There is an increasing demand for effective treatments for depression, particularly for individuals grappling with treatment-resistant depression. Over recent years, a surge of interest has focused on exploring the safety and efficacy of psilocybin as a potential treatment for depression. However, preliminary findings from phase 2 studies have been inconclusive, prompting critical examination of issues such as maintaining blinding and the role of adjunctive psychotherapy. The maintenance of double-blinding and the role of adjunctive psychotherapy introduce biases that complicate the attainment of conclusive results in clinical research. Examining historical data reveals a recurrent pattern linked to the use of psychoactive substances, which starts with an excess of optimism and ends with general addictive behaviors and a heightened risk of serious public health problems. Considering these findings, a cautious and measured approach is imperative, given that the efficacy and safety of psilocybin treatment have yet to be unequivocally established. The potential for excessive optimism among researchers is a notable concern, as unwarranted enthusiasm may inadvertently facilitate the widespread adoption of this treatment without sufficient empirical support. In navigating the complexities of depression treatment, it is necessary to strike a balance between innovation and prudence to ensure evidence-based advancement of therapeutic approaches.

Serotonergic hallucinogens also referred to as psychedelics, are psychoactive substances that profoundly alter perception, mood, and cognitive processes. These substances, historically intertwined with religious and cultural rituals, offer profound effects that extend beyond mere hallucinations to profoundly altered states of consciousness. Notable compounds like Lysergic acid diethylamide (LSD) and psilocybin, potent in their action on serotonin receptors, play pivotal roles in influencing brain functions. Despite societal misconceptions that have overshadowed their potential, contemporary research increasingly recognizes their therapeutic value. These substances have shown promise in treating neuropsychiatric disorders such as depression, post-traumatic stress disorder (PTSD), and anxiety, leveraging their influence on neuroplasticity. Furthermore, they exhibit therapeutic potential across various conditions, challenging conventional treatment methodologies. Compared to substances like alcohol, traditional psychedelics like LSD and psilocybin emerge as relatively safer substances. The modern revival of scientific interest in psychedelics necessitates a renewed perspective, viewing them not just as recreational entities but as potent therapeutic tools. Harnessing their actual value mandates rigorous scientific investigations and a receptive societal discourse. A re-evaluation of their classification following international criteria is necessary in light of this increasing understanding. Hallucinogens or psychedelic drugs, if used correctly, can potentially be potential treatments for mental illness, signalling a paradigm shift from traditional techniques. To dispel myths and use their therapeutic advantages, embracing this potential necessitates thorough scientific investigation together with an open societal discourse.

BACKGROUND: Rave music parties (RMP) are a world-wide socio-cultural phenomenon, where people listen to rave music while frequently consuming psychedelic drugs. Epidemiological studies have emphasized the hazardous consequences following the consumption of psychedelic drugs at RMP, and qualitative studies have shown social and psycho-spiritual experiences. Yet, phenomenological inquiry into subjective experiences of attendees is scant. This study aimed to examine physical, emotional, perceptual and social experiences of RMP participants in Israel, and their view on Israel\'s policy toward rave events. In addition, the study aimed to contribute useful information for policymakers and society on rave music and psychedelic drugs experiences at RMP.
METHODS: Interpretative phenomenological analysis was used to analyze transcriptions of semi-structured interviews with 27 individuals attending RMP regularly and consume psychedelic drugs.
RESULTS: Analysis revealed four significant themes: the first theme, the impact of Israel\'s drug policy on participants\' sense of safety, relates to participants\' sense of insecurity and anxiety at Israeli RMP due to government drug ban policy. The second theme, the stigma on rave culture, relates to participants\' perception regarding the stigma on rave culture in law enforcement agencies and in society in general. The third theme, negative experiences, describes short-term experiences after consuming psychedelics at RMP, including hallucinations and disorientation. The fourth theme, positive experiences, describes positive sensory, emotional and self/world attitudinal aspects after consuming psychedelics at RMP. Sensory experiences included intensified auditory, visual and tactile experiences; emotional experiences included positive feelings toward others, reduced stress and ability to vent difficult emotions; self/world attitudinal aspects included self-acceptance, higher appreciation of life and connectedness to nature.
CONCLUSIONS: The study highlights RMP participants\' sense of insecurity due to Israel\'s strict drug policy and absence of harm reduction strategies at rave scenes. The study also notes participants\' experience of stigmatization as drug addicts by society and law enforcement agencies. Reducing police presence and adopting harm reduction policies at rave scenes in Israel may increase participants\' sense of security, reduce stigmatization and decrease overdose risk. Hence, the findings may contribute to new knowledge useful for policymakers and society concerning RMP and the use of psychedelics.

Serotonergic psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, dimethyltryptamine (DMT), and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), are currently being investigated for the treatment of psychiatric disorders such as depression and anxiety. Clinical trials with psilocybin and LSD have shown improvement in emotional and psychological scores. Although these drugs are reported to be safe in a controlled environment (such as clinical trials), exposure to low doses of these drugs can result in psychedelic effects, and therefore, occupational safety is an important consideration to prevent adverse effects in the workplace from low daily exposure. This article will discuss the factors involved in the derivation of occupational exposure limits (OELs) and risk assessment of these psychedelic drugs. To support the OEL derivations of psychedelic drugs, information regarding their mechanism of action, adverse effect profiles, pharmacokinetics, clinical effects, and nonclinical toxicity were considered. Additionally, psilocybin and LSD, which are the most extensively researched psychedelic substances, are employed as illustrative examples in case studies. The OELs derived for psilocybin and for LSD are 0.05 and 0.002 μg/m3 , respectively, which indicates that these are highly hazardous compounds, and it is important to take into account suitable safety measures and risk-management strategies in order to minimize workplace exposure.

