Cannabidiol Increases Psychotropic Effects and Plasma Concentrations of Δ9-Tetrahydrocannabinol Without Improving Its Analgesic Properties.

Cannabidiol (CBD), the main non-intoxicating compound in cannabis, has been hypothesized to reduce the adverse effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive and analgesic component of cannabis. This clinical trial investigated the hypothesis that CBD counteracts the adverse effects of THC and thereby potentially improves the tolerability of cannabis as an analgesic. A randomized, double-blind, placebo-controlled, five-way cross-over trial was performed in 37 healthy volunteers. On each visit, a double-placebo, THC 9 mg with placebo CBD, or THC 9 mg with 10, 30, or 450 mg CBD was administered orally. Psychoactive and analgesic effects were quantified using standardized test batteries. Pharmacokinetic sampling was performed. Data were analyzed using mixed-effects model. Co-administration of 450 mg CBD did not reduce, but instead significantly increased subjective, psychomotor, cognitive, and autonomous effects of THC (e.g., VAS "Feeling High" by 60.5% (95% CI: 12.7%, 128.5%, P < 0.01)), whereas THC effects with 10 and 30 mg CBD were not significantly different from THC alone. CBD did not significantly enhance THC analgesia at any dose level. Administration of 450 mg CBD significantly increased AUClast of THC (AUClast ratio: 2.18, 95% CI: 1.54, 3.08, P < 0.0001) and 11-OH-THC (AUClast ratio: 6.24, 95% CI: 4.27, 9.12, P < 0.0001) compared with THC alone, and 30 mg CBD significantly increased AUClast of 11-OH-THC (AUClast ratio: 1.89, 95% CI: 1.30, 2.77, P = 0.0013), and of THC (AUClast ratio: 1.44, 95% CI: 1.01, 2.04, P = 0.0446). Present findings do not support the use of CBD to reduce adverse effects of oral THC or enhance THC analgesia.

Tolerability of High-Dose Oral Δ9-THC: Implications for Human Laboratory Study Design.

Background: Δ9-tetrahydrocannabinol (THC), the primary intoxicating compound in cannabis, has been tested extensively in controlled administration human studies. Some studies require a high THC dose that may induce adverse events (AEs), such as those testing novel treatments for cannabinoid overdose. Although there are ethical concerns related to administering high THC doses, there is no systematic analysis on studies utilizing these doses. In this review, we examine studies that administered oral THC doses ≥30 mg ("high-dose THC"), focusing on reported tolerability, subjective effects, and pharmacokinetics (PK), with the objective to inform the design of future studies. Methods: A comprehensive PubMed search was performed to identify studies meeting pre-specified criteria. Results: Our search identified 27 publications from 17 high-dose oral THC laboratory studies, with single doses up to 90 mg and multiple doses up to 210 mg per day. The maximum plasma THC concentration (Cmax) appeared to increase in a dose-proportional manner over this dose range. All high-dose THC studies enrolled participants with previous cannabis experience, although current use ranged from nonusers to regular cannabis users. High-dose THC was generally well tolerated with transient mild to moderate AE, including nausea and vomiting, anxiety, paranoia, and sedation. There were occasional participant withdrawals due to AEs, but there were no serious AE. Participants with frequent cannabis use tolerated high-dose THC best. Conclusion: Although based on limited data, THC was generally adequately tolerated with single oral doses of at least 50 mg in a controlled laboratory setting in healthy participants with past cannabis experience.

Pharmacokinetics of Two Nanoemulsion Formulations of Δ8-Tetrahydrocannabinol in Rats.

The use of Δ8-tetrahydrocannabinol (Δ8-THC) has increased in recent years. Given that the oral absorption of cannabinoids in oil formulations is typically slow and variable, nanoemulsions may be an improved delivery vehicle. Therefore, we characterized the pharmacokinetics (PK) in Sprague-Dawley rats following the administration of three different oral formulations containing 10 mg/kg Δ8-THC: a translucent liquid nanoemulsion, a reconstituted powder nanoemulsion, and a medium chain triglyceride (MCT) oil solution for comparison. Δ8-THC was also administered intravenously at 0.6 mg/kg. Plasma samples were quantified for Δ8-THC and two metabolites, 11-hydroxy-Δ8-THC (11-OH-Δ8-THC) and 11-carboxy-Δ8-THC (COOH-Δ8-THC). Non-compartmental PK parameters were calculated, and a PK model was developed based on pooled data. Despite a smaller median droplet size of the translucent liquid nanoemulsion (26.9 nm) compared to the reconstituted powder nanoemulsion (168 nm), the PK was similar for both. The median Tmax values of Δ8-THC for the nanoemulsions (0.667 and 1 h) were significantly shorter than the median Tmax of Δ8-THC in MCT oil (6 h). This resulted in an approximately 4-fold higher Δ8-THC exposure over the first 4 h for the nanoemulsions relative to the MCT oil solution. The active 11-OH-Δ8-THC metabolite followed a similar pattern to Δ8-THC. The non-compartmental bioavailability estimates of Δ8-THC for the nanoemulsions (11-16.5%) were lower than for the MCT oil solution (>21.5%). However, a model-based analysis indicated similar bioavailability for all three oral formulations. These results demonstrate favorable absorption properties of both nanoemulsions, despite the difference in droplet sizes, compared to an MCT oil formulation.

