Doses Of Tetrahydrocannabinol Research Articles

Edible cannabis for chronic low back pain: associations with pain, mood, and intoxication.

Cannabis, commonly known for both therapeutic and intoxicating effects, is gaining accessibility on legal markets and traction as a potential alternative therapy for pain mediation, particularly in those suffering from chronic low back pain. However, the effectiveness in this population of legal market forms of cannabis, particularly commonly used edibles, is unknown. Therefore, this study utilized a naturalistic prospective design where participants with chronic low back pain with intentions to initiate cannabis use for treatment were recruited and self-selected edible cannabis products containing varying amounts of delta- 9 tetrahydrocannabinol (THC) and cannabidiol (CBD). Products were categorized as CBD-dominant, THC-dominant, or combined THC and CBD (THC + CBD). 249 participants [140 female (56.62%), mean (SD) age of 46.30 (16.02), 90% White] were tracked over 2weeks of ad libitum use and assessed during a naturalistic acute cannabis administration session on changes in pain, mood, and subjective drug effects. During acute administration, a significant correlation between THC dose and short-term pain relief was found, suggesting that higher THC doses were associated with greater pain reduction (p < .05). In addition, THC was associated with higher levels of subjective cannabis drug effects (p < .001), regardless of whether CBD was also in the edible product. Acute CBD dose was primarily associated with short-term tension relief (p < .05); however, there were no associations between CBD dose and acute pain. Over the 2-week ad libitum administration period results suggested pain reductions across participants using all forms of cannabis. However, trends suggested that more frequent use of CBD-dominant edible cannabis may be associated with greater reductions in perceived pain over the 2-week observation period (p = .07). These findings support the short-term analgesic effects of THC and anxiolytic effects of CBD and further suggest that orally-administered THC and CBD should continue to be evaluated for the potential to provide both acute and extended relief from chronic low back pain. https://clinicaltrials.gov/study/NCT03522324?locStr=Boulder,%20CO&country=United%20States&state=Colorado&city=Boulder&cond=chronic%20low%20back%20pain&intr=Cannabis&rank=1, identifier NCT03522324.

Medicinal cannabis tea contains variable doses of cannabinoids and no terpenes.

Tea is a recommended way of administration of prescribed cannabis plant products in Denmark. We aimed to investigate the cannabinoid and terpene doses contained in different teas. We analysed tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), and terpene concentrations in three repeated preparations of each type of tea, and in plant material. In standard tea, concentrations of THC were [median (min-max)] 9.5 (2.3-15), 19 (13-34), and 36 (26-57) μg/mL for products with a labelled content of 6.3%, 14%, and 22% total THC (THC + THCA), respectively. The CBD concentration in tea from a product labelled with 8% total CBD (CBD + CBDA) was 7.5 (1.9-10) μg/mL. Based on this, the recommended starting amount of 0.2L of the different teas would contain between 0.46 and 11.3mg THC, and 0.38 to 2.0mg CBD. Adding creamer before, but not after boiling, increased the THC and CBD concentration 2.3-4.4 and 2.1-fold, respectively. Terpenes were detected in plant material, but not in tea. The study elucidates THC and CBD doses in different teas, which may assist the clinician's choice of cannabis product. Moreover, it underscores the need for caution as administration as tea can result in exposure to different doses, even when the same cannabis product is used.

Randomized Laboratory Study of Single-Dose Cannabis, Dronabinol, and Placebo in Patients With Schizophrenia and Cannabis Use Disorder.

Up to 43% of people with schizophrenia have a lifetime cannabis use disorder (CUD). Tetrahydrocannabinol (THC) has been shown to exacerbate psychosis in a dose-dependent manner, but little research has assessed its effects on schizophrenia and co-occurring CUD (SCZ-CUD). In this double-dummy, placebo-controlled trial (total n = 130), we hypothesized that a modest dose of THC would worsen cognitive function but not psychosis. Effects of single-dose oral THC (15mg dronabinol) or smoked 3.5% THC cigarettes vs placebo in SCZ-CUD or CUD-only on positive and negative symptoms of schizophrenia (only for SCZ-CUD), cognition, and drug experiences assessed several hours after drug administration. SCZ-only and healthy control participants were also assessed. Drug liking was higher in THC groups vs placebo. Neither smoked THC nor oral dronabinol predicted positive or negative symptom subscale scores 2 and 5h, respectively, after drug exposure in SCZ-CUD participants. The oral dronabinol SCZ-CUD group, but not smoked THC SCZ-CUD group, performed worse than placebo on verbal learning (B = -9.89; 95% CI: -16.06, -3.18; P = .004) and attention (B = -0.61; 95% CI: -1.00, -0.23; P = .002). Every 10-point increment in serum THC + THCC ng/ml was associated with increased negative symptoms (0.40 points; 95% CI: 0.15, 0.65; P = .001; subscale ranges 7-49) and trends were observed for worse positive symptoms and performance in verbal learning, delayed recall, and working memory. In people with SCZ-CUD, a modest single dose of oral THC was associated with worse cognitive functioning without symptom exacerbation several hours after administration, and a THC dose-response effect was seen for negative symptoms.

