The semisynthetic cannabinoid hexahydrocannabinol (HHC) is currently getting a lot of media attention because the legal status in many countries is not clearly specified. In this study, a GC–MS method for the quantification of Δ9‐tetrahydrocannabinol (THC), 11‐hydroxy‐Δ9‐tetrahydrocannabinol (11‐OH‐THC), and 11‐nor‐9‐carboxy‐Δ9‐tetrahydrocannabinol (THC‐COOH) was extended to (9R)‐ and (9S)‐HHC. The applicability was proven by serum/plasma samples from drivers suspected of cannabis consumption. Limit of detection (LOD) and lower limit of quantification (LLOQ) were 0.15 and 0.25 ng/mL, respectively. Within‐run imprecision was <6.5% and between‐run imprecision was <10.0%. Inter‐injection stability, processed sample stability (3 days), freeze–thaw stability (three cycles), and storage stability (1 week room temperature; 1 month 4°C, −20°C) could be proven. Both HHC diastereomers could be detected in 17 (5.3%) out of 321 analyzed samples from traffic controls in Western Saxony. The mean ratio between (9R)‐ and (9S)‐HHC was 1.99 (CV = 14.6%). Quantification resulted in concentrations between <LLOQ and 35.35 ng/mL for (9R)‐HHC and <LLOQ and 21.76 ng/mL for (9S)‐HHC. Additionally, cross‐reactivities of HHC, 11‐hydroxy‐hexahydrocannabinol (11‐OH‐HHC), 11‐nor‐9‐carboxy‐hexahydrocannabinol (HHC‐COOH), hexahydrocannabiphorol (HHC‐P), hexahydrocannabinol acetate (HHC‐O), and tetrahydrocannabidiol (H4‐CBD) were evaluated in five immunological screening tests for serum, urine, and saliva. Urine test strips and ELISA tests for the detection in serum seem to be beneficial to detect HHC consumption in comparison with saliva tests. HHC analogs and H4‐CBD showed no cross‐reactivity with any of the tests.

The semi-synthetic cannabinoid hexahydrocannabinol (HHC) has become a highly discussed topic in forensic toxicology since 2022 due to its legal availability at this time and its psychoactive effects. This study aimed to investigate the pharmacokinetics, effects, and immunological detectability of HHC after oral (25 mg HHC fruit gum) and inhalative (three puffs from HHC vape) consumption with three participants per group. Serum (up to 48 h), urine (up to five days), and saliva (up to 48 h) samples were collected at different relevant time points and analyzed by HPLC-MS/MS for (9R)/(9S)-HHC, 11-hydroxy-HHC, and (9R)/(9S)-HHC carboxylic acid with a fully validated method. Additionally, immunological detectability was investigated with three different commercially available tests. To address the psychoactive effects, the subjective “high” feeling (scale 0–10) was monitored and different psychophysical tests (e.g. modified Romberg test, walk and turn) were conducted. Overall, the pharmacokinetics and effects of HHC were comparable to tetrahydrocannabinol (THC). However, the route of administration as well as inter-individual factors played a crucial role regarding maximum concentrations, pharmacokinetic profiles, and psychoactive effects.

The use of cannabis during pregnancy is increasing, in line with its growing societal acceptance and legalization. Cannabis use mainly concerns its active components Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). While cannabis has therapeutic effects on pain, nausea, and vomiting, its impact on fetal development remains a significant public health concern. Given the existence of a local endocannabinoid system (ECS) in the placenta, with proven effects on placental development and blood flow, it is likely that THC and CBD exert effects via interference with the placental ECS. This review summarizes how cannabis use affects the placental ECS and describes the consequences of such use on placental function and fetal development. It starts with discussing the placental ECS, the effects of THC and CBD on placental function, and the pharmacokinetics of cannabinoids during pregnancy. It then describes the effects of both paternal and maternal cannabis use and provides epidemiological data linking placental insufficiency, impaired fetal growth, and preeclampsia to cannabis use. It also raises awareness for the possibility that cannabis use, by altering DNA methylation, might result in transgenerational effects. It is concluded that current evidence supports abstaining from cannabis use during preconception, pregnancy, and lactation to optimize maternal, fetal, and intergenerational health outcomes.

