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BackgroundSynthetic cannabinoids (SCs) are the largest class of novel psychoactive substances (NPS) and are associated with an increased risk of overdosing and adverse events such as psychosis. JWH-018 is one of the earliest SCs and still widely available in large parts of the world. Controlled studies to assess the safety and behavioural profiles of SCs are extremely scarce.AimThe current study was designed to assess the psychotomimetic effects of a moderate dose of JWH-018.MethodsTwenty-four healthy participants (10 males, 14 females) entered a placebo-controlled, double blind, within-subjects trial and inhaled vapour of placebo or 75μg/kg bodyweight JWH-018. To ascertain a minimum level of intoxication, a booster dose of JWH-018 was administered on an as-needed basis. The average dose of JWH-018 administered was 5.52 mg. Subjective high, dissociative states (CADSS), psychedelic symptoms (Bowdle), mood (POMS) and cannabis reinforcement (SCRQ) were assessed within a 4.5-h time window after drug administration.ResultsJWH-018 caused psychedelic effects, such as altered internal and external perception, and dissociative effects, such as amnesia, derealisation and depersonalisation and induced feelings of confusion.ConclusionOverall, these findings suggest that a moderate dose of JWH-018 induces pronounced psychotomimetic symptoms in healthy participants with no history of mental illness, which confirms that SCs pose a serious risk for public health.

Rationale Typical users of 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”) are polydrug users, combining MDMA with alcohol or cannabis [most active compound: delta-9-tetrahydrocannabinol (THC)]. Objectives The aim of the present study was to investigate whether co-administration of alcohol or THC with MDMA differentially affects ongoing electroencephalogram (EEG) oscillations compared to the administration of each drug alone. Methods In two separate experiments, 16 volunteers received four different drug conditions: (1) MDMA (100 mg); (2) alcohol clamp (blood alcohol concentration = 0.6‰) or THC (inhalation of 4, 6 and 6 mg, interval of 1.5 h); (3) MDMA in combination with alcohol or THC; and (4) placebo. Before and after drug administration, electroencephalography was recorded during an eyes closed resting state. Results Theta and alpha power increased after alcohol intake compared to placebo and reduced after MDMA intake. No interaction between alcohol and MDMA was found. Significant MDMA × THC effects for theta and lower-1-alpha power indicated that the power attenuation after the combined intake of MDMA and THC was less than the sum of each drug alone. For the lower-2-alpha band, the intake of MDMA or THC alone did not significantly affect power, but the intake of combined MDMA and THC significantly decreased lower-2-alpha power. Conclusions The present findings indicate that the combined intake of MDMA and THC, but not of MDMA and alcohol, affects ongoing EEG oscillations differently than the sum of either one drug alone. Changes in ongoing EEG oscillations may be related to the impaired task performance that has often been reported after drug intake.

Prospective memory refers to the realization of delayed intentions. Several studies have shown that 3,4-methylenedioxy-methamphetamine (MDMA) users perform worse on measures of prospective memory as compared to nondrug users. Interpretation of these data may be limited because of polydrug use, psychosocial stressors, and increased psychopathology that have been reported in MDMA users. This study was designed to directly assess the pharmacological effect of MDMA on prospective memory and brain activity in a double-blind, placebo-controlled, cross-over study. Twelve recreational MDMA users received MDMA 75 mg and placebo and performed an objective prospective memory task during functional imaging. During prospective memory task performance subjects were engaged in a foreground task that consisted of a simple reaction time to visual stimuli (Go trials) and a prospective task of withholding a response during trials that were part of a dynamic memory set (No go trials). Behavioral data showed that a single dose of MDMA increased prospective memory failures in the No go trials, and that number of prospective memory failures was positively correlated to MDMA concentration in plasma. Functional imaging showed that MDMA decreased BOLD activation during Go trials in the thalamus (left), putamen (left), precuneus (left), and the inferior parietal lobules (bilateral), as compared to placebo. During No go trials, MDMA reduced BOLD deactivation in the inferior parietal lobules (bilateral), as compared to placebo. It is concluded that the loss of deactivation in inferior parietal lobules may account for increments in memory failures observed during MDMA intoxication.