Sex differences in the acute effects of oral THC: a randomized, placebo-controlled, crossover human laboratory study.

Recent reports have shown increased cannabis use among women, leading to growing concerns about cannabis use disorder (CUD). While there is preclinical evidence suggesting biological sex influences cannabinoid effects, human research remains scant. We investigated sex differences in the acute response to oral tetrahydrocannabinol (THC) in humans. 56 healthy men and women with prior exposure to cannabis but no history of CUD participated in a randomized, placebo-controlled, human laboratory study where they received a single 10mg dose of oral THC (dronabinol). Subjective psychoactive effects were assessed by the visual analog scale of "high", psychotomimetic effects by the Clinician-Administered Dissociative Symptoms Scale and Psychotomimetic States Inventory, verbal learning and memory by Rey Auditory Verbal Learning Test (RAVLT), and physiological effects by heart rate. Outcomes were regularly measured on the test day, except for the RAVLT, which was assessed once. Peak differences from baseline were analyzed using a nonparametric method for repeated measures. Oral THC (10mg) demonstrated significant dose-related effects in psychotomimetic and physiological domains, but not in RAVLT outcomes. A notable interaction between THC dose and sex emerged concerning the subjective "high" scores, with women reporting heightened sensations (p = 0.05). No other significant effects of sex and THC dose interaction were observed. Oral THC (10mg) yields similar acute psychotomimetic and physiological effects across sexes, but women may experience a pronounced subjective psychoactive effect. Further research is needed to identify individual vulnerabilities and facilitate tailored interventions addressing CUD. GOV REGISTRATION: https://clinicaltrials.gov/study/NCT02781519?term=Ranganathan&intr=THC&rank=3 .

Assessing dental student knowledge on cannabis and demonstrating the need for cannabis education.

The American Dental Association advocates for dentists' education on therapeutic and legal issues related to medical cannabis. It is important to understand current knowledge of cannabis and cannabinoids and to have a practical knowledge assessment instrument. This exploratory study is the first of its kind to assess dental students' knowledge of cannabis and aims to determine if there is a need for more instruction regarding cannabis in a dental school's curriculum. Predoctoral dental students at the University at Buffalo School of Dental Medicine were recruited to participate. A validated, anonymous 22-item online survey was adapted and administered to students in all 4 years of the dental program. There was a total of 56 knowledge points. The average knowledge score was 21.6 points (SD=5.2, range: 7-34), corresponding to 38.5% (SD=9.2) of the answers correct. There were no overall differences in knowledge by gender, years in dental school, or by any reported source of formal education on cannabis. Those who reported doing their own research had higher knowledge scores. Most participants knew that there is an endogenous cannabinoid system (72.3%) and that Tetrahydrocannabinol (THC) is responsible for the "high" experienced with cannabis (76.6%). Most participants reported that they did not know the effective doses of THC (58.2%) and Cannabidiol (CBD) (66.7%); few provided an answer for THC (34%) or CBD (17%) in the acceptable range of 2-10mg. Dental students did not have adequate knowledge on cannabis and cannabinoids. Given the rapid expansion of cannabis legalization, additional efforts are needed to integrate cannabis topics into coursework and learning experiences.

The Use of Tetrahydrocannabinol Is Associated with an Increase in Survival Time in Palliative Cancer Patients: A Retrospective Multicenter Cohort Study

Introduction: Tetrahydrocannabinol (THC) is often prescribed for ambulatory palliative patients to improve sleep quality and appetite and to reduce anxiety, stress, and pain. However, it is not known if THC has also an effect on the mortality of these patients. Method: The objective was the impact of THC on mortality of ambulatory palliative patients. For this purpose, data from the palliative treatment documentation from 5 ambulatory palliative care teams in Brandenburg, Germany were used for this analysis. Survival time was calculated for 3 groups of patients: (1) without THC; (2) with THC in a low dosage (≤4.7 mg per day); and (3) THC in higher doses (≥4.7 mg per day). The analysis was done for 2 cohorts of patients. Cohort 1: all patients with a survival time of at least 7 days after inclusion in specialized ambulatory palliative care (SAPC) and cohort 2: a subgroup of patients with a survival time between 7 and 100 days. Kaplan-Meier curves were created, and multivariate analysis was done to investigate the impact of THC on mortality. Results: A total of 9,419 patients with a survival time of at least 7 days after inclusion in SAPC were included in the analysis (cohort 1). 7,085 among them had a survival time between 7 and 100 days (cohort 2). In both cohorts, survival time was significantly prolonged by THC, but only when the daily THC dose was above the median of 4.7 mg. Survival time was 15 days longer in cohort 2 (40 vs. 25 days), when more than 4.7 mg THC were prescribed per day. Conclusion: Use of THC is associated with a significant increase in survival time in ambulatory palliative patients which survive longer than 7 days the initiation of THC prescription and which use of THC >4.7 mg/day.

