The revival of the psychedelic experience scale: Revealing its extended-mystical, visual, and distressing experiential spectrum with LSD and psilocybin studies.

BACKGROUND: Research with the Psychedelic Experience Questionnaire/Scale (PES) focuses on questions relating to mystical experience (Mystical Experience Questionnaire (MEQ)). The psychometric potential of the non-MEQ items of the PES remains largely unexplored. AIMS: We investigated whether the PES also yields subscales besides the MEQ30 subscales. METHODS: Data from 239 PES measurements (140 healthy participants) from six studies with moderate to high doses of lysergic acid diethylamide and/or psilocybin were included. New subscales (with items other than MEQ30) were created and validated as follows: (1) theoretical derivation of candidate items; (2) removal of items with rare experiences; (3) exploratory factor analysis; and (4) confirmatory factor analysis. Correlations of subscales within the PES and between the PES and the 5-Dimensional Altered States of Consciousness Scale (5D-ASC) were performed. In addition, a cluster analysis using all items (except rare experiences) was performed. RESULTS: The reliability of the four original factors of the MEQ30 was confirmed and four additional factors for the non-MEQ items were revealed: paradoxicality, connectedness, visual experience, and distressing experience. The first two additional factors were strongly correlated with the MEQ30 mystical subscale. Adding the new subscales to the MEQ30 subscales increased the explained variance with the 5D-ASC. The cluster analysis confirmed our main results and provided additional insights for future psychedelic psychometrics. CONCLUSION: The study yields a new validated 6-factor structure for extended mystical experience (MEQ40: MEQ30 + Paradoxicality + Connectedness) and covers psychedelic experience as a whole more comprehensively than has hitherto been possible within a single questionnaire (PES48). The entire PES (PES100) can also be used for further future psychedelic-psychometric research.

Acute effects of MDMA and LSD co-administration in a double-blind placebo-controlled study in healthy participants.

There is renewed interest in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. Although acute subjective effects of LSD are mostly positive, negative subjective effects, including anxiety, may occur. The induction of overall positive acute subjective effects is desired in psychedelic-assisted therapy because positive acute experiences are associated with greater therapeutic long-term benefits. 3,4-Methylenedioxymethamphetamine (MDMA) produces marked positive subjective effects and is used recreationally with LSD, known as "candyflipping." The present study investigated whether the co-administration of MDMA can be used to augment acute subjective effects of LSD. We used a double-blind, randomized, placebo-controlled, crossover design with 24 healthy subjects (12 women, 12 men) to compare the co-administration of MDMA (100 mg) and LSD (100 µg) with MDMA and LSD administration alone and placebo. Outcome measures included subjective, autonomic, and endocrine effects and pharmacokinetics. MDMA co-administration with LSD did not change the quality of acute subjective effects compared with LSD alone. However, acute subjective effects lasted longer after LSD + MDMA co-administration compared with LSD and MDMA alone, consistent with higher plasma concentrations of LSD (Cmax and area under the curve) and a longer plasma elimination half-life of LSD when MDMA was co-administered. The LSD + MDMA combination increased blood pressure, heart rate, and pupil size more than LSD alone. Both MDMA alone and the LSD + MDMA combination increased oxytocin levels more than LSD alone. Overall, the co-administration of MDMA (100 mg) did not improve acute effects or the safety profile of LSD (100 µg). The combined use of MDMA and LSD is unlikely to provide relevant benefits over LSD alone in psychedelic-assisted therapy. Trial registration: ClinicalTrials.gov identifier: NCT04516902.

Purification and concentration of infectious koi herpesvirus using steric exclusion chromatography.