The risk of chronic psychedelic and MDMA microdosing for valvular heart disease.

Psychedelic microdosing is the practice of taking very low doses of psychedelic substances, typically over a longer period of time. The long-term safety of chronic microdosing is relatively uncharacterized, but valvular heart disease (VHD) has been proposed as a potential risk due to activation of the serotonin 5-HT2B receptor. However, this risk has not yet been comprehensively assessed. This analysis searched for all relevant in vitro, animal, and clinical studies related to the VHD risk of lysergic acid diethylamide (LSD), psilocybin, mescaline, N,N-dimethyltryptamine (DMT), and the non-psychedelic 3,4-methylenedioxymethamphetamine (MDMA). All five compounds and some metabolites could bind to the 5-HT2B receptor with potency equal to or greater than that of the 5-HT2A receptor, the primary target of psychedelics. All compounds were partial agonists at the 5-HT2B receptor with the exception of mescaline, which could not be adequately assessed due to low potency. Safety margins relative to the maximum plasma concentrations from typical microdoses were greater than known valvulopathogens, but not without potential risk. No animal or clinical studies appropriately designed to evaluate VHD risk were found for the four psychedelics. However, there is some clinical evidence that chronic ingestion of full doses of MDMA is associated with VHD. We conclude that VHD is a potential risk with chronic psychedelic microdosing, but further studies are necessary to better define this risk.

Review of delta-8-tetrahydrocannabinol (Δ8 -THC): Comparative pharmacology with Δ9 -THC.

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.

A Brief Background on Cannabis: From Plant to Medical Indications.

Cannabis has been used as a medicinal plant for thousands of years. As a result of centuries of breeding and selection, there are now over 700 varieties of cannabis that contain hundreds of compounds, including cannabinoids and terpenes. Cannabinoids are fatty compounds that are the main biological active constituents of cannabis. Terpenes are volatile compounds that occur in many plants and have distinct odors. Cannabinoids exert their effect on the body by binding to receptors, specifically cannabinoid receptors types 1 and 2. These receptors, together with endogenous cannabinoids and the systems for synthesis, transport, and degradation, are called the Endocannabinoid System. The two most prevalent and commonly known cannabinoids in the cannabis plant are delta-9-tetrahydrocannabinol (THC) and cannabidiol. The speed, strength, and type of effects of cannabis vary based on the route of administration. THC is rapidly distributed through the body to fatty tissues like the brain and is metabolized by the cytochrome P450 system to 11-hydroxy-THC, which is also psychoactive. Cannabis and cannabinoids have been indicated for several medical conditions. There is evidence of efficacy in the symptomatic treatment of nausea and vomiting, pain, insomnia, post-traumatic stress disorder, anxiety, loss of appetite, Tourette's syndrome, and epilepsy. Cannabis has also been associated with treatment for glaucoma, Huntington's Disease, Parkinson's Disease, and dystonia, but there is not good evidence to support its efficacy. Side effects of cannabis include psychosis and anxiety, which can be severe. Here, we provided a summary of the history of cannabis, its pharmacology, and its medical uses.

Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on Δ(9)-tetrahydrocannabinol challenge tests.

