THC and CBD blood and brain concentrations following daily administration to adolescent primates.
TL;DR: In adolescent monkeys, blood levels of THC, its metabolites or CBD remain stable after daily dosing for four months, and the model suggests that any pharmacological interactions between CBD and THC are unlikely to result from CBD modulation of THC pharmacokinetics.
About: This article is published in Drug and Alcohol Dependence.The article was published on 2020-06-18 and is currently open access. It has received 11 citations till now. The article focuses on the topics: Cannabidiol.
Citations
More filters
TL;DR: In this article, the long-term effects of daily consumption of a high dose of THC in adolescents and whether a therapeutic dose of cannabidiol (CBD) modulates THC effects were investigated.
12 citations
TL;DR: A comparative analysis of the pharmacokinetic (PK) properties of THC in adolescent and adult rats of both sexes reveals the existence of multiple age and sex differences in the distribution and metabolism of cannabinoids in rats, which might influence the pharmacological response to the drug.
Abstract: Introduction: Studies in rodent models have shown that adolescent exposure to Δ9-THC, the psychotropic constituent of cannabis, produces long-lasting alterations in brain function and behavior. However, our understanding of how age and sex might influence the distribution and metabolism of THC in laboratory rodents is still incomplete. In the present report, we provide a comparative analysis of the pharmacokinetic (PK) properties of THC in adolescent and adult rats of both sexes, and outline several dissimilarities across these groups. Materials and Methods: A single (acute) or 2-week daily (subchronic) administration of THC (0.5 or 5 mg/kg, acute; 5 mg/kg, subchronic; intraperitoneal) was given to adolescent (33-day-old, acute; 30-44-day-old, subchronic) and young adult (70-day-old, acute only) male and female rats. THC and its first-pass metabolites-11-hydroxy-Δ9-THC (11-OH-THC) and 11-nor-9-carboxy-Δ9-THC (11-COOH-THC)-were quantified in plasma and brain tissue using a selective isotope-dilution liquid chromatography/tandem mass spectrometry assay. Changes in body temperature were measured using abdominally implanted microchips. Biotransformation of THC to its metabolites using freshly prepared liver microsomes was assessed. Results: At the acute 5 mg/kg dose, maximal plasma concentrations of THC were twice as high in adult than in adolescent rats. Conversely, in adults, brain concentrations and brain-to-plasma ratios for THC were substantially lower (25-50%) than those measured in adolescents. Similarly, plasma and brain concentrations of THC metabolites were higher in adolescent male rats compared with adult males. Interestingly, plasma and brain concentrations of the psychoactive THC metabolite 11-OH-THC were twofold to sevenfold higher in female animals of both ages compared with males. Moreover, liver microsomes from adolescent males and adolescent and adult females converted THC to 11-OH-THC twice as fast as adult male microsomes. A dose-dependent hypothermic response to THC was observed in females with 0.5 and 5 mg/kg THC, whereas only the highest dose elicited a response in males. Finally, subchronic administration of THC during adolescence did not significantly affect the drug's PK profile. Conclusions: The results reveal the existence of multiple age and sex differences in the distribution and metabolism of THC in rats, which might influence the pharmacological response to the drug.
8 citations
TL;DR: In this article, the authors conducted an online survey using structured questionnaires to determine differences in CBD users with (CBD+MJ) and without co-morbid marijuana use.
Abstract: Background: With the passing of the 2018 Agriculture Improvement Act that legalized hemp-derived products, i.e., cannabidiol (CBD), the use of CBD has increased exponentially. To date, the few studies that have characterized individuals who use CBD suggest that co-use of CBD and tetrahydrocannabinol (THC)-dominant cannabis, i.e., marijuana, is highly prevalent. It is, therefore, important to investigate the relationship between CBD use and marijuana use to understand the antecedents and consequences of co-use of these two cannabis products. Methods: We conducted an online survey using structured questionnaires to determine differences in CBD users with (CBD+MJ) and without co-morbid marijuana use. Group comparisons were carried out using chi-square tests and ANOVA. Multiple correspondence analysis (MCA) with bootstrap ratio testing was performed to examine the relationship between the categorical data. Results: We received 182 survey responses from current CBD users. CBD+MJ had more types of CBD administration (F = 17.07, p < 0.001) and longer lifetime duration of CBD use (χ2 = 12.85, p < 0.05). Results from the MCA yielded two statistically significant dimensions that accounted for 77% of the total variance. Dimension 1 (representing 57% of the variance) associated CBD+MJ with indication of CBD use for medical ailments, use of CBD for more than once a day for longer than 2 years, applying CBD topically or consuming it via vaping or edibles, being female, and, having lower educational attainment. Dimension 2 (representing 20% of the variance) separated the groups primarily on smoking-related behaviors where CBD+MJ was associated with smoking CBD and nicotine. Conclusions: Identifying the factors that influence use of CBD and marijuana can inform future studies on the risks and benefits associated with each substance as well as the impacts of policies related to cannabis-based products.
