Taikasieniä ja psilosybiiniä koskevat tutkimusjulkaisut

[Arvalis]

• Psilocybin and Obsessive Compulsive Disorder (Wilcox, 2014)
  

  Obsessive Compulsive Disorder (OCD) is a psychiatric disorder with considerable morbidity and mortality. This condition disables many individuals and is often refractory to treatment. Research suggests that serotonin plays a role in OCD symptom reduction. We present a case of an individual who successfully used psilocybin, a serotonergic agent, to reduce the core symptoms of OCD for several years. Although not endorsing this form of treatment, we feel that the successful use of this agent highlights the role of serotonergic factors in OCD and the need for further, legitimate research into the value of psilocybin in the treatment of anxiety disorders.

[Arvalis]

• Variation of psilocybin and psilocin levels with repeated flushes (harvests) of mature sporocarps of Psilocybe cubensis (Earle) Singer (Bigwood & Beug, 1982)
  

  Analysis of Psilocybe cubensis (Earle) Singer grown in controlled culture showed that the level of psilocin was generally zero in the first (or sometimes even the second) fruiting of the mushroom from a given culture and that the level reached a maximum by the fourth flush. The level of psilocybin, which was nearly always at least twice the level of psilocin, showed no upward or downward trend as fruiting progressed, but was variable over a factor of four. Samples obtained from outside sources had psilocybin levels varying by over a factor of ten from one collection to the next.
  
  It is clear that entheogenic and recreational users of this species have no way of predicting the amount of psilocybin and psilocin they are ingesting with a given dry weight of the mushroom. It thus seems likely that variations in the subjective experience will not only come from the effects of set and setting but will also stem in very real measure from large dosage differences.

[Arvalis]

• Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study (Bogenschutz et al., 2015)
  

  Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants’ responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5–8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms.

[Arvalis]

Tämä tutkimuskatsaus ei käsittele sinällään taikasieniä ja/tai psilosybiiniä, vaan tarkastelee sitä, onko psykedeelisen kokemuksen läpikäyminen terapeuttisen vaikutuksen kannalta olennainen asia, vai ovatko aivokemialliset mekanismit pääasiallinen syy psykedeelien vaikuttavuuteen tiettyjen terveydentilojen hoidossa. Koin kuitenkin tärkeäksi mainita täälläkin.

• Peak experiences and the afterglow phenomenon: When and how do therapeutic effects of hallucinogens depend on psychedelic experiences? (Majić et al., 2015)
  

  Interest in the therapeutic potential of psychedelic substances has recently resumed. During an early phase of human psychedelic research, their therapeutic application in different pathologies had been suggested, and the first evidence for efficacy was provided. The range of recent clinical applications of psychedelics spans from cluster headaches and obsessive-compulsive disorder to addiction and the treatment of fear and anxiety in patients suffering from terminal illness, indicating potentially different therapeutic mechanisms. A variety of approaches in psychotherapy emphasize subjective experiences, such as so-called peak experiences or afterglow phenomena, as differentially mediating therapeutic action. This review aims to re-evaluate earlier and recent concepts of how psychedelic substances may exert beneficial effects. After a short outline of neurophenomenological aspects, we discuss different approaches to how psychedelics are used in psychotherapy. Finally, we summarize evidence for the relationship between subjective experiences and therapeutic success. While the distinction between pharmacological and psychological action obviously cannot be clear-cut, they do appear to contribute differently from each other when their effects are compared with regard to pathologies.

[Arvalis]

• Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers (Johnson et al., 2011)
  

  Background: Psilocybin is a well-characterized classic hallucinogen (psychedelic) with a long history of religious use by indigenous cultures, and nonmedical use in modern societies. Although psilocybin is structurally related to migraine medications, and case studies suggest that psilocybin may be efficacious in treatment of cluster headache, little is known about the relationship between psilocybin and headache.
  
  Methods: This double-blind study examined a broad range of psilocybin doses (0, 5, 10, 20, and 30 mg/70 kg) on headache in 18 healthy participants.
  
  Results: Psilocybin frequently caused headache, the incidence, duration, and severity of which increased in a dose-dependent manner. All headaches had delayed onset, were transient, and lasted no more than a day after psilocybin administration.
  
