BackgroundPeripartum mood disorders (PMDs) are a major public health concern; they present in 20% of birthing parents and are responsible for 1 in 4 maternal deaths in the United States. The psychedelic antidepressant psilocybin (PSI) increases social connectedness, self-compassion, and has strong clinical transdiagnostic efficacy for mental illness – making it a candidate treatment to reduce maternal disconnect, personal shame, and blunted affect seen in peripartum mood disorders (PMDs). Despite phase 2 clinical trials actively recruiting postpartum parents to determine if a novel PSI analogue could address peripartum mood disorders [NCT06342310], to date there remains no clinical nor preclinical data describing the safety of psychedelic use during the postpartum period.Aims & ObjectivesWe aimed to examine the efficacy of psilocybin in a preclinical mouse model of PMD. We further assessed the long-term behavioral consequences of PSI exposure on parous mice and their offspring.MethodOur group recently developed a model in C57BL6/J mice that examines social stress and limited resources as factors that interfere with mother-infant infant bonding in the early postpartum period. In this model, limited bedding and repeated exposure to an infanticidal male mouse destabilizes maternal care and triggers prolonged stress-related behaviors that remain even in the absence of a social threat. Using this paradigm, we investigated the effects of a single PSI dose on maternal care behaviors, as well as long-term anxiety- and depressive-like behaviors in a standardized behavioral battery after offspring were weaned two weeks later (N=11-16 mice/group). This was compared to the behaviors of virgin female mice two weeks after a single dose of PSI (N=10 mice/group). Finally, we examined the long-term behavioral consequences of adult male and female mice reared by dams exposed to maternal stress and/or PSI using a standardized test battery of social, emotional and cognitive behaviors (N=7-14 mice/sex/group).ResultsPMD model-exposed mice displayed dramatically impaired caregiving behavior, maternal withdrawal and avoidance from pups, and increased anxiety-like behaviors – none of which were ameliorated by PSI treatment. In fact, two weeks following injection, PSI-treated dams were more anxious and had increased risk of overall behavioral impairments. This was specific to the postpartum period as, by stark contrast, virgin female mice treated with a single dose of PSI exhibited an anxiolytic phenotype and decreased risk of overall behavioral impairments – consistent with previous descriptions of PSI in the literature. Furthermore, just a single postnatal exposure to PSI through breastmilk increased the risk of behavioral phenotypes related to mood and sociability disorders in both male and female mice when aged to adulthood.Discussion & ConclusionsAltogether, these data suggest that while PSI has been consistently shown to be safe and effective for treating depression in the general human patient population, as well as in preclinical models of mental health disorders, the same may not be true for exposure during the postpartum period. PSI may pose a major risk for both parous mums and their offspring, and as such, these data highlight the importance of including lactating females and their offspring in preclinical efficacy and safety testing of drugs aimed to be delivered postpartum.

