Pharmacokinetic investigation of synthetic cannabidiol oral formulations in healthy volunteers.

Recent advances in the research of medicinal cannabis has placed the non-intoxicating cannabinoid cannabidiol (CBD) at the front of scientific research. The reasons behind this popularity is the compound's therapeutic properties, alongside a safe profile of administration lacking addictive properties such as euphoric state of mind and a wide dosing range. Oral administration of CBD is challenging due to poor solubility in the gastro-intestinal system and susceptibility to extensive first pass metabolism. As a result, the practice in clinic and investigational trials is to administer cannabinoids in edible oils or oil-based solutions. Nonetheless, reported pharmacokinetics of cannabinoids and CBD in particular are not uniform among research groups and are affected by the vehicle of administration. The purpose of the work presented here is to investigate oral absorption processes of synthetic CBD when given in different oral formulations in healthy volunteers. The study design was a three way, blind, cross-over single administration study of 12 healthy male volunteers. CBD was administered in powder form, dissolved in sesame oil and in self-nano-emulsifying drug delivery system (SNEDDS). Administration of CBD in lipid-based vehicles resulted in a significant increase in Cmax and AUC of CBD, as compared to powder form. Overall plasma exposure of CBD did not differ between sesame oil vehicle and the SNEDDS formulation. However, administration of CBD in pure oil resulted in two absorption behaviors of early and delayed absorption among subjects, as opposed to SNEDDS platform that resulted in a uniform early absorption profile. Results of this trial demonstrate the importance of solubilization process of lipophilic drugs such as CBD and demonstrated the ability of the nano formulation to achieve a reliable, predictable PK profile of the drug. These findings offer a standardized oral formulation for the delivery of cannabinoids and contribute data for the growing field of cannabinoid pharmacokinetics.

The health threat of new synthetic opioids as adulterants of classic drugs of abuse.

Extensive scientific evidence shows that there is a broad spectrum of substances used as adulterants, whose effects on the user's health may be extremely harmful. The degree of purity of the drugs most commonly abused is highly variable depending on the region or epidemiological context. Practices of drug adulteration have been substantially evolving over the years: a significant trend has been observed in the last decade indicating a decline in the average purity of most drugs. Although the most frequent adulterants of common street drugs have long been well known, the rise of synthetic opioids has inevitably entailed gaps in knowledge in terms of the substances being used and their composition, which constitutes an even greater threat to public health.

Synthetic cathinones - From natural plant stimulant to new drug of abuse.

As recreational substances, synthetic cathinones started to be used at the beginning of the 21st century. There is still limited data on these compounds, introduced to the illicit drug market for the most part after 2009. Considering that synthetic cathinones are currently the second largest group of new psychoactive and dangerous substances among over 670 new psychoactive substances identified in Europe and monitored by the EMCDDA, research on them should be regarded as extremely important. This review focuses on the availability of synthetic cathinones on the illicit drug market, presentation of current trends in the use of these substances, and their mechanisms of action and toxicity. The authors discuss cases of intoxication with synthetic cathinones and post-mortem diagnostics as well as the problem of combined used of synthetic cathinones with other psychoactive substances. Literature as well as clinical and forensic data indicate the need for further research on the metabolism, toxicokinetics, toxicodynamics, clinical effects, and addictive potential of synthetic cathinones, especially in the context of potential threats caused by increased consumption of this group of drugs in future.

Development of a specific fragmentation pattern-based quadrupole-Orbitrap™ mass spectrometry method to screen drugs in illicit products.

Over the past decade, illicit drugs have been founded in marketed products, which pose a risk to public health. In particular, newly designed analogues synthesized by chemical modification of parent compounds to avoid detection by authorities are frequently detected worldwide. Although many analytical methods for determination of drugs have been reported, analytical methods using high-resolution mass spectrometry, which has the advantage of rapid screening and accurate identification of new substances, are necessary to control illicit drugs in marketed products. In this study, a rapid analytical method using an Orbitrap™ mass spectrometer for identification of illicit drugs in marketed products was developed. The 32 drugs were classified as benzodiazepine-, synthetic cannabinoid-, amphetamine- and benzylpiperazine-type drugs according to their chemical structures, and from their fragmentation patterns in tandem mass spectrometry spectra of an established method. The method validation gave a limit of detection of 0.06-5.30 ng/mL and a limit of quantification of 0.18-16.50 ng/mL, high linearity (R2 > 0.994) and mean recoveries of spiked matrix-blank samples ranging from 83.7% to 117.1%. Approximately 71% of 21 samples collected over 3 years were found to individually contain one of four types of benzodiazepines or two different synthetic cannabinoids. In one case, levels as high as 827.2 mg/g were measured suggesting adulteration at high levels, which suggests that potential illicit products containing drugs should be regularly screened to protect public health.