CFPD-PK simulation of inhaled Delta-9-tetrahydrocannabinol aerosol dynamics: Transport, deposition, and translocation in a mouth-to-G10 subject-specific human airway

Medical cannabis is increasingly used as an alternative therapy for various conditions, including chronic pain, multiple sclerosis, epilepsy, and cancer-related symptoms. However, it is crucial to ensure that patients receive the intended dose of tetrahydrocannabinol (THC) from inhaled cannabis for optimal therapeutic effect without overdose risk. This requires a comprehensive understanding of the factors that influence the pharmacokinetics (PKs) of THC in the respiratory system. However, accurate estimation of lung dosimetry and blood concentration of inhaled THC remains challenging partially because the influence of diversified patient-specific puff patterns on inhaled THC transport, deposition, and translocation is still not well quantified. To address the knowledge gap mentioned above, this study employed a hybrid computational fluid-particle dynamics (CFPD) and PK model to evaluate factors that influence delivered doses of THC to the human respiratory system and the resultant THC-plasma concentration-time profile. Specifically, this study compared multiple puff waveforms for inhalation-holding-exhalation (IHE) with total puff volumes from 55 to 82 ml for 2 or 3 s, hold durations from 0 to 5 s, and three puff waveforms (i.e., square, sinusoidal, and realistic). THC deposition in the airways was recorded during all phases for each case using either 452,849 particles per second for the 1.128-μm monodisperse cases or 399,866 particles per second for the polydisperse cases, with the mass median aerodynamic diameter (MMAD) of 1.128 μm. Pulmonary air-THC particle flow transport dynamics, THC particle deposition data, and THC vapor absorption were predicted using CFPD for four airway regions, then scaled by region-specific bioavailability factors. The deposited THC mass in airway regions represents the initial mass entering a 3-compartment PK model, to predict the THC-plasma concentration-time profiles. The CFPD-PK results revealed significant variability in THC transport, deposition, and plasma concentration based on IHE factors. Specifically, larger puff volumes and longer holding times enhanced THC deposition in deeper airways and increased THC-plasma concentrations. Realistic transient puff waveforms predicted higher particle deposition and THC-plasma concentrations than simplified square waveforms. Polydisperse particle distributions show more realistic deposition patterns than monodisperse particle simulations. This study provides insights into the complexity of THC inhalation therapy, emphasizing the importance of considering individualized puff patterns and realistic particle size distributions in accurately predicting therapeutic outcomes, which is highly related to THC deposition in the lung and THC plasma concentration. These findings and the CFPD-PK modeling framework offer guidance for clinicians in prescribing personalized THC dosages, support regulatory science in evaluating inhalation devices, and contribute to ongoing research aimed at optimizing THC delivery for maximum therapeutic effectiveness while minimizing potential overdose risks.

Drug Interactions of Tetrahydrocannabinol and Cannabidiol in Cannabinoid Drugs.

Cannabinoid drugs containing tetrahydrocannabinol (THC), or its structural analogues, as monotherapeutic agents or as extracts or botanical preparations with or without cannabidiol (CBD) are often prescribed to multimorbid patients who are taking multiple drugs. This raises the question of the risk of drug interactions. This review of the pharmacokinetics and pharmacodynamics of interactions with cannabinoid drugs and their potential effects is based on pertinent publications retrieved by a selective literature search. As THC and CBD are largely metabolized in the liver, their bioavailability after oral or oral-mucosal administration is low (6-8% and 11-13%, respectively). The plasma concentrations of THC and its active metabolite 11-OH-THC can be increased by strong CYP3A4 inhibitors (verapamil, clarithromycin) and decreased by strong CYP3A4 inductors (rifampicin, carbamazepine). The clinical significance of these effects is unclear because of the variable plasma level and therapeutic spectrum of THC. The metabolism of CBD is less dependent on cytochrome P450 enzymes than that of THC. THC and CBD inhibit CYP2C and CYP3A4; the corresponding clinically relevant drug interactions probably are likely to arise only with THC doses above 30 mg/day and CBD doses above 300 mg/day. Potential drug interactions with THC and CBD are probably of little importance at low or moderate doses. Strong CYP inhibitors or inductors can intensify or weaken their effect. Slowly ramping up the dose of oral cannabinoid drugs can lessen their pharmacodynamic interactions, which can generally be well controlled. Administration by inhalation can worsen the interactions.