BackgroundThe full therapeutic potential of serotonergic psychedelics (SP) in treating neuropsychiatric disorders, such as depression and schizophrenia, is limited by possible adverse effects, including perceptual disturbances and psychosis, which require administration in controlled clinical environments. This study investigates the potential synergistic benefits of combining psilocybin (PSIL) with N-methyl-D-aspartate receptor (NMDAR) modulators D-serine (DSER) and D-cycloserine (DCS) to enhance both efficacy and safety. We have hypothesized (Heresco-Levy and Lerer, 2024) that concurrent administration of SPs and NMDAR modulators may synergistically upgrade SP efficacy and attenuate SP-induced subjective reactions and side effects. This study seeks preclinical proof of concept for this hypothesis.Aims & ObjectivesTo determine the potential efficacy of PSIL-DSER and PSIL-DCS treatment combinations by establishing their hallucinogenic potential, their possible antipsychotic effects, and their effects on neuroplasticity.MethodUsing male ICR mice, we examined the effect of PSIL-DSER and PSIL-DCS combination treatment on head twitch response (HTR), MK-801-induced hyperlocomotion, and neuroplasticity-related synaptic protein levels in the frontal cortex, hippocampus, amygdala, and striatum. HTR is closely correlated with hallucinogenic (psychedelic) effects in humans and was measured using a magnetometer. MK-801-induced hyperlocomotion is a well-established preclinical predictor of antipsychotic effects and was assayed in an open field using the Ethovision system. Synaptic proteins (GAP43, PSD95, synaptophysin, and SV2A) were assayed in the frontal cortex, hippocampus, amygdala, and striatum by Western blots.ResultsOur results indicate that PSIL significantly increased HTR—a surrogate measure for hallucinogenic effects—which was reduced by the co-administration of DSER or DCS in a dose-dependent manner. Similarly, combining PSIL with DSER or DCS significantly decreased MK-801-induced hyperactivity, modeling antipsychotic effects. PSIL alone did not affect MK-801-induced hyperactivity. Neuroplasticity-related synaptic protein assays demonstrated that the PSIL-DSER combination enhanced GAP43 expression over all 4 brain areas examined and overall expression of the 4 assayed synaptic proteins in the hippocampus, while PSIL-DCS elevated PSD95 levels across all 4 brain regions.Discussion & ConclusionsThese findings support the hypothesis that combinations of SPs with NMDAR modulators could optimize the therapeutic potential of SPs by mitigating adverse effects and enhancing neuroplasticity. Future studies should focus on refining administration protocols and evaluating translational applicability for broader clinical use.

The full therapeutic potential of serotonergic psychedelics (SP) in treating neuropsychiatric disorders, such as depression and schizophrenia, is limited by possible adverse effects, including perceptual disturbances and psychosis, which require administration in controlled clinical environments. This study investigates the synergistic benefits of combining psilocybin (PSIL) with N-methyl-D-aspartate receptor (NMDAR) modulators D-serine (DSER) and D-cycloserine (DCS) to enhance both efficacy and safety. Using ICR male mice, we examined head twitch response (HTR), MK-801-induced hyperlocomotion, and neuroplasticity related synaptic protein levels in the frontal cortex, hippocampus, amygdala, and striatum. Our results indicate that PSIL significantly increased HTR—a surrogate measure for hallucinogenic effects—which was reduced by the co-administration of DSER or DCS in a dose-dependent manner. Similarly, combining PSIL with DSER or DCS significantly decreased MK-801-induced hyperactivity, modeling antipsychotic effects. Neuroplasticity-related synaptic protein assays demonstrated that the PSIL-DSER combination enhanced GAP43 expression over all 4 brain examined and overall expression of the 4 assayed synaptic proteins in the hippocampus, while PSIL-DCS elevated PSD95 levels across all 4 brain regions, suggesting a synaptogenic synergy. These findings support the hypothesis that combinations of SP with NMDAR modulators could optimize the therapeutic potential of SP by mitigating adverse effects and enhancing neuroplasticity. Future studies should focus on refining administration protocols and evaluating translational applicability for broader clinical use.

Psilocybin (PSIL) is a psychedelic drug and a promising experimental therapeutic for many psychiatric conditions. Precision functional mapping (PFM) combines densely repeated resting state fMRI sampling and individual-specific network mapping to improve signal-to-noise ratio (SNR) and effect size in brain imaging research. We present a randomized cross-over study in which PFM was used to characterize acute and persistent effects of psilocybin or methylphenidate (MTP) on brain networks. Seven healthy volunteers (mean age 34.1 years, SD = 9.8; n = 3 females, n = 6 Caucasians) underwent (1) extensive baseline imaging, (2) imaging beginning 60–90 minutes after drug exposure, and (3) longitudinal imaging for up to two weeks after drug exposure. Four individuals also participated in an open-label PSIL replication protocol over 6 months later. This dataset includes resting state (using advanced high-resolution multi-echo fMRI), task fMRI, structural, and diffusion basis spectral imaging as well as assessments of subjective experience. We are releasing this unique dataset as a resource for neuroscientists to study the acute and persistent effects of PSIL and MTP on brain networks.

