•Adolescent primates dosed daily show stable THC, CBD blood levels for 4 months.•Pharmacokinetic tolerance does not develop to THC or CBD.•CBD did not modulate THC pharmacokinetics during daily ...dosing.•THC concentrations in brain were higher than blood 24 h after the final daily dose.•Prolonged presence of THC in brain may contribute to persistent behavioral disruption.
Cannabis availability with high concentrations of Δ-9-tetrahydrocannabinol (THC) and a range of THC to cannabidiol (CBD) ratios has increased in parallel with a rise in daily cannabis consumption by adolescents. Unanswered questions in adolescents include: 1) whether THC blood concentrations and THC metabolites remain stable or change with prolonged daily dosing, 2) whether CBD modulates THC pharmacokinetic properties and alters THC accumulation in brain, 3) whether blood THC levels reflect brain concentrations.
In adolescent squirrel monkeys (Saimiri boliviensis), we determined whether a four-month regimen of daily THC (1 mg/kg) or CBD (3 mg/kg) + THC (1 mg/kg) administration (IM) affects THC, THC metabolites, and CBD concentrations in blood or brain.
Blood THC concentrations, THC metabolites and CBD remained stable during chronic treatment. 24 h after the final THC or CBD + THC injection, blood THC and CBD concentrations remained relatively high (THC: 6.0–11 ng/mL; CBD: 9.7−19 ng/mL). THC concentrations in cerebellum and occipital cortex were approximately twice those in blood 24 h after the last dose and did not significantly differ in subjects given THC or CBD + THC.
In adolescent monkeys, blood levels of THC, its metabolites or CBD remain stable after daily dosing for four months. Our model suggests that any pharmacological interactions between CBD and THC are unlikely to result from CBD modulation of THC pharmacokinetics. Finally, detection of relatively high brain THC concentrations 24 h after the final dose of THC suggests that the prolonged actions of THC may contribute to persistent cognitive and psychomotor disruption after THC- or cannabis-induced euphoria wane.
The use of the intoxicating cannabinoid delta‐8‐tetrahydrocannabinol (Δ8‐THC) has grown rapidly over the last several years. There have been dozens of Δ8‐THC studies dating back over many decades, ...yet no review articles have comprehensively covered these findings. In this review, we summarize the pharmacological studies of Δ8‐THC, including receptor binding, cell signalling, in vivo cannabimimetic activity, clinical activity and pharmacokinetics. We give special focus to studies that directly compared Δ8‐THC to its more commonly studied isomer, Δ9‐THC. Overall, the pharmacokinetics and pharmacodynamics of Δ8‐THC and Δ9‐THC are very similar. Δ8‐THC is a partial agonist of the cannabinoid CB1 receptor and has cannabimimetic activity in both animals and humans. The reduced potency of Δ8‐THC in clinical studies compared with Δ9‐THC can be explained by weaker cannabinoid CB1 receptor affinity, although there are other plausible mechanisms that may contribute. We highlight the gaps in our knowledge of Δ8‐THC pharmacology where further studies are needed, particularly in humans.
In hair analysis, identification of 11‐nor‐9‐carboxy‐∆9‐tetrahydrocannabinol (THC‐COOH), one of the major endogenously formed metabolites of the psychoactive cannabinoid tetrahydrocannabinol (THC), ...is considered unambiguous proof of cannabis consumption. Due to the complex hair matrix and low target concentrations of THC‐COOH in hair, this kind of investigation represents a great analytical challenge. The aim of this work was to establish a fast, simple, and reliable LC–MS3 routine method for sensitive detection of THC‐COOH in hair samples. Furthermore, the LC–MS3 method developed also included the detection of derivatized 11‐hydroxy‐∆9‐THC (11‐OH‐THC) as an additional marker of cannabis use. Hair sample preparation prior to detection of the two THC metabolites was based on digestion of the hair matrix under alkaline conditions followed by an optimized liquid–liquid extraction (LLE) procedure. Sample preparation by LLE proved to be more suitable than solid‐phase extraction (SPE) due to less laborious and time‐consuming steps while still yielding satisfactory results. A significant improvement in analytical detection was introduced by multistage fragmentation (MS3), which led to enhanced sensitivity and selectivity and thus low limits of quantification (0.1 pg/mg hair). The MS3 method included two transitions for THC‐COOH (m/z 343 → 299 → 245 and m/z 343 → 299 → 191) encompassing the quantifier (m/z 245) and the qualifier ion (m/z 191). The method was fully validated, and successful application to authentic toxicology case samples was demonstrated by the analysis of more than 2000 hair samples from cannabis users with THC‐COOH concentrations determined ranging from 0.1 to >15 pg/mg hair.
