Brandt, SD (2019) Critical Review Report: 4F-MDMB-BINACA. Technical Report. World Health Organisation, Geneva, Switzerland.

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Abstract

Executive Summary Substance identification: The identification of 4F-MDMB-BINACA (4F-MDMB-BUTINACA) (IUPAC name: methyl (2S)-2-{[1-(4fluorobutyl)-1H-indazole-3-carbonyl]amino}-3,3-dimethylbutanoate) has been described first in 2018. Information obtained from seizures and collections suggests that it has been encountered in powdered form, in liquids used for vaping, and as a synthetic constituent in herbal plant mixtures most commonly distributed for the purpose of smoking. It is a homologue of 5F-ADB (5F-MDMBPINACA) that is listed in Schedule II of the Convention on Psychotropic Substances of 1971. WHO Review History: 4F-MDMB-BINACA has not been previously pre-reviewed or critically reviewed. Chemistry: There is no specific information available about the routes of synthesis employed for seized 4-FMDMB-BINACA products circulating on the drug market but straightforward methods for its preparation exist without requiring access to precursors that are controlled internationally. The presence of an asymmetric carbon atom gives rise to the (R)- and (S)-enantiomer and it seems likely for 4F-MDMB-BINACA to be most commonly available as the (S)-enantiomer. Ease of convertibility into controlled substances: There is no specific information available but it appears unlikely that 4F-MDMB-BINACA is converted into a substance currently listed in any of the international drug conventions. Similarity to known substances / Effects on the central nervous system: The information currently available suggests that 4F-MDMB-BINACA functions as a synthetic cannabinoid receptor agonist (SCRA). Information about effects induced in vivo is currently not available but the existing data suggest that 4F-MDMB-PICA will likely exhibit a profile shared by other SCRAs controlled internationally (potent full agonists at cannabinoid receptors) such as 5FADB. General pharmacology: 4F-MDMB-BINACA, in its pure form but mostly as a synthetic constituent added to a plant matrix, is primarily smoked (or vaped) although reliable data about dosage are unavailable. Results obtained from one in vitro study suggest that 4F-MDMB-BINACA binds to and activates human CB1 receptors at low nanomolar concentrations. Similar to other SCRAs listed in the Convention on Psychotropic Substances of 1971, 4F-MDMB-BINACA was more potent than Δ9-THC although it displayed lower efficacy under the experimental conditions used. Data collected from in vitro metabolism studies and detections in biological specimens revealed that the biotransformation steps observed included cleavage of the methyl ester, hydrolytic defluorination of the alkyl chain, oxidation to a butanoic acid metabolite, hydroxylation of aromatic and alkyl structures, dehydrogenation, and combinations thereof. Detections of the N-dealkylated species and the N-dealkylated ester hydrolysis product were also reported. Toxicology: Information could not be identified. Adverse reactions in humans: Detailed information about the clinical features associated with the consumption of 4F-MDMBBINACA specifically is not available. Aggregated data have been reported that featured the detection of 4F-MDMB-BINACA in biological specimen obtained from cases involving deaths and impaired driving. It appeared that at least in some cases, other substances including SCRAs were also detected. SCRA-like effects for 4F-MDMB-BINACA were documented based on self-reports, which included auditory and visual hallucinations, vomiting, paranoia, euphoria, relaxation, irregular heartbeat, agitation, confusion, insomnia, and chest pain. Data collected from intoxication cases with other SCRAs suggest that clinical features might include a range of adverse effects on gastrointestinal, neurological, and cardiovascular systems. Dependence potential: No studies carried out in humans or animals could be identified. Abuse potential: Studies specifically linked to 4F-MDMB-BINACA could not be identified. Therapeutic applications / usefulness: 4F-MDMB-BINACA is not known to have any therapeutic uses. Listing on WHO Model List of Essential Medicines: 4F-MDMB-BINACA is not listed. Marketing authorizations: 4F-MDMB-BINACA is not known to have any marketing authorisations. Industrial use: 4F-MDMB-BINACA is not known to have any agricultural, industrial or cosmetic uses. Non-medical use: The mode of use may involve the combinational use (intentionally or unintentionally) of other drugs and users may be unaware of the exact dose or compound being ingested (by whatever route). Household or subpopulation surveys that specifically probe for prevalence of 4F-MDMBBINACA could not be identified. People who use SCRAs in general include recreational users, high risk substance users but also individuals who are subject to drug testing such as people in drug treatment, prisoners, abstinence control programs and drivers. Nature and magnitude of public health problems: Products sold as herbal smoking mixtures frequently change in drug composition and quantity, often without indications on product labels, which results in challenges to unambiguously correlate harms to public health with a specific drug such as 4F-MDMB-BINACA. People who use these drugs are most likely not aware of the identity of the constituent and the quantity. The consumption of these products might be attractive to a variety of users, such as regular users of cannabis and those who believe that SCRA use might help with avoiding a positive finding in drug testing procedures. There are indications that socially vulnerable and stigmatised substance users, for example found in homeless and prison populations, are increasingly associated with problematic use of SCRA products. Heavy use of SCRAs has been associated with problematic withdrawal symptoms and further research is needed to evaluate the underlying mechanisms. Licit production, consumption, and international trade: 4F-MDMB-BINACA is available as standard reference material and produced for scientific research by a number of commercial suppliers. Other uses could not be identified. Illicit manufacture and traffic: 4F-MDMB-BINACA began to emerge in 2018 both in Europe and the United States of America. SCRAs are often imported in their pure form and converted into herbal forms on the domestic level. In recent years it has emerged that SCRAs have been smuggled into prisons in the form of impregnated papers (e.g. letters) and textiles and this extended to the detection of 4F-MDMBBINACA. Current international controls and their impact: 4F-MDMB-BINACA is not controlled under the 1961, 1971 or 1988 United Nations Conventions. Current and past national controls: 4F-MDMB-BINACA is controlled in some UN Member States.

Item Type:	Monograph (Technical Report)
Subjects:	R Medicine > RA Public aspects of medicine R Medicine > RM Therapeutics. Pharmacology
Divisions:	Pharmacy & Biomolecular Sciences
Publisher:	World Health Organisation
Date Deposited:	03 Oct 2019 09:56
Last Modified:	29 Oct 2021 10:56
URI:	https://researchonline.ljmu.ac.uk/id/eprint/11447

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