BackgroundSAPAP3-knockout (SAPAP3-KO) mice develop excessive self-grooming behavior at 4-6 months of age, serving as a model for obsessive-compulsive disorder (OCD). Given that anxiety often precedes OCD diagnosis in humans, this study investigated whether juvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing the self-grooming phenotype, and whether such behaviors respond to psilocybin (PSIL) treatment. The study also examined 4 key neuroplasticity-related synaptic proteins—GAP43, PSD95, synaptophysin, and SV2A—as SAPAP3 is a postsynaptic scaffold protein that interacts with PSD95 and may affect synaptic function.MethodsTwo studies were conducted using male and female juvenile (10-13 weeks) SAPAP3-KO mice. Study 1 compared behavioral phenotypes between homozygous (HOM), heterozygous, and wild-type (WT) mice. Study 2 evaluated a different sample of HOM and WT mice and assessed the effect of PSIL (4.4 mg/kg) on identified behavioral differences. Both studies included comprehensive behavioral testing focused on anxiety-like behavior, social interaction, and cognitive function. Additionally, levels of 4 synaptic proteins were measured by western blots in the frontal cortex, hippocampus, amygdala, and striatum of juvenile and adult SAPAP3-KO mice.ResultsIn both studies, juvenile HOM SAPAP3-KO mice showed significant anxiety-like behaviors compared to WT mice, spending less time in open field center, and elevated plus maze open arms. They also buried fewer marbles and found fewer buried Oreos than WT mice. Psilocybin treatment did not improve these behavioral manifestations. Analysis of synaptic proteins revealed significant increases in GAP43, synaptophysin, and SV2A across multiple brain regions in adult male HOM mice and of SV2A in the frontal cortex of HOM females compared to WT, but not in juvenile mice of either sex.ConclusionsJuvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing the characteristic excessive self-grooming phenotype, paralleling the prodromal anxiety often seen in human OCD. Unlike in adult SAPAP3-KO mice, these manifestations were not responsive to PSIL treatment. The age-dependent increases in synaptic proteins observed in adult (but not juvenile) male SAPAP3-KO mice HOM for the deletion and to a lesser extent in female homozygotes, may represent compensatory plasticity changes in response to the phenotype. These results provide insights into the developmental trajectory of OCD-like behaviors and associated neuroplastic adaptations.

Abstract Background Psilocybin research in depression has been generated using chemically synthesized psilocybin (PSI). Psychedelic mushrooms produce additional tryptamines that may enhance the neuroplastic effect of psilocybin. In a rodent depression model, an extract of a psychedelic mushroom (PME) had a stronger and more prolonged effect than PSI on behavior[1]. Aims and Objectives To establish a zebrafish depression model and contrast the effects PSI and PME, using behavioral phenotyping and whole brain metabolomics. Methods To induce a depression-like phenotype, individual zebrafish were isolated and restrained in a 50 mL falcon tube, submerged in a 200ml tank water chamber (AIS - acute, isolated restraint). On day 1, AIS was applied 3 times for 20 minutes, with an interval of 90 min and once on day 2 and four hours later, the fish were treated in a 200 mL chamber with 5 mg/L of tank water of PSI, an equivalent psilocybin dose of PME or tank water (VEH) for 20 min. The control group (CON), not subjected to AIS, were placed on day 2, for 20 minutes in 200ml treatment chamber containing tank water. On day 3, following a 20- minute AIS session, individual PSI, PME and CON zebrafish were transferred to an open field arena tank (50 x 50 x 4 cm) and following 5 minutes of acclimation, video tracked for 5 minutes, and analysis of trajectories was undertaken using Noldus EthoVision XT. Three fish were randomly selected from each group for whole brain metabolomics using an Orbitrap-IQX mass spectrometer. Results In 2D spatiotemporal reconstructions of the zebrafish swim paths, the VEH group displayed a higher degree of thigmotaxis in comparison to the CON, PSI and PME groups (n=8/group). There was an increase in average distance traveled (cm) (p <0.001), average velocity (cm/s) (p <0.001), and a decrease in meandering (deg/cm) (p <0.001) when comparing the VEH to the CON group. Average velocity for the PSI and PME groups was decreased as compared to the VEH group (p <0.05) and an increase in meandering for the PSI (p <0.05) group was noted. The PSI and PME groups displayed similar average velocity, distance traveled and meandering to the CON group. No significant behavioral phenotyping differences could be found between the PSI and PME groups. Metabolomic analysis of whole brain extracts demonstrated increases in GABA, Vitamin B6, glutamine and NADH, with a decrease in xanthosine in the PSI and PME brains as compared to VEH. More neurotransmitter precursors were present in the PME treated, as compared to the PSI treated, brains. Discussion and Conclusions PSI and PME administration in an AIS depression model resulted in zebrafish manifesting a behavioural phenotype that approximated that of zebrafish that had not been subjected to AIS. Metabolomic evidence of increases in neurotransmitter and glutamate precursors and a decrease in xanthosine are possible indicators of a neuroplastic effect of PSI and PME. This work demonstrates the potential of zebrafish models in psychedelics research. References Lerer L., Botvinnik A., Spear K., Shahar O., Lipski P., Calderon H., Blakolmer K., Lifschytz T. and Lerer B. 2022. Tripping Mice and Stoned Fish: Head Twitch Response (HTR) and Behavioral Phenotypic Evidence of Effect Differences Between Synthetic Psilocybin and Psychedelic Mushroom Extract. ACNP 611h Annual Meeting, Dec 4th, Phoenix, Arizona, USA. https://doi.org/10.1038%2Fs41386-022-01485-0