In the area of psychotropic drugs, tryptamines are known to be a broad class of classical or serotonergic hallucinogens. These drugs are capable of producing profound changes in sensory perception, mood and thought in humans and act primarily as agonists of the 5-HT 2A receptor. Well-known tryptamines such as psilocybin contained in Aztec sacred mushrooms and N , N -dimethyltryptamine (DMT), present in South American psychoactive beverage ayahuasca, have been restrictedly used since ancient times in sociocultural and ritual contexts. However, with the discovery of hallucinogenic properties of lysergic acid diethylamide (LSD) in mid-1900s, tryptamines began to be used recreationally among young people. More recently, new synthetically produced tryptamine hallucinogens, such as alpha-methyltryptamine (AMT), 5-methoxy- N , N -dimethyltryptamine (5-MeO-DMT) and 5-methoxy- N , N -diisopropyltryptamine (5-MeO-DIPT), emerged in the recreational drug market, which have been claimed as the next-generation designer drugs to replace LSD (‘legal’ alternatives to LSD). Tryptamine derivatives are widely accessible over the Internet through companies selling them as ‘research chemicals’, but can also be sold in ‘headshops’ and street dealers. Reports of intoxication and deaths related to the use of new tryptamines have been described over the last years, raising international concern over tryptamines. However, the lack of literature pertaining to pharmacological and toxicological properties of new tryptamine hallucinogens hampers the assessment of their actual potential harm to general public health. This review provides a comprehensive update on tryptamine hallucinogens, concerning their historical background, prevalence, patterns of use and legal status, chemistry, toxicokinetics, toxicodynamics and their physiological and toxicological effects on animals and humans.

Introduction 3,4-methylenedioxymethamphetamine (MDMA) is known to improve psychomotor function and mood when measured during daytime. However, MDMA users tend to take this drug at dance parties while staying awake for prolonged periods of time. Subjects and methods This study was designed to assess dose-related residual effects of MDMA on psychomotor function and mood after a night without sleep. Sixteen recreational MDMA users received single doses of 25, 50, and 100 mg MDMA in a randomized, double-blind, placebo-controlled cross-over study. Results Results showed that sleep loss significantly impaired psychomotor function. MDMA generally did not affect performance but did improve rapid information processing at the highest dose in the morning after administration. In the evening, MDMA also increased subjective ratings of positive mood at every dose and subjective arousal at the highest dose. These subjective effects were no longer present after a night of sleep loss. Discussion It is concluded that sleep deprivation impairs psychomotor function and that stimulant effects of MDMA are not sufficient to compensate for this impairment.

RationaleIn recent years, psychedelic substances with serotonergic mechanisms have accumulated substantial evidence that they may provide therapeutic benefits for people suffering with psychiatric symptoms. Psychiatric disorders targeted by these psychedelic-assisted therapies are managed with serotonergic drugs like selective serotonin reuptake inhibitors (SSRIs) as the current standard of care, so it is important to evaluate the potential risks of drug-drug interactions and serotonin toxicity (ST) between these agents.ObjectivesA critical evaluation of the scientific literature is necessary to delineate the risks of ST when combining psychedelics with available serotonergic pharmacotherapy options. This review article describes signs and symptoms of ST, characterizes mechanisms of ST risk, summarizes what is known about serotonergic psychedelic drug interactions, and outlines potential management strategies.ResultsTrue ST typically occurs with a serotonergic drug overdose or in combinations in which a drug that can increase intrasynaptic serotonin is combined with a monoamine oxidase inhibitor (MAOI). Serotonergic psychotropics that do not contain MAOIs are low risk in combination with psychedelics that also do not contain MAOIs. Signs and symptoms warranting immediate medical attention include myoclonus, extreme and fluctuating vital signs, agitation or comatose mental state, muscle rigidity, pronounced hyperthermia (fever), and/or seizure activity.ConclusionsSerotonin-related adverse reactions exist along a spectrum with serotonin syndrome being the most severe manifestations of ST. Due to varying serotonergic mechanisms of psychedelics and psychotropics, with varying propensities to increase intrasynaptic serotonin, some combinations may present a significant risk for serotonin toxicity (ST) while others are likely benign.

New psychoactive substances (NPSs) are a heterogenous group of psychotropic molecules and diverted pharmaceutical drugs sold worldwide as legal substitutes for controlled drugs. The psychiatric consequences of NPS use are relatively unknown, although evidence of related psychotic symptoms has been described in the literature. We sought to summarize the available evidence on NPS-related psychiatric disorders, to facilitate the interpretation of the molecular mechanism underlying their specific pathologies. A literature search of Scopus, PubMed and Google Scholar was conducted including studies published between 2013 and 2024, in which a correlation between NPS consumption and psychiatric symptoms was reported. Furthermore, the short- and long-term psychopathological effects were included. The literature search resulted in 109 NPS-related intoxication cases in which acute or chronic psychiatric symptoms were reported, mostly related to synthetic cannabinoids, followed by synthetic cathinones, hallucinogens, natural NPSs and stimulants. The most common acute symptoms were hallucinations, aggressiveness, and psychotic and bizarre behavior, related to the molecular disbalance of neurotransmitters in the central nervous systems, with different mechanisms. The lack of clear diagnostic criteria and toxicological analyses has resulted in crucial complications in psychiatric diagnoses related to NPS intoxication. Hence, the implementation of toxicological screening procedures in emergency rooms, including the main NPS classes, should support the diagnosis of acute intoxication and its proper therapeutic treatment. Finally, proper follow-up should be implemented to assess the chronic sequelae.