AIM: The severe psychiatric side effects of cannabinoid receptor type 1 (CB1 ) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of different CB1 antagonists in Δ(9) -tetrahydrocannabinol (THC) challenge tests in healthy volunteer were constructed. METHODS: The pharmacokinetic models of THC and four CB1 antagonists were built separately. THC-induced effects on heart rate and the visual analogue scale of feeling high in healthy volunteers and inhibitive effects of CB1 antagonists on THC-induced effects were modelled in PD models linked to the PK models. Simulations were then applied to evaluate the reduction rate of each antagonist on the reversal of the THC-induced effect in a unified simulation scenario. RESULTS: The final PK model of THC and antagonists was a two compartment model. An Emax model and logistic regression model were used for effect measures and the antagonist effect was added in these models in a competitive binding manner. t1/2ke0 ranged from 0.00462 to 63.7 h for heart rate and from 0.964 to 150 h for VAS. IC50 ranged from 6.42 to 202 ng ml(-1) for heart rate and from 12.1 to 376 ng ml(-1) for VAS. Benchmark simulation showed different dose-efficacy profiles of two efficacy measures for each CB1 antagonist. CONCLUSIONS: PK/PD modelling and simulation approach was suitable for describing and predicting heart rate and feeling high for CB1 antagonists in THC challenge tests. Direct comparison of four antagonists based on simulated efficacy profiles might be of benefit to guide future studies.

Peripheral selectivity of the novel cannabinoid receptor antagonist TM38837 in healthy subjects.

AIM: Cannabinoid receptor type 1 (CB1 ) antagonists show central side effects, whereas beneficial effects are most likely peripherally mediated. In this study, the peripherally selective CB1 antagonist TM38837 was studied in humans. METHODS: This was a double-blind, randomized, placebo-controlled, crossover study. On occasions 1-4, 24 healthy subjects received 5 × 4 mg THC with TM38837 100 mg, 500 mg or placebo, or placebos only. During occasion 5, subjects received placebo TM38837 + THC with rimonabant 60 mg or placebo in parallel groups. Blood collections and pharmacodynamic (PD) effects were assessed frequently. Pharmacokinetics (PK) and PD were quantified using population PK-PD modelling. RESULTS: The TM38837 plasma concentration profile was relatively flat compared with rimonabant. TM38837 showed an estimated terminal half-life of 771 h. THC induced effects on VAS feeling high, body sway and heart rate were partly antagonized by rimonabant 60 mg [-26.70% [90% confidence interval (CI) -40.9, -12.6%]; -7.10%, (90%CI -18.1, 5.3%); -7.30%, (90% CI -11.5%, -3.0%) respectively] and TM38837 500 mg [-22.10% (90% CI -34.9, -9.4%); -12.20% (90% CI -21.6%, -1.7%); -8.90% (90% CI -12.8%, -5.1%) respectively]. TM38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects. CONCLUSIONS: Rimonabant showed larger effects than TM38837, but the heart rate effects were similar. TM38837 100 mg had no impact on CNS effects, suggesting that this dose does not penetrate the brain. This TM38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models. These results provide support for further development of TM38837 as a peripherally selective CB1 antagonist for indications such as metabolic disorders, with a reduced propensity for psychiatric side effects.

Surinabant, a selective cannabinoid receptor type 1 antagonist, inhibits Δ9-tetrahydrocannabinol-induced central nervous system and heart rate effects in humans.

AIM: Cannabinoid receptor type 1 (CB1 ) antagonists have been developed for the treatment of obesity and associated risk factors. Surinabant is a high affinity CB1 antagonist in vitro. The aim of this study was to assess the magnitude of inhibition by surinabant of CNS effects and heart rate induced by Δ(9) -tetrahydrocannabinol (THC) in humans. METHODS: This was a double-blind, placebo-controlled, randomized, four period six sequence crossover study. Thirty healthy young male occasional cannabis users (<1 per week) were included. A single oral dose of surinabant (5, 20 or 60 mg) or placebo was administered followed 1.5 h later by four intrapulmonary THC doses (2, 4, 6 and 6 mg) or vehicle, administered at 1 h intervals. The wash-out period was 14-21 days. Subjective and objective pharmacodynamic (PD) measurements were performed. A population PK-PD model for THC and surinabant quantified PK and PD effects. RESULTS: Surinabant 20 and 60 mg inhibited all THC-induced PD effects in a similar range for both doses with inhibition ratios ranging from 68.3% (95% CI = 32.5, 104.2; heart rate) to 91.1% (95% CI = 30.3, 151.8; body sway). IC50 ranged from 22.0 ng ml(-1) [relative standard error (RSE) = 45.2%; body sway] to 58.8 ng ml(-1) (RSE = 44.2%; internal perception). Surinabant 5 mg demonstrated no significant effects. CONCLUSIONS: The dose-related inhibition by surinabant, without any effect of its own, suggests that this compound behaves as a CB1 receptor antagonist in humans at these concentrations. A single surinabant dose between 5 to 20 mg and above was able to antagonize THC-induced effects in humans.

Manipulating brain connectivity with δ9-tetrahydrocannabinol: a pharmacological resting state FMRI study.