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).ReferencesGOTVALDOVA, 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.

Abstract The full therapeutic potential of serotonergic psychedelics (SP) in treating neuropsychiatric disorders, such as depression and schizophrenia, is limited by possible adverse effects, including perceptual disturbances and psychosis, which require administration in controlled clinical environments. This study investigates the synergistic benefits of combining psilocybin (PSIL) with N-methyl-D-aspartate receptor (NMDAR) modulators D-serine (DSER) and D-cycloserine (DCS) to enhance both efficacy and safety. Using ICR male mice, we examined head twitch response (HTR), MK-801-induced hyperlocomotion, and neuroplasticity related synaptic protein levels in the frontal cortex, hippocampus, amygdala, and striatum. Our results indicate that PSIL significantly increased HTR—a surrogate measure for hallucinogenic effects—which was reduced by the co-administration of DSER or DCS in a dose-dependent manner. Similarly, combining PSIL with DSER or DCS significantly decreased MK-801-induced hyperactivity, modeling antipsychotic effects. Neuroplasticity-related synaptic protein assays demonstrated that the PSIL-DSER combination enhanced GAP43 expression over all 4 brain examined and overall expression of the 4 assayed synaptic proteins in the hippocampus, while PSIL-DCS elevated PSD95 levels across all 4 brain regions, suggesting a synaptogenic synergy. These findings support the hypothesis that combinations of SP with NMDAR modulators could optimize the therapeutic potential of SP by mitigating adverse effects and enhancing neuroplasticity. Future studies should focus on refining administration protocols and evaluating translational applicability for broader clinical use.

RationaleOur study aimed to unravel the unknown mechanisms behind the exceptional efficacy of Psilocybin (PSI) in treating treatment-resistant depression (TRD). Focusing on Wistar-Kyoto (WKY) rats with a TRD phenotype and Wistar (WIS) rats as a normative comparison, we investigated behavioral and neuroplasticity-related responses to PSI, striving to shed light on the distinctive features of its antidepressant effects.ObjectivesWe set out to assess the behavioral impact of acute and prolonged PSI administration on WKY and WIS rats, employing Novel Object Recognition (NORT), Social Interaction (SI), and Forced Swimming Test (FST). Our secondary objectives involved exploring strain-specific alterations in neuroplasticity-related parameters, including brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated protein (Arc).MethodsConducting post-acute and extended assessments after a single PSI administration, we applied behavioral tests and biochemical analyses to measure serum BDNF levels and neuroplasticity-related parameters in the prefrontal cortex. Statistical analyses were deployed to discern significant differences between the rat strains and assess the impact of PSI on behavioral and biochemical outcomes.ResultsOur findings uncovered significant behavioral disparities between WKY and WIS rats, indicating passive behavior and social withdrawal in the former. PSI demonstrated pronounced pro-social and antidepressant effects in both strains, each with its distinctive temporal trajectory. Notably, we identified strain-specific variations in BDNF-related signaling and observed the modulation of Arc expression in WKY rats.ConclusionsOur study delineated mood-related behavioral nuances between WKY and WIS rat strains, underscoring the antidepressant and pro-social properties of PSI in both groups. The distinct temporal patterns of observed changes and the identified strain-specific neuroplasticity alterations provide valuable insights into the TRD phenotype and the mechanisms underpinning the efficacy of PSI.