Koi herpesvirus (KHV) is the causative agent of a koi herpesvirus disease (KHVD) inducing high mortality rates in common carp and koi (Cyprinus carpio). No widespread effective vaccination strategy has been implemented yet, which is partly due to side effects of the immunized fish. In this study, we present an evaluation of the purification of infectious KHV from host cell protein and DNA, using the steric exclusion chromatography. The method is related to conventional polyethylene glycol (PEG) precipitation implemented in a chromatographic set-up and has been applied for infectious virus particle purification with high recoveries and impurity removal. Here, we achieved a yield of up to 55% of infectious KHV by using 12% PEG (molecular weight of 6 kDa) at pH 7.0. The recoveries were higher when using chromatographic cellulose membranes with 3-5 µm pores in diameter instead of 1 µm. The losses were assumed to originate from dense KHV precipitates retained on the membranes. Additionally, the use of >0.6 M NaCl was shown to inactivate infectious KHV. In summary, we propose a first step towards a purification procedure for infectious KHV with a possible implementation in fish vaccine manufacturing.

Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants.

Mescaline, lysergic acid diethylamide (LSD), and psilocybin are classic serotonergic psychedelics. A valid, direct comparison of the effects of these substances is lacking. The main goal of the present study was to investigate potential pharmacological, physiological and phenomenological differences at psychoactive-equivalent doses of mescaline, LSD, and psilocybin. The present study used a randomized, double-blind, placebo-controlled, cross-over design to compare the acute subjective effects, autonomic effects, and pharmacokinetics of typically used, moderate to high doses of mescaline (300 and 500 mg), LSD (100 µg), and psilocybin (20 mg) in 32 healthy participants. A mescaline dose of 300 mg was used in the first 16 participants and 500 mg was used in the subsequent 16 participants. Acute subjective effects of 500 mg mescaline, LSD, and psilocybin were comparable across various psychometric scales. Autonomic effects of 500 mg mescaline, LSD, and psilocybin were moderate, with psilocybin causing a higher increase in diastolic blood pressure compared with LSD, and LSD showing a trend toward an increase in heart rate compared with psilocybin. The tolerability of mescaline, LSD, and psilocybin was comparable, with mescaline at both doses inducing slightly more subacute adverse effects (12-24 h) than LSD and psilocybin. Clear distinctions were seen in the duration of action between the three substances. Mescaline had the longest effect duration (mean: 11.1 h), followed by LSD (mean: 8.2 h), and psilocybin (mean: 4.9 h). Plasma elimination half-lives of mescaline and LSD were similar (approximately 3.5 h). The longer effect duration of mescaline compared with LSD was due to the longer time to reach maximal plasma concentrations and related peak effects. Mescaline and LSD, but not psilocybin, enhanced circulating oxytocin. None of the substances altered plasma brain-derived neurotrophic factor concentrations. In conclusion, the present study found no evidence of qualitative differences in altered states of consciousness that were induced by equally strong doses of mescaline, LSD, and psilocybin. The results indicate that any differences in the pharmacological profiles of mescaline, LSD, and psilocybin do not translate into relevant differences in the subjective experience. ClinicalTrials.gov identifier: NCT04227756.

Acute effects of intravenous DMT in a randomized placebo-controlled study in healthy participants.

N,N-dimethyltryptamine (DMT) is distinct among classic serotonergic psychedelics because of its short-lasting effects when administered intravenously. Despite growing interest in the experimental and therapeutic use of intravenous DMT, data are lacking on its clinical pharmacology. We conducted a double-blind, randomized, placebo-controlled crossover trial in 27 healthy participants to test different intravenous DMT administration regimens: placebo, low infusion (0.6 mg/min), high infusion (1 mg/min), low bolus + low infusion (15 mg + 0.6 mg/min), and high bolus + high infusion (25 mg + 1 mg/min). Study sessions lasted for 5 h and were separated by at least 1 week. Participant's lifetime use of psychedelics was ≤20 times. Outcome measures included subjective, autonomic, and adverse effects, pharmacokinetics of DMT, and plasma levels of brain-derived neurotropic factor (BDNF) and oxytocin. Low (15 mg) and high (25 mg) DMT bolus doses rapidly induced very intense psychedelic effects that peaked within 2 min. DMT infusions (0.6 or 1 mg/min) without a bolus induced slowly increasing and dose-dependent psychedelic effects that reached plateaus after 30 min. Both bolus doses produced more negative subjective effects and anxiety than infusions. After stopping the infusion, all drug effects rapidly decreased and completely subsided within 15 min, consistent with a short early plasma elimination half-life (t1/2α) of 5.0-5.8 min, followed by longer late elimination (t1/2ß = 14-16 min) after 15-20 min. Subjective effects of DMT were stable from 30 to 90 min, despite further increasing plasma concentrations, thus indicating acute tolerance to continuous DMT administration. Intravenous DMT, particularly when administered as an infusion, is a promising tool for the controlled induction of a psychedelic state that can be tailored to the specific needs of patients and therapeutic sessions.Trial registration: ClinicalTrials.gov identifier: NCT04353024.