The current standard of care in most uses of psychedelic medicines for the treatment of psychiatric indications includes the provision of a supportive therapeutic context before, during, and after drug administration. A diversity of psychedelic-assisted psychotherapy (PAP) models has been created to meet this need. The current article briefly reviews the strengths and limitations of these models, which are divided into basic support models and EBT-inclusive therapy models. It then discusses several shortcomings both types of models share, including a lack of adequate attention to embodied and relational elements of treatment, and insufficient attention to ethical concerns. The article then introduces the EMBARK model, a transdiagnostic, trans-drug framework for the provision of supportive psychotherapy in PAP clinical trials and the training of study therapists. EMBARK was designed to overcome challenges that prior models have had in conceptualizing therapeutic change in psychedelic treatment, incorporating elements of non-psychedelic evidence-based therapies, incorporating therapists\' prior skills and clinical orientations, delimiting therapist interventions for research standardization, and determining specific factors that contribute to treatment outcomes. The article explains EMBARK\'s six clinical domains, which represent parallel conceptualizations of how therapists may support therapeutic benefit in PAP treatment, and its four care cornerstones, which reflect therapists\' broad ethical responsibility to participants. The article describes how these elements of the model come together to structure and inform therapeutic interventions during preparation, medicine, and integration sessions. Additionally, the article will discuss how EMBARK therapist training is organized and conducted. Finally, it will demonstrate the broad applicability of EMBARK by describing several current and upcoming PAP clinical trials that have adopted it as the therapeutic frame.

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The active hallucinogen of magic mushrooms, psilocin, is being repurposed to treat nicotine addiction and treatment-resistant depression. Psilocin belongs to the tryptamine class of psychedelic compounds which include the hormone serotonin. It is believed that psilocin exerts its effect by binding to the serotonin 5-HT2A receptor. However, recent in-vivo evidence suggests that psilocin may employ a different mechanism to exert its effects. Membrane-mediated receptor desensitization of neurotransmitter receptors is one such mechanism. We compare the impact of the neutral and charged versions of psilocin and serotonin on the properties of zwitterionic and anionic lipid membranes using molecular dynamics simulations and calorimetry. Both compounds partition to the lipid interface and induce membrane thinning. The tertiary amine in psilocin, as opposed to the primary amine in serotonin, limits psilocin\'s impact on the membrane although more psilocin partitions into the membrane than serotonin. Calorimetry corroborates that both compounds induce a classical melting point depression like anesthetics do. Our results also lend support to a membrane-mediated receptor-binding mechanism for both psilocin and serotonin and provide physical insights into subtle chemical changes that can alter the membrane-binding of psychedelic compounds.

Sociology of drugs and digital sociology-albeit for different reasons-need the analysis of interactions, an approach underdeveloped in current scholarship. We address this gap by providing a specific analytical framework for the analysis of digital interactions which enables an ethnomethodological account of micro-interactional dynamics within a cryptomarket: an anonymous darknet market of  illicit drugs. As a case study we chose the \'PsychForumMarket\' which is unusual in that it operates as a forum based market space and explicitly rejects centralised technical market solutions such as escrow and encryption systems. Instead, it emphasises personal relationships between buyers and vendors as the basis of trust. Hence it forms a community of exchange, both material and cultural. The data were collected through a process of manual scraping from the forum from 2017 to 2020. The data was purposefully sampled to construct a \'thick data\' set, and analysed thematically to examine the micro interactional turn taking, sanctioning and norming processes by which the market culture is normalized and embedded. This market is a laboratory  to investigate the constitutive nature of digital group interactions. Due to the very nature of this market the disciplining process cannot lie with external authorities. Interactions between community members are permeated with mutual monitoring and policing. We find that in and through digital communication a particular culture emerges to which individuals who wish to join this community have to ascribe. We refer to this particular culture as a \'psychedelic assemblage,\' i.e., a local constellation of cultural constructs which frames the experience of drug using and trading. Our investigation reveals the constitutive methods which enable the norming of members\' practices and underpin the emergence of a shared lifeworld which in turn ensures the operability of this cryptomarket.

Treatment of major depressive disorder (MDD) including treatment-resistant depression (TRD) remains a major unmet need. Although there are several classes of dissimilar antidepressant drugs approved for MDD, the current drugs have either limited efficacy or are associated with undesirable side effects and withdrawal symptoms. The efficacy and side effects of antidepressant drugs are mainly attributed to their actions on different monoamine neurotransmitters (serotonin, norepinephrine, and dopamine). Development of new antidepressants with novel targets beyond the monoamine pathways may fill the unmet need in treatment of MDD and TRD. The recent approval of intranasal Esketamine (glutamatergic agent) in conjunction with an oral antidepressant for the treatment of adult TRD patients was the first step toward expanding beyond the monoamine targets. Several other glutamatergic (AXS-05, REL-1017, AV-101, SLS-002, AGN24175, and PCN-101) and GABAergic (brexanolone, zuranolone, and ganaxolone) drugs are currently in different stages of clinical development for MDD, TRD and other indications. The renaissance of psychedelic drugs and the emergence of preliminary positive clinical trial results with psilocybin, Ayahuasca, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and lysergic acid diethylamide (LSD) may pave the way towards establishing this class of drugs as effective therapies for MDD, TRD and other neuropsychiatric disorders. Going beyond the monoamine targets appears to be an effective strategy to develop novel antidepressant drugs with superior efficacy, safety, and tolerability for the improved treatment of MDD and TRD.

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