Background: Immediate early genes (IEGs) are rapidly activated and initiate diverse cellular processes including neuroplasticity. We report the effect of psilocybin (PSIL), PSIL-containing psychedelic mushroom extract (PME) and 5-hydroxytryptophan (5-HTP) on expression of the IEGs, cfos, egr1, and egr2 in mouse somatosensory cortex (SSC). Methods: In our initial experiment, male C57Bl/6j mice were injected with PSIL 4.4mg/kg or 5-HTP 200mg/kg, alone or immediately preceded by serotonergic receptor modulators. IEG mRNA expression 1hour later was determined by real time qPCR. In a replication study a group of mice treated with PME was added. Results: In our initial experiment, PSIL but not 5-HTP significantly increased expression of all three IEGs. No correlation was observed between the head twitch response (HTR) induced by PSIL and its effect on the IEGs. The serotonergic receptor modulators did not significantly alter PSIL-induced IEG expression, with the exception of the 5-HT2C antagonist (RS102221), which significantly enhanced PSIL-induced egr2 expression. 5-HTP did not affect IEG expression. In our replication experiment, PSIL and PME upregulated levels of egr1 and cfos while the upregulation of egr2 was not significant. Conclusions: We have shown that PSIL and PME but not 5-HTP (at a dose sufficient to induce HTR), induced a significant increase in cfos and egr1 expression in mouse SSC. Our findings suggest that egr1 and cfos expression may be associated with psychedelic effects.

Psilocybin, a naturally occurring, tryptamine alkaloid prodrug, is currently being investigated for the treatment of a range of psychiatric disorders. Preclinical reports suggest that the biological effects of psilocybin-containing mushroom extract or “full spectrum” (psychedelic) mushroom extract (PME), may differ from those of chemically synthesized psilocybin (PSIL). We compared the effects of PME to those of PSIL on the head twitch response (HTR), neuroplasticity-related synaptic proteins and frontal cortex metabolomic profiles in male C57Bl/6j mice. HTR measurement showed similar effects of PSIL and PME over 20 min. Brain specimens (frontal cortex, hippocampus, amygdala, striatum) were assayed for the synaptic proteins, GAP43, PSD95, synaptophysin and SV2A, using western blots. These proteins may serve as indicators of synaptic plasticity. Three days after treatment, there was minimal increase in synaptic proteins. After 11 days, PSIL and PME significantly increased GAP43 in the frontal cortex (p = 0.019; p = 0.039 respectively) and hippocampus (p = 0.015; p = 0.027) and synaptophysin in the hippocampus (p = 0.041; p = 0.05) and amygdala (p = 0.035; p = 0.004). PSIL increased SV2A in the amygdala (p = 0.036) and PME did so in the hippocampus (p = 0.014). In the striatum, synaptophysin was increased by PME only (p = 0.023). There were no significant effects of PSIL or PME on PSD95 in any brain area when these were analyzed separately. Nested analysis of variance (ANOVA) showed a significant increase in each of the 4 proteins over all brain areas for PME versus vehicle control, while significant PSIL effects were observed only in the hippocampus and amygdala and were limited to PSD95 and SV2A. Metabolomic analyses of the pre-frontal cortex were performed by untargeted polar metabolomics utilizing capillary electrophoresis – Fourier transform mass spectrometry (CE-FTMS) and showed a differential metabolic separation between PME and vehicle groups. The purines guanosine, hypoxanthine and inosine, associated with oxidative stress and energy production pathways, showed a progressive decline from VEH to PSIL to PME. In conclusion, our synaptic protein findings suggest that PME has a more potent and prolonged effect on synaptic plasticity than PSIL. Our metabolomics data support a gradient of effects from inert vehicle via chemical psilocybin to PME further supporting differential effects. Further studies are needed to confirm and extend these findings and to identify the molecules that may be responsible for the enhanced effects of PME as compared to psilocybin alone.

