An emerging trend in Novel Psychoactive Substances (NPSs): designer THC

Since its discovery as one of the main components of cannabis and its affinity towards the cannabinoid receptor CB1, serving as a means to exert its psychoactivity, Delta 9-tetrahydrocannabinol (Delta 9-THC) has inspired medicinal chemists throughout history to create more potent derivatives. Initially, the goal was to synthesize chemical probes for investigating the molecular mechanisms behind the pharmacology of Delta 9-THC and finding potential medical applications. The unintended consequence of this noble intent has been the proliferation of these compounds for recreational use. This review comprehensively covers the most exhaustive number of THC-like cannabinoids circulating on the recreational market. It provides information on the chemistry, synthesis, pharmacology, analytical assessment, and experiences related to the psychoactive effects reported by recreational users on online forums. Some of these compounds can be found in natural cannabis, albeit in trace amounts, while others are entirely artificial. Moreover, to circumvent legal issues, many manufacturers resort to semi-synthetic processes starting from legal products extracted from hemp, such as cannabidiol (CBD). Despite the aim to encompass all known THC-like molecules, new species emerge on the drug users' pipeline each month. Beyond posing a significantly high public health risk due to unpredictable and unknown side effects, scientific research consistently lags behind the rapidly evolving recreational market

Delta9-THC determination by the EU official method: evaluation of measurement uncertainty and compliance assessment of hemp samples

Hemp cultivation is living a period of renewed interest worldwide after long years of opposition and abandonment. The European Union (EU) allows and subsidizes the growing of fiber and oilseed cultivars of Cannabis sativa L. with respect to the THC content limit of 0.2%. The EU method for the quantitative determination of Delta 9-tetrahydrocannabinol (THC) content in hemp varieties provides to apply a tolerance of 0.03 g of THC per 100 g of sample concerning compliance assessment to that limit. However, the method does not report any precision data, especially useful as a function of THC content to evaluate measurement uncertainty and therefore to establish the conformity of hemp at different THC legal limits. Measurement uncertainty of the method by both bottom-up and top-down approach, besides repeatability and reproducibility, was investigated and estimated in the THC concentration range 0.2-1.0%, which includes the different legal limits set out for hemp around the world. We proposed Decision Rules for conformity of hemp showing that a non-compliant declaration beyond reasonable doubt should be stated when the THC content, as a mean result on a duplicate analysis, exceeds the limit by at least 11-15%, depending on THC limit. We highlighted other issues concerning practical aspects of hemp analysis, from sampling to evaluation of results, as well as the need to carry out collaborative studies on the EU method

Δ9-Tetrahydrocannabiphorol: Identification and quantification in recreational products

A 9-Tetrahydrocannabinol ( A 9-THC) is known to be the component of the cannabis plant responsible for the psychoactive effects generated by the activation of the endocannabinoid receptor 1 (CBR1). Following extensive structure-activity relationship (SAR) studies on A 9-THC, new molecules with increased CBR1 affinity were designed and synthesized over the last decades. The knowledge arising from the pharmacological and synthetic investigations has been extensively used in the recent past by the industry of substances for recreational use also thanks to the 2018 Farm Bill Act in the USA and the incentive for low-THC cannabis (hemp) cultivation in Europe, which have boosted the availability of hemp derived precursors. As a result, new semi-synthetic natural and pseudo natural cannabinoids related to the most famous A 9-THC and often not subjected to legal restrictions are now available in the online market in a broad array of retail products with no preventive study on their pharmacodynamics and pharmacokinetics. Some of these products (gummies, cannabis flower and a vape cartridge), all declared to contain the most potent among all the known cannabinoids, A 9-Tetrahydrocannabiphorol ( A 9-THCP), were bought from an online shop and tested through LC-HRMS to determine the effective amount of A 9-THCP and of other cannabinoids. All the three samples were found to contain A 9-THCP in amounts significantly different from those declared by the producer. Moreover, the application of an untargeted metabolomics approach (cannabinomics) enabled the identification of other cannabinoids including the emerging semi-synthetic hexahydrocannabinol (HHC) and tetrahydrocannabidiol (H4-CBD) together with byproducts of synthetic origin

Drugs price and reimbursement regulation: comparators, endpoints and role of the cost-effectiveness

This document illustrates the results of a discussion of two multi-disciplinary expert panels on pricing and reimbursement of medicines. Experts work in different organizations. The discussion focused on comparator(s), endpoint(s), negotiation of prices of new medicines and/or indications to include in the List 648, as well as the role of cost-effectiveness in the price and reimbursement negotiation. The debate took place during the fourth edition of the Seminari di Mogliano, organized on the 30th of September/1st of October, 2021. The two panels agreed on a general need to enhance interaction among the different stakeholders, in the early assessment and negotiation phases, and to increase the transparency/reproducibility of the decisions taken. The experts have also emphasized the need (i) to improve clarity in the evaluation of additional therapeutic value and the place in therapy with respect to comparators and how comparators are identified; (ii) to create work groups to identify the most appropriate endpoint(s), for each therapeutic area and level of unmet needs; (iii) to provide for a systematic use of cost-effectiveness when an added therapeutic value is delivered by a new medicine. With regard to the 648 List, the experts advocated for an overall reorganization of the current rules governing the special uses of drugs