UR-144

Substance identification
Chemically, UR-144 is (1-Pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl) methanone. It has no stereoisomers.

Previous review
UR-144 was previously critically reviewed at the thirty-sixth ECDD meeting in 2014. The Committee had recommended that UR-144 not be placed under international control at that time but be kept under surveillance. Of particular significance to the Committee was the lack of analytically confirmed cases of nonfatal and fatal intoxications involving solely UR-144. Subsequent data collected from the literature and from different countries indicating that this substance may cause substantial harm and that it has no medical use warranted an updated critical review.

Similarity to known substances and effects on the central nervous system
UR-144 is a metabolite of XLR-11, a drug in Schedule II under the UN Convention on Psychotropic Substances of 1971. UR-144 binds to both cannabinoid CB1 and CB2 receptors, and has a 1.4 times higher binding affinity to the CB1 receptor than that of THC. It acts as a full agonist at these receptors in in vitro assays. UR-144 produces a complete cannabinoid profile in the mouse tetrad assay. The pyrolysed form of UR-144 (UR-144 degradant) shows a four-fold higher agonist activity at the CB1 receptor and augments the hypothermic and akinetic actions in mice compared to the parent, indicating that smoking the drug may augment the pharmacological effects on the central nervous system. In other animal studies, UR-144 substitutes for the discriminative stimulus effects of THC in rats, and also in mice, effects which are blocked by the CB1 receptor antagonist, rimonabant.

Dependence potential
Currently, there are no controlled human or other animal studies available that document the dependence potential of UR-144.

Actual abuse and/or evidence of likelihood of abuse
UR-144 produces several effects similar to other SCRAs, which are predictive of the likelihood of a similar abuse potential. Nonmedical use has been reported in numerous countries. Seizures of products containing UR-144 have been reported from East Asia, Europe and North America. UR-144 was one of the most frequently seized synthetic cannabinoids in Europe in 2015. More than 5000 reports identified UR-144 use in one country. Several reports have analytically identified UR-144 in cases of impaired driving, including some involving accidents. The most common clinical effects observed were slurred speech and dilated pupils; others included poor coordination, unsteady gait and difficulty standing, as well as abnormal pupillary reaction. Acute kidney injury requiring haemodialysis following UR-144 use has been described. Numerous countries have brought UR-144 under national legislation.

Therapeutic usefulness
UR-144 has no current therapeutic use, and there are no ongoing applications for medical use.

Recommendation
UR-144 produces cannabimimetic effects similar to other SCRAs and THC, drugs controlled under Schedule II of the UN Convention on Psychotropic Substances of 1971. UR-144 binds to, and functions as a full agonist at both cannabinoid CB1 and CB2 receptors. UR-144 substitutes for the discriminative stimulus effects of THC in laboratory animals. Nonmedical use of UR-144 has been reported in more than a dozen countries and has been analytically confirmed in samples from people involved in impaired driving instances. In 2015, UR-144 was one of the most frequently seized synthetic cannabinoids. UR-144 appears to constitute a substantial threat to public health and poses a social problem. There is insufficient evidence to draw a conclusion regarding its capacity to produce dependence-like effects. However, there is sufficient evidence to conclude that it has the capacity to produce similar effects to controlled SCRAs.

The Committee considered that the degree of risk to public health and society associated with the abuse of UR-144 is substantial. Therapeutic usefulness has not been recorded. It recognized that UR-144 has similar abuse potential and similar ill effects to other SCRAs in Schedule II of the UN Convention on Psychotropic Substances of 1971. The Committee considered that there is sufficient evidence that UR-144 is being or is likely to be abused so as to constitute a public health and social problem warranting the placing of the substance under international control. The Committee recommended that UR-144 ((1-Pentyl-1H- indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone) be placed in Schedule II under the UN Convention on Psychotropic Substances of 1971.