O-053 Link between cannabis use and fertility: effects on gamete competence and early embryonic development

Worldwide human fertility has been facing a significant decline over recent years. Therefore, attention has been focused on identifying environmental and lifestyle risk factors that may be contributing to impact human reproductive function. The use of alcohol, tobacco and certain medications have undergone substantial assessment into their effects on fertility. As physicians aim to offer the most appropriate recommendations to their patients, it is of utmost importance to understand the side effects of readily available substances and their mechanisms of action. Cannabis falls into this group of substances used regularly by women and men of reproductive age, with its consumption steadily rising with the onset of legalization in Canada in 2018 also amongst pregnant women. At present, the Society of Obstetricians and Gynecologists of Canada recommends that women of reproductive age, especially if considering pregnancy, discontinue cannabis use. There is, however, inconclusive evidence that links cannabis and fertility. This presentation will outline the most recent data from our laboratory on the effects of Delta-9 tetrahydrocannabinol (THC), the main psychoactive component of cannabis, on oocytes competency and sperm fertilization capability. In fact chronic exposure to cannabis also adversely affects the male reproductive system, inducing oligospermia, morphologically abnormal sperm, and impaired sperm motility in rodents. Using a bovine model as translational model for humans, we identified effects of THC on oocyte developmental parameters, gene expression as well on sperm parameters, such as motility, morphology, capacitation and mitochondrial potential. The general hypothesis at the basis of this research program aims to elucidate the effects of THC at clinically relevant doses on gene and epigenetic modifications in sperm, oocytes and embryos, ultimately affecting fertility and pregnancy outcome. We showed a significantly reduced ability of THC-treated oocytes to undergo nuclear maturation, ultimately leading to decreased oocyte fertilization capability and poor embryonic development. We showed that THC acts as a partial agonist at the Cannabinoid receptors 1 and 2 (CB1 and CB2), as THC effects were reverted by the addition of antagonists. The significant decrease in maturation and cleavage rate of oocytes exposed to the higher doses of THC, representative of high recreational use of Cannabis, allows us to speculate that THC might act as a selection factor for only the highest quality oocytes, that overcome the THC effects. The more immature oocytes may be negatively affected by THC by being pushed towards meiotic resumption, leading to early maturation, prior to gaining developmental competence. Levels of connexin gap-junction proteins were used as indicator of oocyte competency, as they highly correlate to oocyte fertilization potential and embryo quality. Our results demonstrated a significant decrease in connexin 37 (CX37) and connexin 43 (CX43) mRNA levels measured by digital droplet PCR (ddPCR), in oocytes only in the low dose THC group, representative of the therapeutic use of Cannabis. More recently we have also shown how THC affects methylation in granulosa cells, via disrupting methylation and de-methylation enzymes, ultimately determining oocyte competency and, therefore, fertility. THC exerts parallel effects on the male gametes as well, increasing capacitation of in vitro treated sperm, affecting their mitochondrial potential and disrupting the expression of key microRNAs in sperm that are linked to early embryonic development, therefore affecting pre-implantation development and, ultimately, pregnancy outcome. Our results suggest an overall detrimental effect of THC on the competency and fertilization potential of both female and male gametes, negatively influencing fertility and the likelihood of a viable pregnancy, especially of importance when undergoing artificial reproductive technologies procedures. Trial registration number XXXX

Do not let the ideal be the enemy of good enough regulation.

Research on the effectiveness and efficiency of different methods of regulating cannabis potency should be a high priority for public health research that will inform the design of cannabis regulations that minimize public health harms. Our article [1] was intended to alert the addictions field to the critical issue of increased cannabis potency as a public health concern, counter the cannabis industry argument that such regulation is unnecessary and canvas some regulatory options. We thank our commentators for their thoughtful responses, which reveal that regulating tetrahydrocannabinol (THC) potency is more complex than it seems at first sight. Freeman & Lorenzetti highlight consumers’ need for simpler advice on labels, much as standard drinks of alcohol [2]. They have led consensus projects to define standard doses of THC that could be used in this way. They also make the useful point that regulators need to consider setting minimum unit prices for cannabis, much as those that have been implemented to reduce heavy alcohol consumption in some countries. Pardal & Wadsworth highlight the fact that the US model of cannabis legalization—a commercialized for-profit market, with minimal regulation of potency and promotion—is not the only model on offer [3]. Uruguay has limited sales to herbal cannabis and capped the THC content of cannabis sold in pharmacies. The Canadian province of Quebec has banned sales of cannabis extracts, limited the sale of edibles and imposed a cap on the THC content of herbal cannabis. The effectiveness of these policies is well worth investigation. The major empirical question is whether the policies will succeed in the longer term, when neighbouring jurisdictions allow the sale of banned products that can be easily transported across borders. Caulkins points out the economic drivers of increasing cannabis potency in the United States; namely, cannabis producers’ need to make maximum use of whole cannabis plants to compete in a market in which cannabis prices are declining [4]. He argues that bans on the sale of high-potency cannabis products would be simpler and easier to implement than attempting to regulate the potency of the many different cannabis products in US legal cannabis markets. He cites evidence that bans need not generate large-scale illicit markets. We agree that banning high-potency products could be the most effective measure to protect public health in countries contemplating cannabis legalization. We doubt its feasibility, however, in mature US markets that already sell high-potency products and in which cannabis retailers will strenuously oppose the policy. Governments regulating these markets may also prefer the revenue from taxing cannabis products on the basis of their THC content. The regulation of cannabis potency is nowhere near as straightforward as regulating alcohol, but we should not allow the cannabis industry to use this as a reason for failing to regulate cannabis potency. In cannabis regulation, as in any area of public health, we should not allow the ideal to be the enemy of the good enough. Research on the effectiveness and efficiency of different methods of regulating cannabis potency should be a high priority for public health research that will inform the design of cannabis regulations which minimize public health harms. Open access publishing facilitated by The University of Queensland, as part of the Wiley - The University of Queensland agreement via the Council of Australian University Librarians. None.