  Conclusions: Possible mechanisms for these observations are discussed, and include induction of delayed headache through nitric oxide release. These data suggest that headache is an adverse event to be expected with the nonmedical use of psilocybin-containing mushrooms as well as the administration of psilocybin in human research. Headaches were neither severe nor disabling, and should not present a barrier to future psilocybin research.

[Arvalis]

• Research on Acute Toxicity and the Behavioral Effects of Methanolic Extract from Psilocybin Mushrooms and Psilocin in Mice (Zhuk et al., 2015)
  

  The pharmacological activities and acute toxicity of the psilocin (PC) and dried residues of the crude extracts of psychotropic mushrooms were investigated in mice. The hallucinogenic substances were effectively isolated, by using methanol, from the species of Psilocybe semilanceata and Pholiotina cyanopus, that were collected in the north-east region of Poland. The chemical analysis of these extracts, which was performed by liquid chromatography with mass spectrometry detection (LC-MS), indicated the presence of psilocin and other hallucinogenic substances, including indolealkylamines and their phosphorylated analogues. When the pure psilocin or fungal extracts were used, slight differences in determined LD₅₀ values were observed. However, the application of PC evoked the highest level of toxicity (293.07 mg/kg) compared to the activity of extracts from Ph. cyanopus and P. semilanceata, where the level of LD₅₀ was 316.87 mg/kg and 324.37 mg/kg, respectively. Furthermore, the behavioral test, which considered the head-twitching response (HTR), was used to assess the effects of the studied psychotropic factors on the serotonergic system. Both, the fungal extracts and psilocin evoked characteristic serotoninergic effects depending on the dose administered to mice, acting as an agonist/partial agonist on the serotonergic system. A dose of 200 mg/kg 5-hydroxytryptophan (5-HTP) induced spontaneous head-twitching in mice (100% effect), as a result of the formation of 5-hydroxytryptamine (5-HT) in the brain. Compared to the activity of 5-HTP, the intraperitoneal administration of 1mg/kg of psilocin or hallucinogenic extracts of studied mushrooms (Ph. cyanopus and P. semilanceata) reduced the number of head-twitch responses of about 46% and 30%, respectively. In contrast, the administration of PC exhibited a reduction of about 60% in HTR numbers.

[Arvalis]

Linkit lakkasivat toimimasta foorumipäivityksen myötä, mutta artikkelit on tällä hetkellä saatavilla täältä: https://psilosybiini.info/paperit/

Jossain vaiheessa vois varmaan tehdä jonkun koosteen wikin puolelle.

[Arvalis]

• The Effect of 5-HT2A/1a Agonist Treatment On Social Cognition, Empathy, and Social Decision-making (Preller et al., 2015)
  
  

  Social cognition is a crucial factor influencing development, progress, and treatment of psychiatric disorders. However, social cognition skills are insufficiently targeted by current treatment approaches. In particular, patients suffering from depression show an increased negative reaction to social exclusion and deficits in empathy. The 5HT-1A/2A receptor agonist psilocybin has previously been shown to reduce the neural response to negative emotional stimuli. However, it is not known if this extends to negative social interaction and whether 5HT-1A/2A receptor stimulation induces changes in empathy. Given the clear need for improved treatment of socio-cognitive functioning in psychiatric disorders, it is important to better understand the neuronal and neuromodulatory substrates of social cognition.
  
  In a double-blind, randomized, cross-over design we therefore investigated the neural response to ostracism after the acute administration of psilocybin (0.215mg/kg) and placebo in healthy volunteers using fMRI. Furthermore, we assessed cognitive and emotional empathy using the Multifaceted Empathy Test.
  
  The neural response to social exclusion in the ACC – a brain region associated with ‘social pain”- was reduced after psilocybin administration compared to placebo. Furthermore, emotional empathy was enhanced after treatment with psilocybin while no significant differences were found in cognitive empathy.
  
  These results show that the 5HT-1A/2A receptor subtypes play an important role in the modulation of socio-cognitive functioning and therefore may be relevant for the treatment of social cognition deficits in psychiatric disorders. In particular, they may be important for the normalization of empathy deficits and increased negative reaction to social exclusion in depressed patients.

[Arvalis]

• Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms (Carhart-Harris et al., 2017)
  

  Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. A ‘reset’ therapeutic mechanism is proposed.
  

