detection was 200 ng/mL, based on spiked urine standards. No case samples were positive without hydrolysis and derivatization.
In a clinical study eight volunteers received psilocybin (PY) in psychoactive oral doses of 212+/-25 microg/kg body weight. To investigate the elimination kinetics of psilocin (PI), the first metabolite of PY, urine was collected for 24 h and PI concentrations were determined by high-performance liquid chromatography with column switching and electrochemical detection (HPLC-ECD). Sample workup included protection of the unstable PI with ascorbic acid, freeze-drying, and extraction with methanol. Peak PI concentrations up to 870 microg/l were measured in urine samples from the 2-4 h collection interval. The PI excretion rate in this period was 55.5+/-33.8 microg/h. The limit of quantitation (10 microg/L) was usually reached 24 h after drug administration. Within 24 h, 3.4+/-0.9% of the applied dose of PY was excreted as free PI. Addition of beta-glucuronidase to urine samples and incubation for 5 h at 40 degrees C led to twofold higher PI concentrations, although 18+/-7% of the amount of unconjugated PI was decomposed during incubation. We conclude that in humans PI is partially excreted as PI-O-glucuronide and that enzymatic hydrolysis extends the time of detectability for PI in urine samples.
Dietary phytoestrogens have been implicated in the prevention of chronic diseases. However, it is uncertain whether the phytoestrogens or the foods associated with phytoestrogens account for the observed effects. We report here a new liquid chromatography photodiode array mass spectrometry (LC-PDA-MS) assay for the determination of nanomolar amounts of the most prominent dietary phytoestrogens (genistein, dihydrogenistein, daidzein, dihydrodaidzein, glycitein, O-desmethylangolensin, hesperetin, naringenin, quercetin, enterodiol, enterolactone) in human plasma or serum and urine. This assay was found to be suitable for the assessment of quercetin exposure in an onion intervention study by measuring urinary quercetin levels. Other successful applications of this assay in clinical and epidemiologic studies validated the developed method and confirmed previous results on the negative association between urinary isoflavone excretion and breast cancer risk.