State Variation in U.S. Medical Cannabis Limits, Restrictions, and Therapeutic Cannabis Dosing.

Wide variation exists in the possession limits of cannabis products sold for medical use in the U.S. as well as the tetrahydrocannabinol (THC) content of cannabis products. Prior work has found that legal limits on recreational cannabis sold per transaction may promote moderate use and diversion. This paper finds similar results for monthly medical cannabis limits. In the present analyses, state limits on medical cannabis were aggregated and converted into 30-day limits and 5 milligram (mg) THC doses. Grams of pure THC were calculated using plant weight limits and medical cannabis median THC potency aggregated from Colorado and Washington state medical cannabis retail sales data. Weight in pure THC was then broken down into 5 mg doses. Weight-based possession limits of cannabis for medical use varied widely across states (range: 1.5-762.05 grams pure THC per 30 days), with three states lacking a quantifiable weight limit (in which limits are not by weight but by physician's recommendation). States generally do not impose limits on the potency of cannabis products, therefore small differences in weight limits can result in large differences in the amount of total THC allowed to be sold. Assuming a typical medical dose of 5 mg and the median THC potency of 21%, current laws allow for sales of 300 (Iowa) to 152,410 (Maine) doses per month. Current state statutes and methods of cannabis recommendation allow patients to increase therapeutic THC doses independently, and perhaps unknowingly. High THC content products combined with the higher purchase or possession limits allowed by medical cannabis laws may lead to an increased potential for overconsumption or diversion.

The effect of tetrahydrocannabinol:cannabidiol oromucosal spray on cognition: a systematic review.

Previous studies have shown that tetrahydrocannabinol (THC), the main psychoactive component of cannabis, can impair cognitive abilities. There is also some evidence that cannabidiol (CBD), the most abundant non-intoxicating constituent of cannabis, can attenuate these effects. The purpose of this study was to investigate the effects of THC:CBD oromucosal spray (with equal parts THC and CBD) on cognition compared with control conditions in human studies. A systematic literature search was performed on four major bibliographic databases. Studies were included in the present review if they evaluated the cognitive effects of THC:CBD oromucosal spray compared with a control condition. Ten studies were identified (7 on patients with multiple sclerosis, 1 on those with Huntington, and 2 on healthy volunteers) with 510 participants in total. There was considerable heterogeneity among the studies in terms of dose and duration of administration. All studies have used an equal or nearly equal dose of THC and CBD. Although the results across studies were somewhat inconsistent, most evidence revealed that there is no significant difference between THC:CBD oromucosal spray and control treatments in terms of cognitive outcomes. However, more trials are needed with longer follow-up periods, and dose considerations, particularly comparing lower and higher doses of the spray.

Delta-9 tetrahydrocannabinol (THC) effects on the cortisol stress response in bovine granulosa cells

Maternal stress can result in changes in the hypothalamic-pituitary-adrenal (HPA) axis and lead to stress-related behaviours in offspring. Under physiological conditions, delta-9 tetrahydrocannabinol (THC) appears to be detrimental for fertility. However, cannabis is also commonly used for stress-relief. THC acts on the endocannabinoid receptors in granulosa cells (GCs), which affect oocyte competency. The objective of this study was to evaluate the effects of THC on in vitro bovine granulosa cell viability, apoptosis, and stress response pathway. GCs were cultured in vitro in the presence of clinically relevant therapeutic and recreational plasma doses of THC. Cortisol doses reflecting normal and elevated plasma levels were used to evaluate the effects of THC under induced stress in vitro. No effect of THC was observed on cell viability or apoptosis. High and low cortisol concentrations caused significant increases in 11β-HSD1 mRNA expression (n = 6, p < 0.0001). Interestingly, when combined with high [THC], there was a significant decrease in 11β-HSD1 expression compared to high and low cortisol treatments alone (p < 0.001, p < 0.05). GR expression was unaffected by cortisol treatments, and low [THC] treatment maintained increased expression in the presence of high and low cortisol treatments (n = 6, p < 0.01, p < 0.0001). Our findings represent a foundation to obtain useful data for evaluating THC potential therapeutic benefit.

Sex differences in the acute effects of intravenous (IV) delta-9 tetrahydrocannabinol (THC).