  
  
• Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression (Roseman et al., 2018)
  

  Introduction: It is a basic principle of the “psychedelic” treatment model that the quality of the acute experience mediates long-term improvements in mental health. In the present paper we sought to test this using data from a clinical trial assessing psilocybin for treatment-resistant depression (TRD). In line with previous reports, we hypothesized that the occurrence and magnitude of Oceanic Boundlessness (OBN) (sharing features with mystical-type experience) and Dread of Ego Dissolution (DED) (similar to anxiety) would predict long-term positive outcomes, whereas sensory perceptual effects would have negligible predictive value.
  
  Materials and Methods: Twenty patients with treatment resistant depression underwent treatment with psilocybin (two separate sessions: 10 and 25 mg psilocybin). The Altered States of Consciousness (ASC) questionnaire was used to assess the quality of experiences in the 25 mg psilocybin session. From the ASC, the dimensions OBN and DED were used to measure the mystical-type and challenging experiences, respectively. The Self-Reported Quick Inventory of Depressive Symptoms (QIDS-SR) at 5 weeks served as the endpoint clinical outcome measure, as in later time points some of the subjects had gone on to receive new treatments, thus confounding inferences. In a repeated measure ANOVA, Time was the within-subject factor (independent variable), with QIDS-SR as the within-subject dependent variable in baseline, 1-day, 1-week, 5-weeks. OBN and DED were independent variables. OBN-by-Time and DED-by-Time interactions were the primary outcomes of interest.
  
  Results: For the interaction of OBN and DED with Time (QIDS-SR as dependent variable), the main effect and the effects at each time point compared to baseline were all significant (p = 0.002 and p = 0.003, respectively, for main effects), confirming our main hypothesis. Furthermore, Pearson's correlation of OBN with QIDS-SR (5 weeks) was specific compared to perceptual dimensions of the ASC (p < 0.05).
  
  Discussion: This report further bolsters the view that the quality of the acute psychedelic experience is a key mediator of long-term changes in mental health. Future therapeutic work with psychedelics should recognize the essential importance of quality of experience in determining treatment efficacy and consider ways of enhancing mystical-type experiences and reducing anxiety.

[Andalusian Dawg]

Convergent evolution of psilocybin biosynthesis by psychedelic mushrooms (Awan et al., 2018)

Psilocybin is a psychoactive compound with clinical applications produced by dozens of mushroom species. There has been a longstanding interest in psilocybin research with regard to treatment for addiction, depression, and end-of-life suffering. However, until recently very little was known about psilocybin biosynthesis and its ecological role. Here we confirm and refine recent findings about the genes underpinning psilocybin biosynthesis, discover that there is more than one psilocybin biosynthesis cluster in mushrooms, and we provide the first data directly addressing psilocybin’s ecological role. By analysing independent genome assemblies for the hallucinogenic mushrooms Psilocybe cyanescens and Pluteus salicinus we recapture the recently discovered psilocybin biosynthesis cluster and show that a transcription factor previously implicated in its regulation is actually not part of the cluster. Further, we show that the mushroom Inocybe corydalina produces psilocybin but does not contain the established biosynthetic cluster, and we present an alternative cluster. Finally, a meta-transcriptome analysis of wild-collected mushrooms provides evidence for intra-mushroom insect gene expression of flies whose larvae grow inside Psilocybe cyanescens. These larvae were successfully reared into adults. Our results show that psilocybin does not confer complete protection against insect mycophagy, and the hypothesis that it is produced as an adaptive defense compound may need to be reconsidered.

Monoamine Biosynthesis via a Noncanonical Calcium-Activatable Aromatic Amino Acid Decarboxylase in Psilocybin Mushroom (Torrens-Spence et al., 2018)