Introduction: Δ9-tetrahydrocannabinolic acid A (THCA-A) is one of the main ingredients of cannabis plants and is converted to the psychoactive substance Δ9-tetrahydrocannabinol (THC) by decarboxylation during heating above ∼90°C. During the consumption of cannabis, a varying proportion of THCA-A is absorbed into the body. Therefore, the quantification of THCA-A in serum/plasma might provide additional information on consumption behavior in driving under the influence of cannabis cases. Materials and Methods: In this study, an already established gas-chromatography mass-spectrometry (GC-MS) method for the quantification of THC, 11-OH-THC, and THC-COOH in serum and plasma samples was extended to include THCA-A. This validated method was then applied to 1228 routinely achieved serum/plasma samples from drivers suspected of cannabis consumption in Western Saxony. Two different grouping systems for chronic/occasional consumption, one system for acute/subacute consumption, Huestis formulas, and the cannabis influence factor (CIF) were used for evaluation. Results: Method validation showed appropriate results for forensic toxicological routine analysis. Limit of detection and lower limit of quantification (LLOQ) for THCA-A were 0.3 and 1.0 ng/mL, respectively. Reproducibility was <11% and accuracy ranged between 104% and 107%. THCA-A was stable in native samples at least for 2 weeks at room temperature or 4°C as well as 1 month at −20°C. Freeze–thaw stability for three cycles and processed sample stability over 3 days was proven. A total of 865 cases with a THC concentration above the German analytical cutoff of 1 ng/mL as well as the analytical LLOQs of 0.9 and 2.5 ng/mL for 11-OH-THC and THC-COOH, respectively, were included in further statistical analysis. In 407 (47.1%) of these samples, THCA-A was quantifiable. Different statistical analyses indicated a correlation between THCA-A and THC concentrations in cases of chronic and acute consumption. In addition, an increase of chronic and acute cases with increasing THCA-A concentrations was observed. However, no correlation between THCA-A and CIF was found. Discussion: These data show that THCA-A might be an additional indicative marker to provide information about consumption frequency and acuteness. Additional studies with known consumption frequencies and times are required to verify these findings.

Neurochemical imbalances in the striatum are thought to contribute to the patho-physiology of DYT1 dystonia (TOR1A), a severe movement disorder. Parvalbumin- positive GABAergic fast-spiking interneurons (PV+ FSI) exert a powerful inhibition within the striatal microcircuitry. To elucidate the impact of PV+ FSI on striatal neu-rotransmitter dynamics in a DYT1 knock-in (KI) mouse model, we combined optoge-netic inhibition of PV+ FSI with in vivo microdialysis (optodialysis) and LC-MS/MS analysis. Dialysates were collected across baseline (light off), stimulation (light on, 595 nm) and post-stimulation (light off) periods. Basal extracellular concentrations of sev-eral analytes, including GABA, dopamine and adenosine, showed no significant dif-ferences between wildtype (WT) and DYT1 KI mice. In WT mice, PV+ FSI inhibition decreased GABA and adenosine levels. In contrast, DYT1 KI mice showed no change in GABA and only a delayed reduction in adenosine post-stimulation. Dopamine, choline or 5-HIAA were largely unaffected by optogenetic inhibition, with the exception of a genotype-specific reduction of 5-HIAA in the post-stimulation period. These findings suggest impaired inhibitory and neuromodulatory control in the DYT1 KI mice, po-tentially reflecting compensatory circuit adaptations. The results provide novel insights into striatal microcircuit function in DYT1 dystonia, establish a basis for exploring circuit-level alterations in other movement disorders, and may inform future thera-peutic strategies.

The pharmacokinetics of the semisynthetic cannabinoid hexahydrocannabinol (HHC) and its 11-nor-carboxy- as well as 11-hydroxy-metabolites has already been the subject of research in various recent publications. However, further metabolism studies showed the presence of other, especially (side-chain-)hydroxylated metabolites in urine and serum. This study aimed to investigate the pharmacokinetics of these metabolites after oral (25 mg fruit gum) and inhalative (three puffs from vape) consumption, using serum and urine samples from a previous study. Serum (up to 48 h) and urine (up to five days) samples of six participants (three per consumption group) were collected at different time points and analyzed by LC-QqTOF and LC-QqLIT. Three metabolites (M1: side-chain-hydroxylated; M2: hydroxylated on alicyclic moiety; M3: 8-OH-HHC) were further investigated. The peak area ratios of analytes and internal standards were plotted against the time after consumption to obtain pharmacokinetic information. Overall, this study proved the presence of these metabolites in biological samples and provided pharmacokinetic insights for the first time. Differences between serum and urine, oral and inhalative consumption as well as inter-individual differences were observed. The investigated metabolites could partially serve as unambiguous consumption markers for HHC, as they are unlikely to be formed in vivo from corresponding Δ ⁹ -tetrahydrocannabinol (THC) metabolites.