Resting state-functional magnetic resonance imaging (RS-FMRI) is a neuroimaging technique that allows repeated assessments of functional connectivity in resting state. While task-related FMRI is limited to indirectly measured drug effects in areas affected by the task, resting state can show direct CNS effects across all brain networks. Hence, RS-FMRI could be an objective measure for compounds affecting the CNS. Several studies on the effects of cannabinoid receptor type 1 (CB(1))-receptor agonist δ(9)-tetrahydrocannabinol (THC) on task-dependent FMRI have been performed. However, no studies on the effects of cannabinoids on resting state networks using RS-FMRI have been published. Therefore, we investigated the effects of THC on functional brain connectivity using RS-FMRI. Twelve healthy volunteers (9 male, 3 female) inhaled 2, 6 and 6 mg THC or placebo with 90-minute intervals in a randomized, double blind, cross-over trial. Eight RS-FMRI scans of 8 min were obtained per occasion. Subjects rated subjective psychedelic effects on a visual analog scale after each scan, as pharmacodynamic effect measures. Drug-induced effects on functional connectivity were examined using dual regression with FSL software (FMRIB Analysis Group, Oxford). Eight maps of voxel-wise connectivity throughout the entire brain were provided per RS-FMRI series with eight predefined resting-state networks of interest. These maps were used in a mixed effects model group analysis to determine brain regions with a statistically significant drug-by-time interaction. Statistical images were cluster-corrected, and results were Bonferroni-corrected across multiple contrasts. THC administration increased functional connectivity in the sensorimotor network, and was associated with dissociable lateralized connectivity changes in the right and left dorsal visual stream networks. The brain regions showing connectivity changes included the cerebellum and dorsal frontal cortical regions. Clear increases were found for feeling high, external perception, heart rate and cortisol, whereas prolactin decreased. This study shows that THC induces both increases and (to a lesser extent) decreases in functional brain connectivity, mainly in brain regions with high densities of CB(1)-receptors. Some of the involved regions could be functionally related to robust THC-induced CNS-effects that have been found in previous studies (Zuurman et al., 2008), such as postural stability, feeling high and altered time perception.

Novel Δ(9) -tetrahydrocannabinol formulation Namisol® has beneficial pharmacokinetics and promising pharmacodynamic effects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Cannabis based medicines are registered as a treatment for various indications, such as pain and spasms in multiple sclerosis (MS) patients, and anorexia and nausea in patients with HIV or receiving cancer treatment. • the pharmacokinetics of the various administration routes of cannabis and cannabis based medicines are variable and dosing is hard to regulate. WHAT THIS STUDY ADDS: • Namisol is a new tablet containing pure THC (>98%) that has a beneficial pharmacokinetic profile after oral administration. • Namisol gives a quick onset of pharmacodynamic effects in healthy volunteers, which implies a rapid initiation of therapeutic effects in patients. AIMS: Among the main disadvantages of currently available Δ(9) -tetrahydrocannabinol (THC) formulations are dosing difficulties due to poor pharmacokinetic characteristics. Namisol® is a novel THC formulation, designed to improve THC absorption. The study objectives were to investigate the optimal administration route, pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of Namisol®. METHODS: This first in human study consisted of two parts. Panel I included healthy males and females (n = 6/6) in a double-blind, double-dummy, randomized, crossover study with sublingual (crushed tablet) and oral administration of Namisol® (5 mg THC). Based on these results, male and female (n = 4/5) participants from panel I received oral THC 6.5 and 8.0 mg or matching placebo in a randomized, crossover, rising dose study during panel II. PD measurements were body sway; visual analogue scales (VAS) mood, psychedelic and heart rate. THC and 11-OH-THC population PK analysis was performed. RESULTS: Sublingual administration showed a flat concentration profile compared with oral administration. Oral THC apparent t(1/2) was 72-80 min, t(max) was 39-56 min and C(max) 2.92-4.69 ng ml(-1) . THC affected body sway (60.8%, 95% CI 29.5, 99.8), external perception (0.078 log mm, 95% CI 0.019, 0.137), alertness (-2.7 mm, 95% CI -4.5, -0.9) feeling high (0.256 log mm, 95% CI 0.093, 0.418) and heart rate (5.6 beats min(-1) , 95% CI 2.7, 6.5). Namisol® was well tolerated. CONCLUSIONS: Oral Namisol® showed promising PK and PD characteristics. Variability and t(max) of THC plasma concentrations were smaller for Namisol® than reported for studies using oral dronabinol and nabilone. This study was performed in a limited number of healthy volunteers. Therefore, future research on Namisol® should study clinical effects in patient populations.