8 citations
TL;DR: For instance, the authors found that females with earlier age of first use-by-sex interaction in chronic cannabis use tended to have more self-reported sleep issues, whereas this trend was not present among male users.
Abstract: Background: There are known sex differences in behavioral and clinical outcomes associated with drugs of abuse, including cannabis. However, little is known about how chronic cannabis use and sex interact to affect brain structure, particularly in regions with high cannabinoid receptor expression, such as the cerebellum, amygdala, and hippocampus. Based on behavioral data suggesting that females may be particularly vulnerable to the effects of chronic cannabis use, we hypothesized lower volumes in these regions in female cannabis users. We also hypothesized poorer sleep quality among female cannabis users, given recent findings highlighting the importance of sleep for many outcomes related to cannabis use disorder. Methods: Using data from the Human Connectome Project, we examined 170 chronic cannabis users (>100 lifetime uses and/or a lifetime diagnosis of cannabis dependence) and 170 controls that we attempted to match on age, sex, BMI, race, tobacco use, and alcohol use. We performed group-by-sex ANOVAs, testing for an interaction in subcortical volumes, and in self-reported sleep quality (Pittsburgh Sleep Questionnaire Inventory). Results: After controlling for total intracranial volume and past/current tobacco usage, we found that cannabis users relative to controls had smaller cerebellum volume and poorer sleep quality, and these effects were driven by the female cannabis users (i.e., a group-by-sex interaction). Among cannabis users, there was an age of first use-by-sex interaction in sleep quality, such that females with earlier age of first cannabis use tended to have more self-reported sleep issues, whereas this trend was not present among male cannabis users. The amygdala volume was smaller in cannabis users than in non-users but the group by sex interaction was not significant. Conclusions: These data corroborate prior findings that females may be more sensitive to the neural and behavioral effects of chronic cannabis use than males. Further work is needed to determine if reduced cerebellar and amygdala volumes contribute to sleep impairments in cannabis users.
5 citations
TL;DR: In this paper , the authors explore the association between depression or anxiety and dysregulation of the endogenous endocannabinoid system (ECS), as well as the use of phytocannabinoids and synthetic cannabinoids in the remediation of depression/anxiety symptoms.
Abstract: Background: There is a growing liberalization of cannabis-based preparations for medical and recreational use. In multiple instances, anxiety and depression are cited as either a primary or a secondary reason for the use of cannabinoids. Aim: The purpose of this review is to explore the association between depression or anxiety and the dysregulation of the endogenous endocannabinoid system (ECS), as well as the use of phytocannabinoids and synthetic cannabinoids in the remediation of depression/anxiety symptoms. After a brief description of the constituents of cannabis, cannabinoid receptors and the endocannabinoid system, the most important evidence is presented for the involvement of cannabinoids in depression and anxiety both in human and from animal models of depression and anxiety. Finally, evidence is presented for the clinical use of cannabinoids to treat depression and anxiety. Conclusions: Although the common belief that cannabinoids, including cannabis, its main studied components—tetrahydrocannabinol (THC) and cannabidiol (CBD)—or other synthetic derivatives have been suggested to have a therapeutic role for certain mental health conditions, all recent systematic reviews that we report have concluded that the evidence that cannabinoids improve depressive and anxiety disorders is weak, of very-low-quality, and offers no guidance on the use of cannabinoids for mental health conditions within a regulatory framework. There is an urgent need for high-quality studies examining the effects of cannabinoids on mental disorders in general and depression/anxiety in particular, as well as the consequences of long-term use of these preparations due to possible risks such as addiction and even reversal of improvement.
2 citations
References
More filters
TL;DR: Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.
Abstract: Δ9-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for nonreceptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15–30 minutes, and taper off within 2–3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30–90 minutes, reach their maximum after 2–3 hours and last for about 4–12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.
1,135 citations
TL;DR: The cardiovascular and subjective effects of cannabis are blocked by rimonabant, the first CB-1 cannabinoid-receptor antagonist, documenting thatCB-1 receptors mediate these effects of smoked cannabis in humans.