A fast, simple and sensitive LC‐MS3 routine method for the quantitative identification of major endogenously formed cannabis metabolites of the psychoactive cannabinoid tetrahydro‐cannabinol (THC) was developed for proof of active cannabis consumption via hair analysis. The method was fully validated and successfully applied to more than 2000 authentic toxicology case samples demonstrating an appealing combination of sensitive analytical detection (LC‐MS3) and a simple, non‐laborious sample preparation procedure based on liquid–liquid extraction.
The assessment of human postmortem concentrations of Δ9-THC (THC) and its metabolites, 11-nor-9-carboxy-THC (THCCOOH) and 11-hydroxy-THC (11-OH-THC), is routinely performed in forensic toxicology ...laboratories. However, the literature on cannabinoids postmortem redistribution (PMR) is scarce and highlights their complex postmortem changes. This study aims to investigate the postmortem behavior of THC and its metabolites in order to provide practitioners with potential indicators of PMR. To do so, antemortem and postmortem cases positive for cannabinoids were compiled in a database. Its analysis shows significantly higher THC concentrations in postmortem blood than in antemortem blood. Antemortem and postmortem blood also present significantly different profiles for their THC to THCCOOH ratios. Whereas antemortem blood generally shows THCCOOH concentrations higher or equal to THC, several postmortem cases show the opposite, with THC concentrations higher than THCCOOH. While occurrence of postmortem redistribution (PMR) is difficult to measure directly, an evaluation was performed using the central to peripheral (C/P) blood concentrations ratio as a proxy. With a C/P significantly lower than 1.0 for THC and significantly higher than 1.0 for THCCOOH, the PMR hypothesis is supported for both compounds, with redistribution towards peripheral blood for THC and towards central blood for THCCOOH. On the other hand, 11-OH-THC does not show a C/P significantly different than 1.0, suggesting the absence of PMR. Influence of body mass index, conservation state and postmortem interval on C/P was statistically analyzed and no significant impact was observed. To compare and contrast C/P observed in the database with those published in the literature, a meta-analysis was performed using a median of median (MM) model. THC PMR towards peripheral blood is supported by a global estimate of 0.81 (CI95%: 0.51 to 1.2). Redistribution towards femoral blood appears to be stronger than towards iliac blood; indeed, the median estimate of C/P decreases to 0.64 (CI95%: 0.40 to 1.1) when studies with iliac blood were removed from the meta-analysis. THCCOOH PMR towards central blood is supported by a C/P median estimate of 1.3 (CI95%: 0.97 to 1.6). THC PMR can be suspected when these indicators are observed (i) high THC blood concentration (>50 ng/mL), (ii) THC C/P lower than 1.0 (iii) blood THC/THCCOOH concentration ratios greater than 1.0 and (iv) non-detectability of THCCOOH in urine. In postmortem samples, many factors may contribute to the overestimation of THC concentration, therefore a careful interpretation is required, relying on both central and peripheral blood samples.
for the analysis of cannabinoids in bio-matrices are continually improved to achieve best possible sensitivity in their detection and accurate quantification. It has been well documented that CBD ...cyclizes to Δ9-THC and Δ9-THC isomerizes to Δ8-THC under acidic conditions by means of a Lewis-acid-catalyzed process, causing difficulty in accurate quantification of Δ9-THC in the presence of CBD, of CBD itself and of Δ9-THC itself when these compounds have to be derivatized by acylation. The present paper shows that CBD cyclization and Δ9-THC isomerization can be blocked by tertiary amines or azines, which capture protons appearing in the derivatizing mixture during acylation. The efficiency of the described acylation of CBD depends on the time and temperature of the derivatizing process, whereas the degree of CBD acylation, i.e. the synthesis of mono- or di-acylate CBD derivative, depends on the mutual ratio of the cannabinoid, the acylating agent and the proton binding compound. The way of mono- and di-acyl CBD derivatives formation described in the paper has not been reported yet. The paper contains a comprehensive analytical characterization of two types of CBD acyl derivatives, CBD-TFA and CBD-Ac, obtained by NMR, GC–MS and LC–MS.