Neuropsychiatric disorders such as depression are characterized in part by attention deficits. Attention is modulated by the serotonin (5-HT) neurotransmitter system. The 5-HT2A agonist and hallucinogen psilocybin (PSI) is a promising treatment for disorders characterized by attention changes. However, few studies have investigated PSI's direct effect on attention. Using the rodent continuous performance task (CPT), we assessed PSI's effect on attention. We also evaluated the impact of 5-HT2A receptor agonist TCB-2 and antagonist M100907 for comparative purposes. In the CPT, mice learned to distinguish visual targets from non-targets for milkshake reward. Performance was then tested following injections of PSI (0.3, 1, and 3mg/kg), TCB-2 (0.3, 1, and 3mg/kg), or M100907 (0.1, 0.3, and 1mg/kg). Subsequently, drug effects were then evaluated using a more difficult CPT with variable stimulus durations. Mice were then tested on the CPT following repeated PSI injections. Drug effects on locomotor activity were also measured. In the CPT, all three drugs reduced hit and false alarm rate and induced conservative responding. PSI also reduced target discrimination. These effects were seen primarily at doses that also significantly reduced locomotor activity. No drug effects were seen on the more difficult CPT or following repeated PSI injections. Psilocybin, TCB-2, and M100907 impaired performance of the CPT. However, this may be in part due to drug-induced locomotor changes. The results provide little support for the idea that psilocybin alters visual attention, or that 5-HT2A receptors modulate this process.

Since not only psilocybin (PSB) but also PSB-containing mushrooms are used for psychedelic therapy and microdosing, it is necessary to know their concentration variability in wild-grown mushrooms. This article aimed to determine the PSB, psilocin (PS), baeocystin (BA), norbaeocystin (NB), and aeruginascin (AE) concentrations in a large sample set of mushrooms belonging to genera previously reported to contain psychotropic tryptamines. Ultra-high performance liquid chromatography coupled with tandem mass spectrometry was used to quantify tryptamine alkaloids in the mushroom samples. Most mushroom collections were documented by fungarium specimens and/or ITS rDNA/LSU/EF1-α sequencing. Concentrations of five tryptamine alkaloids were determined in a large sample set of 226 fruiting bodies of 82 individual collections from seven mushroom genera. For many mushroom species, concentrations of BA, NB, and AE are reported for the first time. The highest PSB/PS concentrations were found in Psilocybe species, but no tryptamines were detected in the P. fuscofulva and P. fimetaria collections. The tryptamine concentrations in mushrooms are extremely variable, representing a problem for mushroom consumers due to the apparent risk of overdose. The varied cocktail of tryptamines in wild mushrooms could influence the medicinal effect compared to therapy with chemically pure PSB, posing a serious problem for data interpretation.

Background: Psilocybin (PB) is a psychoactive compound commonly found in magic mushroom (Psilocybe cubensis). PB is quickly converted by the body to psilocin (PI), which has a psychedelic effect through the activation of the 5-HT2A receptor in the brain. The objective of this study is to develop a physiologically based pharmacokinetic (PBPK) model of PB and PI in rats and humans for predicting concentrations of the psychoactive substance in the brain. Methods: Following a search in PubMed, three studies were retrieved and information concerning concentration-time profiles of PI were extracted from the selected studies. In the study in rats, PI was orally administered with a dose of 10.1 mg/kg. There were two studies in humans following a single intravenous dose of PB (1 mg) and oral dose of PB (0.224 mg/kg and 0.3 mg/kg). Berkeley Madonna software was used for computer coding and simulations. The developed PBPK model consisted of seven organ compartments (i.e. lung, heart, brain, fat, muscle, kidney, and liver). Results: The simulations show a good agreement between observed and simulated data, although results for oral administration in rats and humans showed under-predictions and results for intravenous administration in humans showed over-predictions. Conclusions: A PBPK model of PB and PI in rats and humans was developed and could predict concentration-time profiles of PI in plasma, particularly in the brain, following intravenous and oral administration of PB. This model may be useful for a safer dosage regimen of PB for patients with some disorders.