New groups of synthetic “designer drugs” have increased in popularity over the past several years. These products mimic the euphoric effects of other well-known illicit drugs but are advertised as “legal” highs and are sold over the internet, at raves and night clubs, and in head shops. The 2C series drugs are ring-substituted phenethylamines that belong to a group of designer agents similar in structure to 3,4-methylenedioxy- N -methylamphetamine (MDMA, Ecstasy). Understanding the pharmacology and toxicology of these agents is essential in order to provide the best medical care for these patients. This review focuses on the pharmacology, pharmacokinetics, clinical effects, and treatment of 2C drug intoxication based on available published literature. Multiple names under which 2C drugs are sold were identified and tabulated. Common features identified in patients intoxicated with 2Cs included hallucinations, agitation, aggression, violence, dysphoria, hypertension, tachycardia, seizures, and hyperthermia. Patients may exhibit sympathomimetic symptoms or symptoms consistent with serotonin toxicity, but an excited delirium presentation seems to be consistent amongst deaths attributed to 2C drugs; at least five deaths have been reported in the literature in patients intoxicated with 2C drugs. 2C drugs are a group of designer intoxicants, many of which are marketed as legal, but may carry risks that consumers are unaware of. These drugs may be characterized by either serotonergic toxicity or a sympathomimetic toxidrome, but a presentation consistent with excited delirium is consistent amongst the reported 2C-related deaths. Treatment of 2C intoxication is primarily supportive, but immediate action is required in the context of excited delirium, hyperthermia, and seizure activity.

RationaleMemory plays a central role in the psychedelic experience. The spontaneous recall and immersive reliving of autobiographical memories has frequently been noted by researchers and clinicians as a salient phenomenon in the profile of subjective effects of classic psychedelic drugs such as psilocybin, LSD, and ayahuasca. The ability for psychedelics to provoke vivid memories has been considered important to their clinical efficacy.ObjectiveThis review aims to examine and aggregate the findings from experimental, observational, and qualitative studies on the acute modulation of memory by classic psychedelics in humans.MethodA literature search was conducted using PubMed and PsycInfo as well as manual review of references from eligible studies. Publications reporting quantitative and/or qualitative findings were included; animal studies and case reports were excluded.ResultsClassic psychedelics produce dose-dependently increasing impairments in memory task performance, such that low doses produce no impairment and higher doses produce increasing levels of impairment. This pattern has been observed in tasks assessing spatial and verbal working memory, semantic memory, and non-autobiographical episodic memory. Such impairments may be less pronounced among experienced psychedelic users. Classic psychedelics also increase the vividness of autobiographical memories and frequently stimulate the recall and/or re-experiencing of autobiographical memories, often memories that are affectively intense (positively or negatively valenced) and that had been avoided and/or forgotten prior to the experience.ConclusionsClassic psychedelics dose-dependently impair memory task performance but may enhance autobiographical memory. These findings are relevant to the understanding of psychological mechanisms of action of psychedelic-assisted psychotherapy.

Anecdotal reports have surfaced concerning misuse of the HIV antiretroviral medication efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one) by HIV patients and non-infected teens who crush the pills and smoke the powder for its psychoactive effects. Molecular profiling of the receptor pharmacology of efavirenz pinpointed interactions with multiple established sites of action for other known drugs of abuse including catecholamine and indolamine transporters, and GABAA and 5-HT(2A) receptors. In rodents, interaction with the 5-HT(2A) receptor, a primary site of action of lysergic acid diethylamine (LSD), appears to dominate efavirenz's behavioral profile. Both LSD and efavirenz reduce ambulation in a novel open-field environment. Efavirenz occasions drug-lever responding in rats discriminating LSD from saline, and this effect is abolished by selective blockade of the 5-HT(2A) receptor. Similar to LSD, efavirenz induces head-twitch responses in wild-type, but not in 5-HT(2A)-knockout, mice. Despite having GABAA-potentiating effects (like benzodiazepines and barbiturates), and interactions with dopamine transporter, serotonin transporter, and vesicular monoamine transporter 2 (like cocaine and methamphetamine), efavirenz fails to maintain responding in rats that self-administer cocaine, and it fails to produce a conditioned place preference. Although its molecular pharmacology is multifarious, efavirenz's prevailing behavioral effect in rodents is consistent with LSD-like activity mediated via the 5-HT(2A) receptor. This finding correlates, in part, with the subjective experiences in humans who abuse efavirenz and with specific dose-dependent adverse neuropsychiatric events, such as hallucinations and night terrors, reported by HIV patients taking it as a medication.