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•CBD cyclization and Δ9-THC isomerization can be blocked by tertiary amines or azines.•CBD acylation degree depends on the ratio of CBD, acylating agent and proton-binder.•Comprehensive analytical characterization of mono- and diacyl CBD and THC derivatives.
Δ9-tetrahydrocannabinol (Δ9-THC) isomers, especially Δ8-tetrahydrocannabinol (Δ8-THC), are increasing in foods, beverages, and e-cigarettes liquids. A major factor is passage of the Agriculture ...Improvement Act (AIA) that removed hemp containing less than 0.3 % Δ9-THC from the definition of “marijuana” or cannabis. CBD-rich hemp flooded the market resulting in excess product that could be subjected to CBD cyclization to produce Δ8-THC. This process utilizes strong acid and yields toxic byproducts that frequently are not removed prior to sale and are currently inadequately studied. Pharmacological activity is qualitatively similar for Δ8-THC and Δ9-THC, but most preclinical studies in mice, rats, and monkeys documented greater ∆9-THC potency. Both isomers caused graded dose-response effects on euphoria, blurred vision, mental confusion and lethargy, although Δ8-THC was at least 25 % less potent. The most common analytical methodologies providing baseline resolution of ∆8-THC and ∆9-THC in non-biological matrices are liquid-chromatography coupled to diode-array detection (LC-DAD or LC-PDA), while liquid chromatography coupled to mass spectrometry is preferred for biological matrices. Other available analytical methods are gas-chromatography-mass spectrometry (GC-MS) and quantitative nuclear magnetic resonance (QNMR). Current knowledge on the pharmacology of ∆8-THC and other ∆9-THC isomers are reviewed to raise awareness of the activity of these isomers in cannabis products, as well as analytical methods to discriminate ∆9-THC qualitatively, and quantitatively and ∆8-THC in biological and non-biological matrices.
•Δ9-THC isomers are increasingly found in cannabinoid products throughout the world.•There are few ∆9-THC isomer pharmacotoxicology data, except for early Δ8-THC studies.•Δ8-THC intoxications are currently emerging at a higher frequency.•Analytical methodologies for identifying and quantifying Δ9-THC isomers are reviewed.
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New oximes short-acting CB1 agonists were explored by the introduction of an internal oxime and polar groups at the C3 alkyl tail of Δ8-THC. The scope of the research was to ...drastically alter two important physicochemical properties hydrophobicity (log P) and topological surface area (tPSA) of the compound, which play a critical role in tissue distribution and sequestration (depot effect). Key synthesized analogs demonstrated sub-nanomolar affinity for CB1, marked reduction in hydrophobicity (ClogP∼2.5–3.5 vs 9.09 of Δ8-THC-DMH), and found to function as either agonists (trans-oximes) or neutral antagonists (cis-oximes) in a cAMP functional assay. All oxime analogs showed comparable affinity at the CB2 receptor, but surprisingly they were found to function as inverse agonists for CB2. In behavioral studies (i.e. analgesia, hypothermia) trans-oxime 8a exhibited a predictable fast onset (∼20 min) and short duration of pharmacological action (∼180 min), in contrast to the very prolonged duration of Δ8-THC-DMH (>24 h), thus limiting the potential for severe psychotropic side-effects associated with persistent activation of the CB1 receptor. We have conducted 100 ns molecular dynamic (MD) simulations of CB1 complexes with AM11542 (CB1 agonist) and both trans-8a and cis-8b isomeric oximes. These studies revealed that the C3 alkyl tail of cis-8b orientated within the CB1 binding pocket in a manner that triggered a conformational change that stabilized the CB1 receptor at its inactive-state (antagonistic functional effect). In contrast, the trans-8a isomer’s conformation was coincided with that of the AM11542 CB1 agonist-bound structure, stabilizing the CB1 receptor at the active-state (agonistic functional effect). We have selected oxime trans-8a based on its potency for CB1, and favorable pharmacodynamic profile, such as fast onset and predictable duration of pharmacological action, for evaluation in pre-clinical models of anorexia nervosa.