Biotransformation of the New Synthetic Cannabinoid with an Alkene, MDMB-4en-PINACA, by Human Hepatocytes, Human Liver Microsomes, and Human Urine and Blood.

Although at a slower rate, new psychoactive substances continue to appear on the illicit drug market, challenging their detection in biological specimens by forensic and clinical toxicologists. Here, we report in vitro and in vivo metabolism of a new synthetic cannabinoid, methyl 3,3-dimethyl-2-[1-(pent-4-en-1-yl)-1H-indazole-3-carboxamido] butanoate (MDMB-4en-PINACA). This is the first report on metabolism of a synthetic cannabinoid with an alkene functional group at the alkyl side chain. MDMB-4en-PINACA was incubated with both human hepatocytes and human liver microsomes (HLM) for up to 5 h and 1 h, respectively. The samples were analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry. An authentic human urine and a corresponding blood sample were analyzed to confirm the in vitro metabolites. A total of 32 metabolites were detected, of which 11 metabolites were detected in hepatocyte samples, 31 in HLM, 2 in urine, and 1 in blood. Analysis of the metabolites revealed that the main metabolic pathway of the terminal alkene group of the pentenyl side chain is dihydrodiol formation, most likely via epoxidation. The majority of the metabolites were generated from ester hydrolysis and/or dihydrodiol formation with further hydroxylation and/or dehydrogenation. Two most abundant metabolites in hepatocyte incubation samples, M8 (ester hydrolysis and dihydrodiol) and M30 (ester hydrolysis), coincided the two detected urinary metabolites. Based on the results, M8 and M30 are proposed to be appropriate urinary markers for MDMB-4en-PINACA intake for screening, while the inclusion of the parent drug itself and M29 (hydroxylation) may be useful for confirmation purposes.

Synthetic cathinone adulteration of illegal drugs.

RATIONALE: Current prevalence estimates of synthetic cathinone ("bath salt") use may be underestimates given that traditional metrics (e.g., surveys, urinalysis) often fail to capture the emergent issue of synthetic cathinone adulteration of more common illegal drugs, such as ecstasy (3,4-methylenedioxymethamphetamine). OBJECTIVES: This review examines the evolution of synthetic cathinones and prevalence of use over the past decade in the United States. We also review methods of self-report and biological testing of these compounds as well as adverse outcomes associated with adulterated drug use. RESULTS: Synthetic cathinone use emerged in the United States by 2009 with use associated with tens of thousands of poisonings. Reported poisonings and self-reported use have substantially decreased over the past five years. However, our review suggests that current estimates of use are underestimates due to underreporting stemming primarily from unknown or unintentional use of adulterated formulations of relatively popular illegal drugs, such as ecstasy. CONCLUSIONS: While intentional synthetic cathinone use has decreased in recent years, evidence suggests that prevalence of use is underestimated. Testing of drugs and/or biological specimens can improve the accuracy of synthetic cathinone use estimates. Furthermore, we advocate that researchers and clinicians should become better aware that exposure to these potent compounds (e.g., as adulterants) often occurs unknowingly or unintentionally. To improve our understanding of synthetic cathinone adulteration, research utilizing a combinatorial approach (survey and biological testing) will help more accurately estimate the prevalence and impact of this public health issue.

The DARK Side of Total Synthesis: Strategies and Tactics in Psychoactive Drug Production.

Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term "psychotropic drug" is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there is no denying the toll drug mis- and overuse is taking on this country. Overdose, fueled by opioids, is the leading cause of death for Americans under 50 years of age, killing ca. 64,000 people in 2016. From a chemistry standpoint, the question is in what ways, if any, did organic chemists contribute to this problem? In this targeted review, we provide brief historical accounts of the main classes of psychoactive drugs and discuss several foundational total syntheses that ultimately provide the groundwork for producing these molecules in academic, industrial, and clandestine settings.