Depresioa gaixotasun psikiatriko ohikoenen artean dago, eta haren intzidentziaren gorakada etengabea da. Depresioaren jatorria eta mekanismo etiologikoak azaltzen dituzten hainbat teoria garatu diren arren, gaixotasunaren oinarri neurobiologikoaren alderdi asko ezezagunak dira oraindik. Hipotesi esanguratsuenak depresioaren teoria monoaminergikoa, neurotrofikoa eta neuroinflamatorioa dira, eta horien eta beste batzuen jatorria, ebidentziak eta xehetasunak aditzera ematen dira berrikuspen honetan. Iraganean depresioa tratatzeko farmakoen aurkikuntza zorizkoa izan da, eta haien ekintza-mekanismoen ikerketak gaixotasunean ageri diren nahasmendu neurobiologikoei buruzko ezagutza eman digu. Azken hamarkadetan, aldiz, paradigma aldatu da, eta tratamendu berriak depresioaren etiopatogeniaren ituetan oinarritzen hasi dira. Patologiaren tratamendu farmakologikoaren oinarrian antidepresibo klasikoak daude. Duela hamarkada ugari aurkitu ziren, eta geroztik erabili dira: monoaminooxidasaren inhibitzaileak, antidepresibo triziklikoak eta monoaminen birxurgapenaren inhibitzaileak. Trazodona eta mirtazapina antidepresiboak, profil farmakodinamiko konplexuagokoak, urte batzuk geroago garatu ziren. Farmako talde horien eragin desiragaitz ohikoak ekiditeko eta tratamenduaren eraginkortasuna hobetzeko xedez ekintza-mekanismo alternatiboak esploratu dira, eta ikerketa horietatik sortu dira, esate baterako, agomelatina, tianeptina eta bortioxetina. Horien eraginkortasuna eta erabilera oso mugatuak dira, dena den. Ketamina, aldiz, denbora laburrean depresioaren tratamenduaren iraultza abian jarri duen substantzia izan da, sintomen hobekuntza nabarmena eta azkarra erakutsi duelako entsegu anitzetan, segurtasun eta tolerantzia egokiarekin batera. Azkenik, nabarmentzekoak dira substantzia haluzinogenoak, depresioaren eta beste gaixotasun psikiatrikoen tratamendurako erakutsi duten potentzial izugarriari esker. Depresioari dagokionez, psilozibina da psikodelikoen artean azpimarragarriena: paziente deprimituen hobekuntza azkarra eta iraunkorra eragiten badu ere, haren mekanismo antidepresiboak ezezagunak dira, eta horiek argitzeko entseguak ikerketaren gailurrean daude egun.

Exploratory studies have examined the usefulness of the hallucinogen psilocybin for depressed cancer patients and patients with treatment-resistant

Existe una gran diversidad de hongos que poseen actividad medicinal en Centroamérica y de ellos se pueden extraer los metabolitos secundarios responsables y adecuados para el tratamiento de distintas enfermedades. En esta revisión se realizó una investigación acerca de seis hongos específicos que se utilizan para el tratamiento de padecimientos físicos: Penicillium chrysogenum (P. chrysogenum), Ganoderma lucidum (G. lucidum), Trametes versicolor (T. versicolor), Schizophyllum commune (S. commune), Pleurotus mutilus (P. mutilus), Lentinula edodes (L. edodes), y un último hongo que tiene propiedades alucinógenas útiles en el tratamiento de enfermedades mentales: Psilocybe cubensis (P. cubensis). Se encontró que los metabolitos secundarios de mayor importancia para la industria médica son la penicilina y la tiamulina como antibióticos, los triterpenos por su actividad anticancerígena, diversos tipos de polisacáridos que tienen actividad antioxidante, antiparasitarios, estimulantes del sistema inmune y reguladores del colesterol. Asimismo, se estudió el alucinógeno psilocibina y su potencial en tratamientos de psicoterapia.

