Cultivation of industrial low-Δ⁹-tetrahydrocannabinol (Δ⁹-THC) hemp has created an oversupply of cannabidiol (CBD)-rich products. The fact that phytocannabinoids, including CBD, can be used as precursors to synthetically produce a range of THC variants—potentially located in a legal loophole—has led to a diversification of cannabis recreational drug markets. ‘Hemp-compliant’, ‘hemp-derived’ and ‘semisynthetic’ cannabinoid products are emerging and being advertised as (legal) alternatives for Δ⁹-THC. This study included a large panel (n = 30) of THC isomers, homologs, and analogs that might be derived via semisynthetic procedures. As a proxy for the abuse potential of these compounds, we assessed their potential to activate the CB₁ cannabinoid receptor with a β-arrestin2 recruitment bioassay (picomolar–micromolar concentrations). Multiple THC homologs (tetrahydrocannabihexol, THCH; tetrahydrocannabiphorol, THCP; tetrahydrocannabinol-C8, THC-C8) and THC analogs (hexahydrocannabinol, HHC; hexahydrocannabiphorol, HHCP) were identified that showed higher potential for CB₁ activation than Δ⁹-THC, based on either higher efficacy (E_max) or higher potency (EC₅₀). Structure–activity relationships were assessed for Δ⁹-THC and Δ⁸-THC homologs encompassing elongated alkyl chains. Additionally, stereoisomer-specific differences in CB₁ activity were established for various THC isomers (Δ⁷-THC, Δ¹⁰-THC) and analogs (HHC, HHCP). Evaluation of the relative abundance of 9(S)-HHC and 9(R)-HHC epimers in seized drug material revealed varying epimeric compositions between batches. Increased abundance of the less active 9(S)-HHC epimer empirically resulted in decreased potency, but sustained efficacy for the resulting diastereomeric mixture. In conclusion, monitoring of semisynthetic cannabinoids is encouraged as the dosing and the relative composition of stereoisomers can impact the harm potential of these drugs, relative to Δ⁹-THC products.

工业低Δ9-四氢大麻酚（Δ9-THC）大麻的种植^造成了^富含大麻二酚（CBD）的产品供应过剩。事实上，包括 CBD 在内的植物大麻素可用作合成生产一系列 THC 变体的前体（可能存在法律漏洞），这一事实导致了大麻休闲药物市场的多样化。 “符合大麻标准”、“大麻衍生”和“半合成”大麻素产品正在出现，并被宣传为 Δ ⁹ -THC 的（合法）替代品。这项研究包括大量可能通过半合成程序衍生的 THC异构体​​、同系物和类似物( n = 30)。作为这些化合物滥用潜力的代表，我们通过 β-arrestin2 募集生物测定（皮摩尔-微摩尔浓度）评估了它们激活 CB ₁大麻素受体的潜力。多种 THC 同系物（四氢大麻六醇，THCH；四氢大麻酚，THCP；四氢大麻酚-C8，THC-C8）和 THC 类似物（六氢大麻酚，HHC；六氢大麻酚，HHCP）经鉴定显示出比 Δ ⁹ -THC更高的 CB ₁激活潜力。更高的功效（E _max）或更高的效力（EC ₅₀）。对包含伸长烷基链的Δ ⁹ -THC 和 Δ ⁸ -THC 同系物的结构-活性关系进行了评估。此外，还确定了各种 THC 异构体​​（Δ ⁷ -THC、Δ ¹⁰ -THC）和类似物（HHC、HHCP）的CB ₁活性的立体异构体特异性差异。对检获药物材料中 9(S)-HHC 和 9(R)-HHC 差向异构体相对丰度的评估揭示了批次之间不同的差向异构体组成。根据经验，活性较低的 9(S)-HHC 差向异构体的丰度增加会导致效力下降，但所得非对映异构体混合物的功效保持不变。总之，鼓励监测半合成大麻素，因为立体异构体的剂量和相对组成会影响这些药物相对于 Δ ⁹ -THC 产品的潜在危害。