Cannabis is the most common illicit drug used in the USA and its use has been rising over the past decade, while the historical gap in rates of use between men and women has been decreasing. Sex differences in the effects of cannabinoids have been reported in animal models, but human studies are sparse and inconsistent. We investigated the sex differences in the acute subjective, psychotomimetic, cognitive, and physiological effects of intravenous (IV) delta-9 tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis. Healthy male and female individuals, with limited exposure to cannabis, participated in a double blind, placebo-controlled study of intravenous (IV) placebo or THC at two doses (0.015mg/kg and 0.03mg/kg). Visual analog scale (VAS) was used to measure subjective effects, Psychotomimetic States Inventory (PSI) and the Clinician-Administered Dissociative Symptoms Scale (CADSS) were used to assess the psychotomimetic effects and perceptual alterations, respectively, and Rey Auditory Verbal Learning Task (RAVLT) was used to evaluate cognitive effects. Outcome variables were represented as the peak change from baseline for each variable, except RAVLT which was used only once per the test day after the subjective effects. A total of 42 individuals participated in this study. There were no significant differences between male and female participants in background characteristics. There was a significant main effect of sex on the VAS scores for THC-induced "High" (F1,38 = 4.27, p < 0.05) and a significant dose × sex interaction (F2,77 = 3.38, p < 0.05) with female participants having greater "High" scores than male participants at the lower THC dose (0.015mg/kg). No other sex differences were observed in acute subjective, psychotomimetic, cognitive, or physiological effects of THC. There were significant sex differences in subjective effects of feeling "High" at a lower dose of THC. However, there were no other sex-related differences in the subjective, physiological, or cognitive effects of THC.

The Potential of Salivary Lipid-Based Cannabis-Responsive Biomarkers to Evaluate Medical Cannabis Treatment in Children with Autism Spectrum Disorder.

Introduction: Autism spectrum disorder (ASD) is a group of heterogeneous neurodevelopmental conditions affecting social communication and social interaction. Medical cannabis (MC) treatment shows promising results as an approach to reduce behavioral difficulties, as determined mainly by subjective observations. We have recently shown the potential of cannabis-responsive biomarkers detected in saliva of children with ASD to objectively quantify the impact of successful MC treatment using a metabolomics approach. Since the pathology of ASD is associated with abnormal lipid metabolism, we used lipidomics on the same samples to (1) expand the repertoire of cannabis-responsive biomarkers and (2) provide preliminary insight into the role of MC on lipid metabolism. Materials and Methods: Saliva samples collected from children with ASD (n=15) treated with MC (both before and at the time of maximal impact of treatment) and an age-matched group of typically developing (TD) children (n=9) were subjected to untargeted lipidomics. The study was observational. Each child from the ASD group was receiving a unique individualized MC treatment regimen using off-the-shelf products as permitted by California law under physician supervision for at least 1 year. Doses of tetrahydrocannabinol (THC) ranged from 0.05 to 50 mg and cannabidiol (CBD) from 7.5 to 200 mg per treatment. The ASD group was evaluated for signs of improvement using parental brief Likert scale surveys. Results: Twenty-two potential lipid-based cannabis-responsive biomarkers exhibiting a shift toward the TD physiological levels in children with ASD after MC treatment were identified. Members from all five lipid subclasses known to be present in saliva were characterized. Preliminary lipid association network analysis suggests involvement of two subnetworks previously linked to (1) inflammation and/or redox regulation and (2) oxidative stress. The significant changes in sphingomyelin in this study and in N-acetyl-aspartate (NAA) previously detected in the metabolomics analysis of the same saliva samples may indicate a role of MC in neuron function. Conclusions: Our findings suggest that lipid metabolites in saliva can potentially serve as cannabis-responsive biomarkers and objectively quantify the impact of MC treatment, and indicate a possible mechanism of action for MC. This preliminary study requires further investigation with a larger population and appropriate clinical trial monitoring.

Acute effects of oral delta-9-tetrahydrocannabinol (THC) on autonomic cardiac activity and their relation to subjective and anxiogenic effects.

Cannabis is the most commonly used psychotropic drug in the United States, after alcohol. Despite its apparent sedative and calming effects, cannabis and its main psychoactive constituent, ∆9 -tetrahydrocannabinol (THC) can produce serious adverse effects including tachycardia and anxiety. These effects can be especially pronounced in women, who remain underrepresented in clinical cannabinoid research. The present study is one of the first to characterize the effects of single doses of oral THC on autonomic nervous system function in healthy adult women. Occasional female cannabis users participated in three laboratory sessions in which they received oral THC (7.5 and 15mg) and placebo. Autonomic measures included heart rate (HR), blood pressure (BP), pre-ejection period (PEP) a measure of cardiac sympathetic functioning, and high frequency heart rate variability (HF-HRV) a measure of parasympathetic cardiac control. Autonomic responses were examined in relation to subjective drug effects. THC dose-dependently increased HR, decreased HF-HRV, and increased ratings of feeling a drug effect, cannabis-like intoxication, and anxiety. Although the drug did not significantly affect BP or PEP, HR was negatively related to both PEP and HF-HRV. HF-HRV, the measure of parasympathetic activity, was significantly negatively related to subjective measures of cannabis intoxication (but not anxiety) at the 15mg dose only. PEP was not significantly related to any subjective measure. These results extend our knowledge of the autonomic effects of THC in relation to subjective drug experience. This and future studies will help us to understand risk factors related to cannabis use.