Abstract: A multitude of roles for the endogenous cannabinoid system has been proposed by recent research efforts. A large number of endogenous cannabinoid neurotransmitters or endocannabinoids have been identified, and the CB-1 and CB-2 cannabinoid receptors have been characterized. The presence of other receptors, transporters, and enzymes responsible for the synthesis or metabolism of endocannabinoids are becoming known at an extraordinary pace. The complex functions of this novel system have created multiple new targets for pharmacotherapies. Research has focused on separating the behavioral psychoactive effects of cannabinoid agonists from therapeutic effects. These efforts have been largely unsuccessful. Another strategy centers on changing the pharmacokinetics of drug delivery to maximize therapeutic effect and minimize cognitive and subjective drug effects. Development of oral, rectal, and transdermal medications of synthetic Δ9-tetrahydrocannabinol (THC)1) are examples of this type of approach. Additionally, the potential therapeutic benefits of administering unique combinations of cannabinoids and other chemicals present in the plant Cannabis sativa is being investigated by the oromucosal route. There also is strong interest in medications based on antagonizing endocannabinoid action.
We have shown that the cardiovascular and subjective effects of cannabis are blocked by rimonabant, the first CB-1 cannabinoid-receptor antagonist, documenting that CB-1 receptors mediate these effects of smoked cannabis in humans. It is clear that the endogenous cannabinoid system plays a critical role in physiological and behavioral processes, and extensive research effort is being devoted to the biology, chemistry, pharmacology, and toxicology of cannabinoids.
Cannabis is one of the oldest and most commonly abused drugs in the world, and its use is associated with pathological and behavioral toxicity. Thus, it is important to understand cannabinoid pharmacokinetics and the disposition of cannabinoids into biological fluids and tissues. Understanding the pharmacokinetics of a drug is essential to understanding the onset, magnitude, and duration of its pharmacodynamic effects, maximizing therapeutic and minimizing negative side effects.
Cannabinoid pharmacokinetics encompasses absorption after diverse routes of administration and from different drug formulations, analyte distribution throughout the body, metabolism by the liver and extra-hepatic tissues, and elimination in the feces, urine, sweat, oral fluid, and hair. Pharmacokinetic processes are dynamic, may change over time, and may be affected by the frequency and magnitude of drug exposure. The many contributions to our understanding of cannabinoid pharmacokinetics from the 1970s and 1980s are reviewed, and the findings of recent research expanding upon this knowledge are detailed. Cannabinoid pharmacokinetics research is challenging due to low analyte concentrations, rapid and extensive metabolism, and physico-chemical characteristics hindering the separation of drugs of interest from biological matrices and from each other. Drug recovery is reduced due to adsorption of compounds of interest to multiple surfaces. Much of the early cannabinoid data are based on radiolabeled cannabinoids yielding highly sensitive, but less specific, measurement of individual cannabinoid analytes. New extraction techniques and mass-spectrometric (MS) developments now permit highly sensitive and specific measurement of cannabinoids in a wide variety of biological matrices, improving our ability to characterize cannabinoid pharmacokinetics.
Cannabis sativa contains over 421 different chemical compounds, including over 60 cannabinoids [1-3]. Cannabinoid plant chemistry is far more complex than that of pure THC, and different effects may be expected due to the presence of additional cannabinoids and other chemicals. Eighteen different classes of chemicals, including nitrogenous compounds, amino acids, hydrocarbons, carbohydrates, terpenes, and simple and fatty acids, contribute to the known pharmacological and toxicological properties of cannabis. THC is usually present in Cannabis plant material as a mixture of monocarboxylic acids, which readily and efficiently decarboxylate upon heating. THC decomposes when exposed to air, heat, or light; exposure to acid can oxidize the compound to cannabinol (CBN), a much less-potent cannabinoid. In addition, cannabis plants dried in the sun release variable amounts of THC through decarboxylation. During smoking, more than 2,000 compounds may be produced by pyrolysis. The pharmacokinetics of THC, the primary psychoactive component of cannabis, its metabolites ‘11-hydroxytetrahydrocannabinol’ (11-OH-THC) and ‘11-nor-9-carboxy-tetrahydrocannabinol’ (THC-COOH)]2), and another cannabinoid present in high concentration, cannabidiol (CBD), a non-psychoactive agent with an interesting array of potential therapeutic indications, are included. Mechoulam et al. elucidated the structure of THC in 1964, enabling studies of the drug's pharmacokinetics [4]. THC, containing no N-atom, but with two stereogenic centers in a trans configuration, has been described by two different atom-numbering systems, either the dibenzopyran (or Δ9) or the monoterpene (or Δ1) system. In this review, the dibenzopyran (Δ9) system is employed.
791 citations
TL;DR: The research on the acute, residual, and long-term effects of cannabis use on executive functions is reviewed and the implications for treatment are discussed.
Abstract: :Cannabis use may impair cognitive functions on a number of levels—from basic motor coordination to more complex executive function tasks, such as the ability to plan, organize, solve problems, make decisions, remember, and control emotions and behavior. These deficits differ in severity dep
571 citations
TL;DR: The integrated inventory of these compounds and their biological macromolecular end-points highlights the opportunities that phytocannabinoids offer to access desirable drug-like space beyond the one associated to the narcotic target CB1.
507 citations