Pharmacokinetics and Pharmacodynamics of Oral Psilocybin Administration in Healthy Participants.

Psilocybin is being investigated as a potential treatment for psychiatric and neurological disorders. Only a few studies have evaluated the pharmacokinetics (PKs) of psilocybin and have used body weight-adjusted dosing. Data on PKs and the PK-pharmacodynamic (PD) relationship of fixed doses that are commonly used are unavailable. The present study characterized the PKs and PK-PD relationship of 15, 25, and 30 mg of orally administered psilocybin in 28, 23, and 28 healthy subjects, respectively. Plasma levels of unconjugated psilocin (the psychoactive metabolite of psilocybin) and corresponding subjective effects were repeatedly assessed up to 24 hours. PK parameters were determined using compartmental modeling. Concentration-subjective effect relationships were described using PK-PD modeling. Mean (95% confidence interval) maximal psilocin concentrations were 11 ng/mL (10-13), 17 ng/mL (16-19), and 21 ng/mL (19-24) after the administration of 15, 25, and 30 mg psilocybin, respectively. Maximal concentrations were reached after an average of 2 hours. Elimination half-lives were 1.8 hours (1.7-2.0), 1.4 hours (1.2-1.7), and 1.8 hours (1.6-1.9) for 15, 25, and 30 mg psilocybin, respectively. Mean (± SD) durations of subjective effects were 5.6 ± 2.2 hours, 5.5 ± 1.6 hours, and 6.4 ± 2.2 hours, and maximal effects ("any drug" effects) were 58% ± 25%, 73% ± 27%, and 80% ± 18% after 15, 25, and 30 mg psilocybin, respectively. Psilocin exhibited dose-proportional PKs. The duration and intensity of subjective effects were dose-dependent. Body weight did not influence pharmacokinetics or the response to psilocybin. These data may serve as a reference for future clinical trials.

Ketanserin Reverses the Acute Response to LSD in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Participants.

BACKGROUND: Lysergic acid diethylamide (LSD) is currently being investigated in psychedelic-assisted therapy. LSD has a long duration of acute action of 8-11 hours. It produces its acute psychedelic effects via stimulation of the serotonin 5-hydroxytryptamine-2A (HT2A) receptor. Administration of the 5-HT2A antagonist ketanserin before LSD almost fully blocks the acute subjective response to LSD. However, unclear is whether ketanserin can also reverse the effects of LSD when administered after LSD. METHODS: We used a double-blind, randomized, placebo-controlled, crossover design in 24 healthy participants who underwent two 14-hour sessions and received ketanserin (40 mg p.o.) or placebo 1 hour after LSD (100 µg p.o.). Outcome measures included subjective effects, autonomic effects, acute adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 12 hours. RESULTS: Ketanserin reversed the acute response to LSD, thereby significantly reducing the duration of subjective effects from 8.5 hours with placebo to 3.5 hours. Ketanserin also reversed LSD-induced alterations of mind, including visual and acoustic alterations and ego dissolution. Ketanserin reduced adverse cardiovascular effects and mydriasis that were associated with LSD but had no effects on elevations of brain-derived neurotrophic factor levels. Ketanserin did not alter the pharmacokinetics of LSD. CONCLUSIONS: These findings are consistent with an interaction between ketanserin and LSD and the view that LSD produces its psychedelic effects only when occupying 5-HT2A receptors. Ketanserin can effectively be used as a planned or rescue option to shorten and attenuate the LSD experience in humans in research and LSD-assisted therapy. TRIAL REGISTRY: ClinicalTrials.gov (NCT04558294).

Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects.

Growing interest has been seen in using lysergic acid diethylamide (LSD) and psilocybin in psychiatric research and therapy. However, no modern studies have evaluated differences in subjective and autonomic effects of LSD and psilocybin or their similarities and dose equivalence. We used a double-blind, randomized, placebo-controlled, crossover design in 28 healthy subjects (14 women, 14 men) who underwent five 25 h sessions and received placebo, LSD (100 and 200 µg), and psilocybin (15 and 30 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales for subjective effects, autonomic effects, adverse effects, effect durations, plasma levels of brain-derived neurotrophic factor (BDNF), prolactin, cortisol, and oxytocin, and pharmacokinetics. The doses of 100 and 200 µg LSD and 30 mg psilocybin produced comparable subjective effects. The 15 mg psilocybin dose produced clearly weaker subjective effects compared with both doses of LSD and 30 mg psilocybin. The 200 µg dose of LSD induced higher ratings of ego-dissolution, impairments in control and cognition, and anxiety than the 100 µg dose. The 200 µg dose of LSD increased only ratings of ineffability significantly more than 30 mg psilocybin. LSD at both doses had clearly longer effect durations than psilocybin. Psilocybin increased blood pressure more than LSD, whereas LSD increased heart rate more than psilocybin. However, both LSD and psilocybin showed comparable cardiostimulant properties, assessed by the rate-pressure product. Both LSD and psilocybin had dose-proportional pharmacokinetics and first-order elimination. Both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration. Any differences between LSD and psilocybin are dose-dependent rather than substance-dependent. However, LSD and psilocybin differentially increased heart rate and blood pressure. These results may assist with dose finding for future psychedelic research.Trial registration: ClinicalTrials.gov identifier: NCT03604744.

Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Subjects.

The psychedelic psilocybin is being investigated for the treatment of depression and anxiety. Unclear is whether antidepressant treatments interact with psilocybin. The present study used a double-blind, placebo-controlled, crossover design with two experimental test sessions to investigate the response to psilocybin (25 mg) in healthy subjects after pretreatment with escitalopram or placebo. The treatment order was random and counterbalanced. Pretreatment consisted of 10 mg escitalopram daily for 7 days, followed by 20 mg daily for 7 days, including the day of psilocybin administration, or 14 days of placebo pretreatment before psilocybin administration. Psilocybin treatments were separated by at least 16 days. The outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor (BDNF) levels, electrocardiogram QTc time, whole-blood HTR2A and SCL6A4 gene expression, and pharmacokinetics. Escitalopram pretreatment had no relevant effect on positive mood effects of psilocybin but significantly reduced bad drug effects, anxiety, adverse cardiovascular effects, and other adverse effects of psilocybin compared with placebo pretreatment. Escitalopram did not alter the pharmacokinetics of psilocin. The half-life of psychoactive free (unconjugated) psilocin was 1.8 hours (range 1.1-2.2 hours), consistent with the short duration of action of psilocybin. Escitalopram did not alter HTR2A or SCL6A4 gene expression before psilocybin administration, QTc intervals, or circulating BDNF levels before or after psilocybin administration. Further studies are needed with a longer antidepressant pretreatment time and patients with psychiatric disorders to further define interactions between antidepressants and psilocybin.

Tauroursodeoxycholic Acid (TUDCA)-Lipid Interactions and Antioxidant Properties of TUDCA Studied in Model of Photoreceptor Membranes.

Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid containing taurine conjugated with the ursodeoxycholic acid (UDCA), has been known and used from ancient times as a therapeutic compound in traditional Chinese medicine. TUDCA has recently been gaining significant interest as a neuroprotective agent, also exploited in the visual disorders. Among several mechanisms of TUDCA's protective action, its antioxidant activity and stabilizing effect on mitochondrial and plasma membranes are considered. In this work we investigated antioxidant activity of TUDCA and its impact on structural properties of model membranes of different composition using electron paramagnetic resonance spectroscopy and the spin labeling technique. Localization of TUDCA molecules in a pure POPC bilayer has been studied using a molecular dynamics simulation (MD). The obtained results indicate that TUDCA is not an efficient singlet oxygen (1O2 (1Δg)) quencher, and the determined rate constant of its interaction with 1O2 (1Δg) is only 1.9 × 105 M-1s-1. However, in lipid oxidation process induced by a Fenton reaction, TUDCA reveals substantial antioxidant activity significantly decreasing the rate of oxygen consumption in the system studied. In addition, TUDCA induces slight, but noticeable changes in the polarity and fluidity of the investigated model membranes. The results of performed MD simulation correspond very well with the experimental results.

Antiviral Actions of 25-Hydroxycholesterol in Fish Vary With the Virus-Host Combination.

Cholesterol is essential for building and maintaining cell membranes and is critical for several steps in the replication cycle of viruses, especially for enveloped viruses. In mammalian cells virus infections lead to the accumulation of the oxysterol 25-hydroxycholesterol (25HC), an antiviral factor, which is produced from cholesterol by the cholesterol 25 hydroxylase (CH25H). Antiviral responses based on CH25H are not well studied in fish. Therefore, in the present study putative genes encoding for CH25H were identified and amplified in common carp and rainbow trout cells and an HPLC-MS method was applied for determination of oxysterol concentrations in these cells under virus infection. Our results give some evidence that the activation of CH25H could be a part of the antiviral response against a broad spectrum of viruses infecting fish, in both common carp and rainbow trout cells in vitro. Quantification of oxysterols showed that fibroblastic cells are capable of producing 25HC and its metabolite 7α,25diHC. The oxysterol 25HC showed an antiviral activity by blocking the entry of cyprinid herpesvirus 3 (CyHV-3) into KFC cells, but not spring viremia of carp virus (SVCV) or common carp paramyxovirus (Para) in the same cells, or viral haemorrhagic septicaemia virus (VHSV) and infectious pancreatic necrosis virus (IPNV) into RTG-2 cells. Despite the fact that the CH25H based antiviral response coincides with type I IFN responses, the stimulation of salmonid cells with recombinant type I IFN proteins from rainbow trout could not induce ch25h_b gene expression. This provided further evidence, that the CH25H-response is not type I IFN dependent. Interestingly, the susceptibility of CyHV-3 to 25HC is counteracted by a downregulation of the expression of the ch25h_b gene in carp fibroblasts during CyHV-3 infection. This shows a unique interplay between oxysterol based immune responses and immunomodulatory abilities of certain viruses.

Terbium Excitation Spectroscopy as a Detection Method for Chromatographic Separation of Lanthanide-Binding Biomolecules.

Studies of biosorption and bioaccumulation of heavy metals deal mostly with challenging, inhomogeneous, and complex materials. Therefore, most reports describe only application studies, while fundamental research is limited to indirect methods and speculations on the binding mechanisms. In this study, we describe a method for detecting and isolating heavy metal-binding biomolecules directly from crude extracts. The underlying principle is terbium sensitization and fluorescence excitation spectroscopy used offline after a chromatographic run. Compounds interacting with metal ions inevitably change the coordination sphere of terbium, which is reflected in the excitation spectrum leading to metal-specific luminescence. Main advantages of our approach include simple, fast, and inexpensive experiment design, nondestructive measurements, and detection limits far below 1 mg. Here, we have applied our method for three promising biosorbents (green algae, moss, and cyanobacterium) and obtained first information on the character of active compounds isolated from each species.