Abstract Background Marijuana is the most widely used illicit drug in the United States and all over the world. Reports indicate that the potency of cannabis preparation has been increasing. This ...report examines the concentration of cannabinoids in illicit cannabis products seized by the U.S. Drug Enforcement Administration over the last 2 decades, with particular emphasis on Δ9 -tetrahydrocannabinol and cannabidiol. Methods Samples in this report were received over time from materials confiscated by the Drug Enforcement Administration and processed for analysis using a validated gas chromatography with flame ionization detector method. Results Between January 1, 1995, and December 31, 2014, 38,681 samples of cannabis preparations were received and analyzed. The data showed that although the number of marijuana samples seized over the last 4 years has declined, the number of sinsemilla samples has increased. Overall, the potency of illicit cannabis plant material has consistently increased over time since 1995 from ~4% in 1995 to ~12% in 2014. The cannabidiol content has decreased on average from ~.28% in 2001 to <.15% in 2014, resulting in a change in the ratio of Δ9 -tetrahydrocannabinol to cannabidiol from 14 times in 1995 to ~80 times in 2014. Conclusions There is a shift in the production of illicit cannabis plant material from regular marijuana to sinsemilla. This increase in potency poses higher risk of cannabis use, particularly among adolescents.
Several studies performed on human subjects have examined the effects of adolescent cannabis consumption on brain structure or function using brain imaging techniques. However, the evidence from ...these studies is usually heterogenous and affected by several confounding variables. Animal models of adolescent cannabinoid exposure may help to overcome these difficulties. In this exploratory study, we aim to increase our understanding of the protracted effects of adolescent Δ9-tetrahydrocannabinol (THC) in rats of both sexes using magnetic resonance (MR) to obtain volumetric data, assess grey and white matter microstructure with diffusion tensor imaging (DTI) and measure brain metabolites with 1H-MR spectroscopy (MRS); in addition, we studied brain function using positron emission tomography (PET) with 2-deoxy-2-18Ffluoro-d-glucose as the tracer. THC-exposed rats exhibited volumetric and microstructural alterations in the striatum, globus pallidus, lateral ventricles, thalamus, and septal nuclei in a sex-specific manner. THC administration also reduced fractional anisotropy in several white matter tracts, prominently in rostral sections, while in vivo MRS identified lower levels of cortical choline compounds. THC-treated males had increased metabolism in the cerebellum and olfactory bulb and decreased metabolism in the cingulate cortex. By contrast, THC-treated females showed hypermetabolism in a cluster of voxels comprising the entorhinal piriform cortices and in the cingulate cortex. These results indicate that mild THC exposure during adolescence leaves a lingering mark on brain structure and function in a sex-dependant manner. Some of the changes found here resemble those observed in human studies and highlight the importance of studying sex-specific effects in cannabinoid research.
Background and Aims
Delta‐8 tetrahydrocannabinol (THC) is a psychoactive substance from the Cannabis plant that has been rising in popularity in the United States since the 2018 US Farm Bill ...implicitly legalized it. This study reviewed research from peer‐reviewed and non‐peer‐reviewed (e.g. anecdotal and news) reports related to delta‐8 THC to summarize current knowledge and implications for public health and safety.
Methods
A scoping review was conducted using PubMed, Scopus, Google Scholar and Google as search engines, leading to the identification of 103 documents that were summarized. The themes that emerged were (1) legality, (2) use (popularity, motives, psychoactivity/potency, benefits/consequences), (3) synthesis (byproducts, laboratory testing) and (4) retail (availability, price, packaging, youth‐oriented marketing). A second author independently coded 20% of the documents, which verified the categorization of articles by these emergent themes.
Results
Most research used animal/cell models or focused upon ways to identify the chemical structure of delta‐8 THC in various products. Findings suggest that people often use delta‐8 THC as a substitute for other substances. Anecdotally, delta‐8 THC is a less potent psychoactive than delta‐9 THC; however, several negative consequences have been reported. There is no federal age restriction for purchase/possession of delta‐8 THC products. Delta‐8 THC is readily accessible on‐line, is typically less expensive than delta‐9 THC and is often marketed in ways that would seemingly appeal to children. There are no regulations on synthesis, resulting in products being contaminated and/or yielding inconsistent effects. There have been thousands of calls to US poison control centers due to accidental delta‐8 THC exposure among minors.
Conclusions
Most research on delta‐8 THC is largely anecdotal, not peer‐reviewed and does not involve human subjects. Future research should examine delta‐8 THC use using nationally representative samples to more clearly understand the prevalence and consequences of use. Laws are needed to mitigate the risks of using delta‐8 THC, particularly quality control of synthesis and minimum purchase age.
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