Aromatic L-amino acid decarboxylases (AAADs) are a phylogenetically diverse group of enzymes responsible for the decarboxylation of aromatic amino acid substrates into their corresponding aromatic arylalkylamines. AAADs have been extensively studied in mammals and plants as they catalyze the first step in the production of neurotransmitters and bioactive phytochemicals, respectively. Unlike mammals and plants, the hallucinogenic psilocybin mushroom Psilocybe cubensis reportedly employs an unrelated phosphatidylserine-decarboxylase-like enzyme to catalyze L-tryptophan decarboxylation, the first step in psilocybin biosynthesis. To explore the origin of this chemistry in psilocybin mushroom, we generated the first de novo transcriptomes of P. cubensis and investigated several putative L-tryptophan-decarboxylase-like enzymes. We report the biochemical characterization of a noncanonical AAAD from P. cubensis (PcncAAAD) that exhibits substrate permissiveness towards L-phenylalanine, L-tyrosine, and L-tryptophan, as well as chloro-tryptophan derivatives. The crystal structure of PcncAAAD revealed the presence of a unique C-terminal appendage domain featuring a novel double-β-barrel fold. This domain is required for PcncAAAD activity and regulates catalytic rate and thermal stability through calcium binding. PcncAAAD likely plays a role in psilocybin production in P. cubensis and offers a new tool for metabolic engineering of aromatic-amino-acid-derived natural products.

A draft reference assembly of the Psilocybe cubensis genome (McKernan et al., 2021)

We describe the use of high-fidelity single molecule sequencing to assemble the genome of the psychoactive Psilocybe cubensis [P. Envy] mushroom. The genome is 46.6Mb, 46% GC, and in 32 contigs with an N50 of 3.3Mb. The BUSCO completeness scores are 97.6% with 1.2% duplicates. The Psilocybin synthesis cluster exists in a single 3.2Mb contig.

A whole genome atlas of 81 Psilocybe genomes as a resource for psilocybin production (McKernan et al., 2021)

The Psilocybe genus is well known for the synthesis of valuable psychoactive compounds such as Psilocybin, Psilocin, Baeocystin and Aeruginascin. The ubiquity of Psilocybin synthesis in Psilocybe has been attributed to a horizontal gene transfer mechanism of a ~20Kb gene cassette. A recently published highly contiguous reference genome derived from long read single molecule sequencing has underscored interesting variation in this Psilocybin synthesis gene cassette. This reference genome has also enabled the shotgun sequencing of spores from many Psilocybe strains to better catalog the genomic diversity in the Psilocybin synthesis pathway. Here we present the de novo assembly of genomes of 81 Psilocybe genomes compared to the P.Envy reference genome. Surprisingly, the genomes of Psilocybe galindoi, Psilocybe tampanensis and Psilocybe azurescens lack sequence coverage over the previously described Psilocybin synthesis pathway but do demonstrate amino acid sequence homology to an alternative pathway and may illuminate previously proposed convergent evolution of Psilocybin synthesis.

Tämä viimeisin McKernanin julkaisu tehtiin kuulemma osin siitä syystä, että NCBI:n tietokantoihin ladattua dataa ei voi enää yksikään yhtiö patentoida. Eli ainakin osa tunnetuimmista kannoista on nyt julkisomisteisia. 

[Andalusian Dawg]

Taking Different Roads: l-Tryptophan as the Origin of Psilocybe Natural Products (Lenz et al., 2020)

Psychotropic fungi of the genus Psilocybe, colloquially referred to as "magic mushrooms", are best known for their l-tryptophan-derived major natural product, psilocybin. Yet, recent research has revealed a more diverse secondary metabolism that originates from this amino acid. In this minireview, the focus is laid on l-tryptophan and the various Psilocybe natural products and their metabolic routes are highlighted. Psilocybin and its congeners, the heterogeneous blue-colored psilocyl oligomers, alongside β-carbolines and N,N-dimethyl-l-tryptophan, are presented as well as current knowledge on their biosynthesis is provided. The multidisciplinary character of natural product research is demonstrated, and pharmacological, medicinal, ecological, biochemical, and evolutionary aspects are included.

From the perspective of pure research, the chemical mechanism of the blueing reaction is now understood, and β-carbolines were added to the natural product repertoire of Psilocybe.

Still, the fundamental question remains to be answered: why do Psilocybe mushrooms make psilocybin? Is the ecologically relevant compound mono- or oligomeric? And why do these fungi make β-carbolines? Do these two classes of compounds exert their ecological functions independently or synergistically? And do the β-carbolines contribute to the psychedelic pharmacology in humans? These questions show that Psilocybe compounds exemplify natural product research as an interfacing endeavour and a hub that connects multiple disciplines.