The fully automated system of single drop microextraction coupled with capillary electrophoresis (SDME-CE) was developed for in-line preconcentration and determination of muscimol (MUS) and psilocin (PSC) from urine samples. Those two analytes are characteristic active metabolites of Amanita and Psilocybe mushrooms, evoking visual and auditory hallucinations. Study analytes were selectively extracted from the donor phase (urine samples, pH 4) into the organic phase (a drop of octanol layer), and re-extracted to the acidic acceptor (background electrolyte, BGE), consisting of 25 mM phosphate buffer (pH 3). The optimized conditions for the extraction procedure of a 200 µL urine sample allowed us to obtain more than a 170-fold enrichment effect. The calibration curves were linear in the range of 0.05–50 mg L−1, with the correlation coefficients from 0.9911 to 0.9992. The limit of detections was determined by spiking blank urine samples with appropriate standards, i.e., 0.004 mg L−1 for PSC and 0.016 mg L−1 for MUS, respectively. The limits of quantification varied from 0.014 mg L−1 for PSC and 0.045 mg L−1 for MUS. The developed method practically eliminated the sample clean-up step, which was limited only to simple dilution (1:1, v/v) and pH adjustment.

We find it self-explanatory that we perceive our waking world through the physical body, via the five senses whose relay centre is the brain. Yet it is not so simple to explain who the dreamer is in the physical body, as it sleeps. An exploration of this evinces that the traditional hypothesis of material reductionism drives us into a dead end street since its proposed creative process is based on the supposition that matter was created first from which it purportedly emanates consciousness. Once it is understood that consciousness comes before matter and that without it nothing can exist, it quickly becomes apparent that consciousness is not just light and intelligence, but also the matrix and indeed the ‘creatrix’ or mother of all there is. Under such circumstances the creative process is best seen as analogous to a prism revealing the inherent colours of white light, as it projects them into a dark room, which ultimately suggests that the brain is a kind of a projector. Both the waking and the dream world are seen as either internal or external projections. Certainly, the brain shows to be an adept projector when it comes to eidetic visions, for instance. An example of this phenomenon is provided from personal experience. Another support of the projecting phenomenon is the hypnotic projection, of which there is an example provided from yet another personal experience. Further evidence in favour of cerebral projection is the hypnagogic, as well as the hypnopompic vision. Karl Pribram’s findings that the world is a cerebral projection of holograms certainly underpin all the adduced examples. Ultimately they all affirm the view that the brain is a projector with multiple modes of operation. The two most common of these are, of course, waking and dreaming. In other words the brain, so it would appear, creates both the waking person and the dreamer, depending in which ‘gear’ it operates. However, when we examine the experiments with psilocybin, for instance, something puzzling eventuates: while the chemistry of the mushroom induces vastly expanded consciousness, or indeed mystical epiphanies, brain functions are considerably reduced. This is, of course, the precise opposite to what is to be expected while we presume that it is the brain that is responsible for both the generation of consciousness and the projection of waking life and dreams. There is only one event that can shed sufficient light on this conundrum: The NDE of Pam Reynolds. The operation on her aneurism required hypothermic arrest, thus rendering her body to a state of medical death. To everyone’s surprise Pam, like Lazarus, returned from the dead, reporting that the world can be seen in the brain dead state, moreover in a superior manner, thus leading us to the inference that we are not the physical body, but a subtle body within the body of flesh and blood, serving as a template for the latter. Pam’s report upon her return to her earthly body also confirms the ancient view that our etheric, or soul, ascends to an astral plain where in some cases at least, it sojourns as light being for a time, presumably reincarnating on earth once again in order to mature towards the ultimate at-one-ment with Absolute Consciousness, as experiments with psilocybin may lead us to infer. The same experiment also suggests an illustration of why we normally are unaware of the oceanic realm of Absolute Consciousness. It is because the brainwaves of ordinary waking experience project the imagery of the waking world into the ‘sea’ of Absolute Consciousness, so deflecting our attention from its very embrace.

T263. Psilocybin Improves Cognitive Control and Downregulates Parietal Cortex in Treatment-Seeking Smokers