Li Kaixi, Xu Deli, Qiao Yanling, Kuai Lixin, Luo Xuwen, Di Bin, Xu Peng
School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Office of China National Narcotics Control Commission, Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Beijing, 100193, China.
Psychopharmacology (Berl). 2025 Mar;242(3):533-544. doi: 10.1007/s00213-024-06703-9. Epub 2024 Oct 15.
The newly emerging synthetic cannabinoids (SCs) 5F-EDMB-PICA, CUMYL-PEGACLONE, and NM-2201 have been observed to produce effects by activating cannabinoid type 1 (CB1) receptors. Nevertheless, the pharmacological effects and potential for abuse of these three substances remain to be studied. These substances have yet to be regulated in many countries.
We investigated the safety, pharmacological effects, rewarding effects, and cannabinoid withdrawal of 5F-EDMB-PICA, CUMYL-PEGACLONE, and NM-2201.
This study evaluated the drug safety and the cannabinoid-specific pharmacological effects of the three substances through acute toxicity experiments (in which the LD of each substance was obtained) and tetrad experiments (comprising assessments of hypothermia, analgesia, locomotion inhibition, and catalepsy). Furthermore, the conditioned place preference (CPP) experiments and withdrawal experiments were conducted to evaluate the rewarding effect and cannabinoid withdrawal potential of the substances in question.
The results demonstrated that all three drugs exhibited certain acute toxic effects and could potentially induce tetrad effects. The data were analyzed using non-linear regression, and the corresponding ED values and 95% confidence intervals (CI) were obtained. The rank order of potency was determined to be CUMYL-PEGACLONE > 5F-EDMB-PICA > NM-2201. In the CPP experiments, it was demonstrated that 5F-EDMB-PICA significantly induced an increase in CPP score at a dose of 0.3 mg/kg, while NM-2201 caused an increase in CPP score and a significant aversion effect at a dose of 2 and 3 mg/kg, respectively. It is noteworthy that all three types of SCs were observed to produce a significant biphasic effect, indicating that CPP scores were biphasic for all compounds. Following the administration of the CB1 receptor antagonist rimonabant, a notable increase in head twitches and paw tremors was observed, indicating that these three SCs induce cannabinoid withdrawal through the mediation of CB1 receptors.
The results of this study indicated that these SCs possess cannabinoid-specific pharmacological effects and abuse potential, which provides substantial experimental data to support the future regulation of these substances.
新出现的合成大麻素（SCs）5F-EDMB-PICA、CUMYL-PEGACLONE和NM-2201已被观察到通过激活1型大麻素（CB1）受体产生作用。然而，这三种物质的药理作用和滥用潜力仍有待研究。这些物质在许多国家尚未受到监管。
我们研究了5F-EDMB-PICA、CUMYL-PEGACLONE和NM-2201的安全性、药理作用、奖赏作用和大麻素戒断反应。
本研究通过急性毒性实验（获取每种物质的半数致死量）和四联实验（包括体温过低、镇痛、运动抑制和僵住症评估）评估了这三种物质的药物安全性和大麻素特异性药理作用。此外，进行了条件性位置偏爱（CPP）实验和戒断实验，以评估这些物质的奖赏作用和大麻素戒断潜力。
结果表明，所有三种药物都表现出一定的急性毒性作用，并可能诱导四联效应。使用非线性回归分析数据，获得了相应的半数有效量值和95%置信区间（CI）。效价顺序确定为CUMYL-PEGACLONE＞5F-EDMB-PICA＞NM-2201。在CPP实验中，结果表明，5F-EDMB-PICA在剂量为0.3mg/kg时显著诱导CPP评分增加，而NM-2201在剂量分别为2mg/kg和3mg/kg时导致CPP评分增加并产生显著的厌恶效应。值得注意的是，观察到所有三种类型的SCs都产生了显著的双相效应，表明所有化合物的CPP评分都是双相的。在给予CB1受体拮抗剂利莫那班后，观察到头部抽搐和爪子震颤显著增加，表明这三种SCs通过CB1受体介导诱导大麻素戒断。
本研究结果表明，这些SCs具有大麻素特异性药理作用和滥用潜力，为未来对这些物质的监管提供了大量实验数据支持。
