In vitro activation of the CB1 receptor by the semi-synthetic cannabinoids hexahydrocannabinol (HHC), hexahydrocannabinol acetate (HHC-O) and hexahydrocannabiphorol (HHC-P).

Semi-synthetic cannabinoids (SSCs) including hexahydrocannabinol (HHC) are emerging on the drug market and sold openly as purportedly legal replacements for cannabis and Δ9-THC. By the beginning of 2024, 24 European countries had identified HHC, often sold openly in edibles (foods/candy), vapes and low-THC cannabis flowers and resins. The SSC market is developing rapidly, with HHC acetate (HHC-O), hexahydrocannabiphorol (HHC-P) and others recently identified. These developments may mark the first major change in the market for 'legal' replacements to cannabis since 'Spice' containing synthetic cannabinoids, such as JWH-018, emerged in 2008. Currently, there are some data available on the pharmacology of SSCs, which is crucial for understanding their effects, evaluating health risks and informing public health responses. This study focused on characterizing the in vitro activation of the human CB1 receptor by the (R)- and (S)-epimers of HHC, HHC-P and HHC-O. Using recombinant CHO-K1 cells expressing the human CB1 receptor, the potency (EC50) and efficacy were determined. It was established that (9R)-HHC and (9R)-HHC-P activated the CB1 receptor as partial agonists and with five and two times lower potency compared to JWH-018, respectively, while the (S)-epimers exhibited even lower potency. The (R)-epimer of HHC-O activate the CB1 receptor to even lesser extent and the (S)-epimer showed no activation. For HHC and HHC-P, all epimers exhibited similar level of efficacy. This available evidence suggests cannabimimetic effects of the tested SSC with the exception for the acetates that likely function as pro-drugs in vivo.

DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles.

Etonitazene and related 2-benzylbenzimidazoles are potent analgetics invented in the research laboratories of the Swiss pharmaceutical giant CIBA in the late 1950s. Though the unprecedented structure distinguishes this class of compounds from poppy-derived and other synthetic analgetics, a range of studies indicate that these drugs are selective µ opioid receptor agonists possessing morphine-like pharmacotoxicological properties in animals as well as humans. Several unscheduled members of this synthetically readily accessible class of opioids that are not controlled under the international and national drug control systems have recently emerged on the illicit drug market. Among them, isotonitazene has been implicated in at least 200 fatalities in Europe and North America. None of the 2-benzylbenzimidazole derivatives have been developed into medicines, but etonitazene and some of its derivatives have been used as receptor probes and in addiction behavior studies in animals. The unique structure has inspired research on such benzimidazoles and related benzimidazolones of which "brorphine" made its debut as one of the newest psychoactive substance to emerge on the illicit opioid drug market in mid-2019. This in-depth review provides a historical introduction, an overview on the chemistry, pharmacological profiles, adverse effects, addiction liability, regulatory status, and the impact on chemical neuroscience of the 2-benzylbenzimidazoles. Structurally related benzimidazoles with opioid and/or analgesic properties are also discussed briefly.

Eutylone and Its Structural Isomers Interact with Monoamine Transporters and Induce Locomotor Stimulation.

Synthetic cathinones are a class of new psychoactive substances that induce psychostimulant effects and pose risk for hospitalizations, overdose, and death. At the present time, derivatives of the synthetic cathinone, methylone, are being confiscated in nonmedical (i.e., recreational) drug markets worldwide. In particular, eutylone is a newly emerging methylone analog that possesses ethyl groups at the α-carbon and amine positions. Little information is available about the pharmacological effects of eutylone, but based on its structure, we surmised that the compound interacts with monoamine transporters in the brain. To test this hypothesis, we compared the effects of eutylone and its structural isomers, dibutylone and pentylone, using in vitro transporter assays in rat brain synaptosomes and in vivo locomotor activity assessments in mice. All drugs displayed dose-related inhibition of [3H]neurotransmitter uptake at dopamine transporters (DAT) and norepinephrine transporters (NET), but effects at DAT were 10-fold more potent (IC50 = 120 nM). Eutylone and pentylone inhibited uptake at serotonin transporters (SERT), while dibutylone did not. Additionally, eutylone and pentylone displayed weak partial releasing actions at SERT which achieved 50% of maximal response. All drugs stimulated dose-related locomotion in mice, and eutylone was most potent and efficacious in this regard (ED50 = 2 mg/kg, sc). Our results demonstrate that eutylone is a hybrid transporter compound with uptake inhibition properties at DAT and NET but substrate activity at SERT. The effects of eutylone are similar to those produced by pentylone, which suggests that eutylone will exhibit abuse liability and pose risks for psychostimulant side-effects in human users.