Efficacy of Δ9 -Tetrahydrocannabinol (THC) Alone or in Combination With a 1:1 Ratio of Cannabidiol (CBD) in Reversing the Spatial Learning Deficits in Old Mice.

Decline in cognitive performance, an aspect of the normal aging process, is influenced by the endocannabinoid system (ECS). Cannabinoid receptor 1 (CB1) signaling diminishes with advancing age in specific brain regions that regulate learning and memory and abolishing CB1 receptor signaling accelerates cognitive aging in mice. We recently demonstrated that prolonged exposure to low dose (3 mg/kg/day) Δ9-tetrahydrocannabinol (THC) improved the cognitive performances in old mice on par with young untreated mice. Here we investigated the potential influence of cannabidiol (CBD) on this THC effect, because preclinical and clinical studies indicate that the combination of THC and CBD often exhibits an enhanced therapeutic effect compared to THC alone. We first tested the effectiveness of a lower dose (1 mg/kg/day) THC, and then the efficacy of the combination of THC and CBD in 1:1 ratio, same as in the clinically approved medicine Sativex®. Our findings reveal that a 1 mg/kg/day THC dose still effectively improved spatial learning in aged mice. However, a 1:1 combination of THC and CBD failed to do so. The presence of CBD induced temporal changes in THC metabolism ensuing in a transient elevation of blood THC levels. However, as CBD metabolizes, the inhibitory effect on THC metabolism was alleviated, causing a rapid clearance of THC. Thus, the beneficial effects of THC seemed to wane off more swiftly in the presence of CBD, due to these metabolic effects. The findings indicate that THC-treatment alone is more efficient to improve spatial learning in aged mice than the 1:1 combination of THC and CBD.

Predicting the Potential of Major Cannabinoids and Their Metabolites to Precipitate Cytochrome P450‐mediated Drug Interactions

Background Cannabis products are used for recreational and medicinal purposes. The major cannabinoids, cannabidiol (CBD) and tetrahydrocannabinol (THC), are inhibitors of several cytochromes P450 (CYPs). However, their low aqueous solubility and significant binding to human liver microsomes (HLM)/proteins or labware have not been considered. Moreover, CYP inhibition by their circulating metabolites, 7-OH CBD/7-COOH CBD and 11-OH THC/11-COOH THC, has not been evaluated. We hypothesized that the inhibitory potencies of CBD and THC and their potential to precipitate CYP-mediated drug interactions have been underestimated. Objectives Our objective was to assess potential CYP-mediated cannabinoid-drug interactions using an IVIVE approach. The aims were to determine the following for each cannabinoid and metabolite: 1) binding to HLM proteins, labware, and plasma; 2) unbound reversible CYP inhibitory potency (IC50,u); and 3) unbound time-dependent CYP inhibition (TDI) potency (KI,u) and apparent maximum inactivation rate constant (kinact,app). These data were used to predict the magnitude of cannabinoid-drug interactions for oral or inhaled doses used for recreational or medicinal purposes. Methods Fraction unbound of CBD, THC, or metabolite in incubations containing HLM and BSA (fu,inc) or plasma (fu,p) was determined by ultracentrifugation. IC50,u,KI,u, andkinact,app were estimated by assessing the effect of varying concentrations of CBD, THC, or metabolite on the formation of CYP-mediated metabolites of phenacetin (CYP1A2), coumarin (CYP2A6), bupropion (CYP2B6), amodiaquine (CYP2C8), diclofenac (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and testosterone (CYP3A) using HLM. These data, along with expected intestinal and unbound hepatic inlet (oral dose) or systemic plasma (inhaled dose) concentrations, were used to predict the potential for interactions between typical doses of CBD (700 mg) or THC (20 mg) and drugs predominantly metabolized by these enzymes. Results fu,inc of CBD, 7-OH CBD, and THC was 0.03, 0.02, and 0.13, respectively; corresponding fu,p was 0.01, 0.02, and 0.01. CBD or THC inhibited all the tested CYPs (IC50,u < 0.68 μM). Comparatively, 7-OH CBD or 11-OH THC were less potent inhibitors (IC50,u < 5.3 μM). Both CBD and 7-OH CBD showed TDI of CYP2C19 and CYP3A; CBD showed TDI of CYP1A2. A mechanistic static model predicted in vivo interactions (AUC ratio > 1.4) between CBD and drugs significantly metabolized by CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A. Oral THC was predicted to interact with drugs metabolized by CYP2C9 and 3A (AUC ratio > 1.7), whereas inhaled THC is unlikely to interact with these drugs. CYP inhibition by CBD or THC metabolites had no effect on the predicted magnitude of CBD- or THC-drug interactions. Conclusion This study is the first to consider binding of CBD, THC, and metabolites to microsomal protein and labware to estimate CYP inhibition potential. A clinical study is ongoing to verify our static model predictions of cannabinoid-drug interactions.

Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years: A systematic review and meta-analysis.

Cannabinoid-based medicines (CBMs) are being used widely in the elderly. However, their safety and tolerability in older adults remains unclear. We aimed to conduct a systematic review and meta-analysis of safety and tolerability of CBMs in adults of age ≥50 years. A systematic search was performed using MEDLINE, PubMed, EMBASE, CINAHL PsychInfo, Cochrane Library, and ClinicalTrials.gov (1 January 1990 to 3 October 2020). Randomised clinical trials (RCTs) of CBMs in those with mean age of ≥50 years for all indications, evaluating the safety/tolerability of CBMs where adverse events have been quantified, were included. Study quality was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two reviewers conducted all review stages independently. Where possible, data were pooled using random-effects meta-analysis. Effect sizes were calculated as incident rate ratio (IRR) for outcome data such as adverse events (AEs), serious AEs (SAEs), and death and risk ratio (RR) for withdrawal from study and reported separately for studies using tetrahydrocannabinol (THC), THC:cannabidiol (CBD) combination, and CBD. A total of 46 RCTs were identified as suitable for inclusion of which 31 (67%) were conducted in the United Kingdom and Europe. There were 6,216 patients (mean age 58.6 ± 7.5 years; 51% male) included in the analysis, with 3,469 receiving CBMs. Compared with controls, delta-9-tetrahydrocannabinol (THC)-containing CBMs significantly increased the incidence of all-cause and treatment-related AEs: THC alone (IRR: 1.42 [95% CI, 1.12 to 1.78]) and (IRR: 1.60 [95% CI, 1.26 to 2.04]); THC:CBD combination (IRR: 1.58 [95% CI,1.26 to 1.98]) and (IRR: 1.70 [95% CI,1.24 to 2.33]), respectively. IRRs of SAEs and deaths were not significantly greater under CBMs containing THC with or without CBD. THC:CBD combination (RR: 1.40 [95% CI, 1.08 to 1.80]) but not THC alone (RR: 1.18 [95% CI, 0.89 to 1.57]) significantly increased risk of AE-related withdrawals. CBD alone did not increase the incidence of all-cause AEs (IRR: 1.02 [95% CI, 0.90 to 1.16]) or other outcomes as per qualitative synthesis. AE-related withdrawals were significantly associated with THC dose in THC only [QM (df = 1) = 4.696, p = 0.03] and THC:CBD combination treatment ([QM (df = 1) = 4.554, p = 0.033]. THC-containing CBMs significantly increased incidence of dry mouth, dizziness/light-headedness, and somnolence/drowsiness. Study limitations include inability to fully exclude data from those <50 years of age in our primary analyses as well as limitations related to weaknesses in the included trials particularly incomplete reporting of outcomes and heterogeneity in included studies. This pooled analysis, using data from RCTs with mean participant age ≥50 years, suggests that although THC-containing CBMs are associated with side effects, CBMs in general are safe and acceptable in older adults. However, THC:CBD combinations may be less acceptable in the dose ranges used and their tolerability may be different in adults over 65 or 75 years of age.

Effects of Delta-9 Tetrahydrocannabinol (THC) on Oocyte Competence and Early Embryonic Development.

Recent changes in legal status and public perception of cannabis have contributed to an increase use amongst women of reproductive age. Concurrently, there is inadequate evidence-based knowledge to guide clinical practice regarding cannabis and its effects on fertility and early embryonic development. This study aimed to evaluate the effects of the primary psychoactive component of cannabis, delta-9 tetrahydrocannabinol (THC), during oocyte maturation, and its impact on the developing embryo. Bovine oocytes were matured in vitro for 24 h under clinically relevant doses of THC mimicking plasma levels achieved after therapeutic (0.032 μM) and recreational (0.32 and 3.2 μM) cannabis use. THC-treated oocytes were assessed for development and quality parameters at both the oocyte and embryo level. Characteristics of oocytes treated with cannabinoid receptor antagonists were also assessed. Oocytes treated with 0.32 and 3.2 μM THC, were significantly less likely to reach metaphase II (p < 0.01) and consequently had lower cleavage rates at day 2 post-fertilization (p < 0.0001). Treatment with cannabinoid receptor antagonists restored this effect (p < 0.05). Oocytes that did reach MII showed no differences in spindle morphology. Oocytes treated with 0.032 μM THC had significantly lower connexin mRNA (p < 0.05) (correlated with decreased quality), but this was not confirmed at the protein level. At the blastocyst stage there were no significant differences in developmental rates or the proportion of trophectoderm to inner cell mass cells between the control and treatment groups. These blastocysts, however, displayed an increased level of apoptosis in the 0.32 and 3.2 μM groups (p < 0.0001). Our findings suggest a possible disruptive effect of cannabis on oocyte maturation and early embryonic development.