Perfluorooctanoic acid and perfluorooctane sulfonate released from a waste water treatment plant in Bavaria, Germany.

PURPOSE: Perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), and precursors and derivatives thereof have been employed as surfactants and anti-adhesives. PFOA and PFOS are environmentally persistent and the discharge of municipal waste waters is one of the principal routes of these compounds into the aquatic environment. In a previous study, the concentrations of PFOA and PFOS in grab samples collected from the waste water treatment plant (WWTP) of Bayreuth, a city of 72,000 inhabitants in Bavaria, Germany, during two periods showed considerable variability. For a better estimate of average mass flows, the surfactants were monitored (five samplings) from 16 March to 18 May 2007. In a second campaign, river water receiving the WWTP effluent was sampled twice a day for five consecutive days. METHODS: Quantitative analysis was done by stable-isotope dilution, pre-cleaning, and pre-concentration by solid-phase extraction, and liquid chromatography followed by electrospray ionization/tandem mass spectrometry. RESULTS: The mass flows of PFOA and PFOS through the WWTP were determined. PFOA is fully discharged into the river, while about half of PFOS is retained in the sewage sludge. The average daily mass load of the river Roter Main by the WWTP of Bayreuth is about 1.2 ± 0.5 g PFOA and 5 ± 2 g PFOS, with variations of up to 140% within one day. CONCLUSION: Overall, the total annual release to the rivers of Germany may be in the range of several hundred kilograms of PFOA and several tons of PFOS.

Perfluorooctanoic acid and perfluorooctane sulfonate in two fish species collected from the Roter Main River, Bayreuth, Germany.

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are widely distributed in the environment. In this study the accumulation potential of PFOA and PFOS in two fish species with different feeding strategies, i.e. chub (Leuciscus cephalus) and river goby (Gobio gobio) inhabiting a river receiving treated waste waters from a municipal waste water treatment plant, were estimated. PFOS was detected in chub (7-250 microg kg(-1) wet weight) and river goby (70-400 microg kg(-1) wet weight) with bioaccumulation factors (BAFs) of 4600 (liver) and 11,000 (organs). PFOA concentrations in both fish were low and in chub mostly below detection limit.

Perfluorooctanoic acid and perfluorooctane sulfonate in the sediment of the Roter Main river, Bayreuth, Germany.

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are widely distributed in aquatic ecosystems. Their sources are known but few studies about their accumulation potential in river sediments exist. The aim of this study is to assess the concentrations of PFOA and PFOS in sediments in relation to their levels in river water receiving effluent from a waste water treatment plant (WWTP). PFOS accumulates by a factor of about 40 relative to river water, PFOA only up to threefold. In contrast to previous suggestions, in this case the enrichment on sediment is not correlated to the total organic carbon contents.

Effects of phenanthrene on lemna minor in a sediment-water system and the impacts of UVB.

The objective of this study was to evaluate if the Lemna-bioassay is appropriate to test contaminated sediments. A mixture of sand was spiked with phenanthrene to investigate whether sediment-bound pollutants can affect the plants via direct contact of the roots or the underside of the leaves. After 24h of equilibration for sorption/desorption processes, the test was carried out in the sediment-water mixture, and another test was performed with the aqueous phase which was separated from the sediment. The growth inhibition of Lemna was nearly the same in both tests. Hence it follows that the toxicant is adsorbed from the aqueous phase via the underside of the leaves and sediment bound phenanthrene is not bioavailable. Polycyclic aromatic hydrocarbons are known to show photoinduced toxicity to plants in the presence of UV which is a result of photosensitization reactions in the plant and photomodification to more toxic and better soluble photoproducts. Photoinduced toxicity could be observed in the water phase during UVB treatment, whereas the presence of suspended sediment probably lowered the UV intensity, resulting in a lower growth inhibition.