Responding to New Psychoactive Substances in the European Union: Early Warning, Risk Assessment, and Control Measures.

New psychoactive substances (NPS) are drugs that are not controlled by the United Nations international drug control conventions of 1961 and 1971 but that may pose similar threats to public health. Many of them are traded as "legal" replacements to controlled drugs such as cannabis, heroin, benzodiazepines, cocaine, amphetamines, and 3,4-methylenedioxymethamphetamine (MDMA). Driven by globalization, there has been a large increase in the availability and, subsequently, harms caused by these substances over the last decade in Europe. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is monitoring more than 670 NPS that have appeared on Europe's drug market in the last 20 years, of which almost 90% have appeared in the last decade. While some recent policy responses have been successful in reducing availability and sales of these substances in some settings - such as "legal highs" and "research chemicals" sold openly in the high street and online - and there are signs that growth in the market is slowing, new challenges have emerged. This includes monitoring a growing number of highly potent substances - including 179 synthetic cannabinoid receptor agonists and 28 fentanils - that can pose a high risk of life-threatening poisoning to users and can cause explosive outbreaks. This chapter briefly traces the origins of NPS, provides an overview of the situation in Europe, and discusses the work of the EMCDDA as part of a legal framework of early warning, risk assessment, and control measures that allows the European Union to rapidly detect, assess, and respond to public health and social threats caused by these substances.

Assessing the toxicological significance of new psychoactive substances in fatalities.

The number of new psychoactive substances (NPS) has increased significantly, especially within the last 5 years. The EMCDDA conducts risks assessments of such substances, especially in relation to serious adverse events. Examination of the individual health risks of a substance is a fundamental requirement of the process. Based on a number of considerations, the Toxicological Significance Score has been developed to support the risk assessment of NPS by allowing the role of a substance in deaths to be better assessed and classified.

Identification and characterization by LC-UV-MS/MS of melanotan II skin-tanning products sold illegally on the Internet.

New methods were developed and validated to determine the identity, contents, and purity of samples of melanotan II, a synthetic melanocortin receptor agonist, sold in vials as injectable skin-tanning products that were purchased from three online shops. Methods were based on liquid chromatography with ultra-violet detection (LC-UV) at wavelength 218 nm, and tandem mass spectrometric detection (MS/MS) after collision-induced fragmentation of the double charged [M+2H](2+) precursor ion (m/z 513). Identification of melanotan II was verified by correct chromatographic retention time, and relative abundance ratios of five qualifying fragment ions. LC-UV was used to quantify melanotan II as well as impurities. Method validation was performed with reference to guidelines for assessing active substances in authorized medicinal products to reach acceptable accuracy and precision. Vials from two shops contained unknown impurities ranging from 4.1 to 5.9%; impurities from one shop were below the quantification limit. The total amount of melanotan II in vials ranged between 4.32 and 8.84 mg, although each shop claimed that vials contained 10 mg melanotan II. A broad range of drugs used for enhancement purposes can be obtained from the illicit market. However, users of these drugs may be exposed to a range of potential harms, as shown in this study, given that these products are manufactured, distributed and supplied from an illicit market.

Prevalence of, and risk factors for, HIV, hepatitis B and C infections among men who inject image and performance enhancing drugs: a cross-sectional study.

OBJECTIVE: To describe drug use, sexual risks and the prevalence of blood-borne viral infections among men who inject image and performance enhancing drugs (IPEDs). DESIGN: A voluntary unlinked-anonymous cross-sectional biobehavioural survey. SETTING: 19 needle and syringe programmes across England and Wales. PARTICIPANTS: 395 men who had injected IPEDs. RESULTS: Of the participants (median age 28 years), 36% had used IPEDs for <5 years. Anabolic steroids (86%), growth hormone (32%) and human chorionic gonadotropin (16%) were most frequently injected, with 88% injecting intramuscularly and 39% subcutaneously. Two-thirds also used IPEDs orally. Recent psychoactive drug use was common (46% cocaine, 12% amphetamine), 5% had ever injected a psychoactive drug and 9% had shared injecting equipment. 'Viagra/Cialis' was used by 7%, with 89% reporting anal/vaginal sex in the preceding year (20% had 5+ female-partners, 3% male-partners) and 13% always using condoms. Overall, 1.5% had HIV, 9% had antibodies to the hepatitis B core antigen (anti-HBc) and 5% to hepatitis C (anti-HCV). In multivariate analysis, having HIV was associated with: seeking advice from a sexual health clinic; having had an injection site abscess/wound; and having male partners. After excluding those reporting male partners or injecting psychoactive drugs, 0.8% had HIV, 8% anti-HBc and 5% anti-HCV. Only 23% reported uptake of the hepatitis B vaccine, and diagnostic testing uptake was poor (31% for HIV, 22% for hepatitis C). CONCLUSIONS: Previous prevalence studies had not found HIV among IPED injectors. HIV prevalence in this, the largest study of blood-borne viruses among IPED injectors, was similar to that among injectors of psychoactive drugs. Findings indicate a need for targeted interventions.

Drogas potenciadoras para la búsqueda de la perfección / Human enhancement drugs and the pursuit of perfection

Hay un gran interés hacia serie de medicamentos usados para la mejora o potenciación de distintos aspectos de la condición humana, lo que les convierte en un nuevo problema de salud pública al que se ha prestado poca atención hasta ahora. En un intento por ser más fuertes, felices o inteligentes, o para parecer más delgados, más jóvenes o más bellos, la gente está recurriendo a diversos productos farmacéuticos. La amplia disponibilidad de fármacos con potencial para mejorar las capacidades humanas, la apariencia y las habilidades ha generado una nueva y cada vez mayor audiencia de usuarios. A diferencia de los usuarios de drogas como la heroína, la cocaína, etc., estos usuarios de este tipo de sustancias no necesariamente se perciben a sí mismos como ‘usuarios de drogas’. Las personas atraídas por estos medicamentos pueden tener un escaso o ningún conocimiento sobre los peligros físicos o psicológicos asociados con estas sustancias o sobre su potencial adictivo. Además de los potentes efectos de muchos de estos medicamentos, existen considerables riesgos asociados a la naturaleza clandestina del mercado. El creciente número de medicamentos no evaluados, prohibidos o adulterados y la falta de garantías y de calidad en el proceso de fabricación ilegal ha dado lugar a serios problemas y muertes. La facilidad con que los productos farmacéuticos pueden ser fabricados y distribuidos, junto con los importantes beneficios que se pueden conseguir desde el mercado ilegal, se ha traducido en un creciente desafío para los responsables de las políticas y los sistemas de salud en muchos países. Esta editorial tiene como objetivo dar a conocer esta nueva situación asociada a estas drogas potenciadoras y a ofrecer una breve visión de alguna de ellas y de los riesgos asociados (AU)

The emerging threat to public health posed by the use of human enhancement drugs has remained largely unrecognised. In attempts to become stronger, happier or smarter, or to look thinner, younger or more beautiful, people are turning to a diverse range of pharmaceuticals. The widespread availability of drugs with the potential to improve human attributes, appearance and abilities has generated a new and growing audience of users. Unlike users of drugs such as heroin, cocaine etc, users of human enhancement drugs do not necessarily perceive themselves as ‘drug users’. Those attracted to these drugs may have little or no knowledge or understanding of the physical or psychological harm associated with these substances or their potential for addiction. In addition to the potent effects of many human enhancement drugs, there are considerable risks associated to the clandestine nature of the market. The growing number of untested, banned or adulterated drugs and the lack of safeguards and quality assurance in the illicit manufacturing process has resulted in serious harms and fatalities. The ease with which pharmaceuticals can be manufactured and distributed, combined with the significant profits that can be made from the illicit market, has resulted in a growing challenge for policy makers and health systems in many countries. This editorial aims to raise awareness of this emerging drugs situation and provide a brief overview of some of the drugs and their associated risks (AU)

Human enhancement drugs and the pursuit of perfection.

The emerging threat to public health posed by the use of human enhancement drugs has remained largely unrecognised. In attempts to become stronger, happier or smarter, or to look thinner, younger or more beautiful, people are turning to a diverse range of pharmaceuticals. The widespread availability of drugs with the potential to improve human attributes, appearance and abilities has generated a new and growing audience of users. Unlike users of drugs such as heroin, cocaine etc, users of human enhancement drugs do not necessarily perceive themselves as 'drug users'. Those attracted to these drugs may have little or no knowledge or understanding of the physical or psychological harm associated with these substances or their potential for addiction. In addition to the potent effects of many human enhancement drugs, there are considerable risks associated to the clandestine nature of the market. The growing number of untested, banned or adulterated drugs and the lack of safeguards and quality assurance in the illicit manufacturing process has resulted in serious harms and fatalities. The ease with which pharmaceuticals can be manufactured and distributed, combined with the significant profits that can be made from the illicit market, has resulted in a growing challenge for policy makers and health systems in many countries. This editorial aims to raise awareness of this emerging drugs situation and provide a brief overview of some of the drugs and their associated risks.

Elephant in the room? The methodological implications for public health research of performance-enhancing drugs derived from the illicit market.

'All scientific work is incomplete-whether it be observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge. That does not confer upon us a freedom to ignore the knowledge we already have, or to postpone the action that it appears to demand at a given time.'