ArticlePDF AvailableLiterature Review

Acute Effects of a Single, Oral dose of d9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) Administration in Healthy Volunteers

Authors:

Abstract and Figures

Rationale: Animal and humans studies suggest that the two main constituents of cannabis sativa, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have quite different acute effects. However, to date the two compounds have largely been studied separately. Objective: To evaluate and compare the acute pharmacological effects of both THC and CBD in the same human volunteers. Methods: A randomised, double-blind, cross-over, placebo controlled trial was conducted in 16 healthy male subjects. Oral THC 10 mg or CBD 600 mg or placebo was administered in three consecutive sessions, at one-month interval. Physiological measures and symptom ratings were assessed before, and at 1, 2 and 3 hours post drug administration. The area under the curve (AUC) between baseline and 3 hours, and the maximum absolute change from baseline at 2 hours were analysed by one-way repeated measures analysis of variance, with drug condition (THC or CBD or placebo) as the factor. Results: Relative to both placebo and CBD, administration of THC was associated with anxiety, dysphoria, positive psychotic symptoms, physical and mental sedation, subjective intoxication (AUC and effect at 2 hours: p < 0.01), an increase in heart rate (p < 0.05). There were no differences between CBD and placebo on any symptomatic, physiological variable. Conclusions: In healthy volunteers, THC has marked acute behavioural and physiological effects, whereas CBD has proven to be safe and well tolerated.
Content may be subject to copyright.
A preview of the PDF is not available
... Only a few controlled laboratory studies have examined PD outcomes following CBD, balanced D-9-THC and CBD, or minor cannabinoid administration. CBD does not produce D-9-THC-like increases in subjective drug effects or objective intoxication [25], cognitive and psychomotor impairment, or changes in cardiovascular function [30][31][32][33][34]. Furthermore, CBD has been shown to produce anxiolytic effects [35] and reduce the frequency of convulsive seizures [36,37]. ...
... Ingestion of edibles at higher doses (25 mg D-9-THC), but not lower doses (10 mg D-9-THC) also produced impairment of performance on tasks of divided attention, and psychomotor performance [47,101], as well as motor coordination and attention [103]. Finally, ingestion of D-9-THC dominant cannabis also increased physiological measures like heart rate and diastolic blood pressure [30,47,101] and reliably induced orthostatic hypotension [104]. In general, PD effects from cannabis edibles peak 1-5 h after ingestion and persist for about 8 h, though considerable variability across individuals has been observed. ...
... With respect to PD outcomes, oral CBD administration produced no difference from placebo on subjective, cognitive and psychomotor function, and cardiovascular effects at doses ranging from 100 to 900 mg [30,31,34,108,109]. However, one study demonstrated that oral CBD at doses of 1500 mg and 4500 mg produced discriminable subjective drug effects, increasing ratings of drug liking compared to placebo [33]. ...
Full-text available
Article
Purpose of Review With cannabis legalization expanding throughout the world, an unprecedented number of people now have access to legal cannabis. This expanded legalization has also created an extensive retail market that includes a litany of cannabis products, which vary on factors such as chemical profile (i.e., chemotype), formulation, and intended route of administration. Despite increases in cannabis access and product variety, research on the effects of product and user characteristics on drug effect profiles is limited. Recent Findings Controlled laboratory studies are important because they can reveal what factors influence the pharmacokinetic (PK) and pharmacodynamic (PD; e.g., subjective, cognitive, psychological) effects of cannabis and its principal constituents D-9-tetrahydrocannbinol (D-9-THC) and cannabidiol (CBD). In this review, we describe the various product (e.g., chemotype, route of administration) and user factors (e.g., frequency of use, sex, and age) that influence the PK and PD effects of cannabis. Summary Understanding the factors that impact the PK/PD profile of cannabis could be used to promote more consistency in drug effects, as well as cannabinoid delivery for medical purposes. Furthermore, such knowledge is key to informing eventual regulatory actions and dosing guidelines for cannabis products.
... Multiple studies have assessed CBD's impact on anxiety. [31][32][33][34][35][36][37][38][39][40][41][42][43] All studies except one used single dose CBD so the efficacy or safety of chronic therapy is unknown. Most studies enrolled normal volunteers, so their response might be different than responses in people with social anxiety or generalized anxiety disorders. ...
... Most studies enrolled normal volunteers, so their response might be different than responses in people with social anxiety or generalized anxiety disorders. [31][32][33][34][35][36][37][38][39][40][41][42][43] The studies used a range of CBD doses from multiple manufacturers. ...
... In several trials, single dose CBD was given to counteract anxiety induced by single dose THC. [31][32][33][34] While concurrent CBD use seemed beneficial as assessed using two validated anxiety scales, ...
Full-text available
Article
After completing the activity, learners will be able to ● Discuss cannabidiol's known pharmacologic profile ● Identify FDA-approved indications for prescription cannabidiol and other indications in which research is promising ● Distinguish the FDA-approved cannabidiol from various nonprescription products in terms of quality and risk/benefit profile ● Maximize the pharmacist's role in helping patients who are good candidates for prescription cannabidiol or use nonprescription cannabidiol products either with or without other prescription drug therapies After completing the continuing education activity, pharmacy technicians will be able to ● Discuss the basic facts about cannabidiol products ● Acquire reputable sources for patients who have an interest in cannabidiol to find information ● Distinguish between nonprescription and prescription cannabidiols ● Infer when to refer patients to the pharmacist for recommendations or referral
... However, results of in vitro experiments have not been consistent in this regard [8]. In vivo conversion of CBD to THC has only been reported in rats [14], whereas it has not been observed in other in vivo studies in animals and humans [15][16][17][18][19][20]. ...
... Besides these in vitro examinations, Hlozek et al. [14] reported positive findings of THC in serum and brain in rats after administration of CBD. In contrast, there are studies in animals and in man, where conversion of CBD to THC has not been observed at all [15][16][17][18][19][20]. ...
Full-text available
Article
Cannabidiol (CBD) products have ascribed an uprising trend for their health-promoting effects worldwide. In contrast to Δ⁹-tetrahydrocannabinol (THC), CBD exhibits no state of euphoria. Since conversion of CBD into THC in an acidic environment has been reported, it has not been proved whether this degradation will also occur in human gastric fluid. A total of 9 subjects ingested 400 mg CBD as a water-soluble liquid together with lecithin as an emulsifier and ethanol as a solubilizer. Blood samples were taken up to 4 h, and urine samples were submitted up to 48 h. THC, 11-hydroxy-Δ⁹-THC (THC-OH), 11-nor-9-carboxy-Δ⁹-THC (THC-COOH), CBD, 7-hydroxy cannabidiol (7-OH-CBD), and 7-carboxy cannabidiol (7-CBD-COOH) were determined in blood and THC-COOH and 7-CBD-COOH in urine by LC–MS/MS. Neither THC, THC-OH, nor THC-COOH were detectable in any serum specimen. Only two urine samples revealed THC-COOH values slightly above the threshold of 10 ng/ml, which could also be caused by trace amounts of THC being present in the CBD liquid. It can be concluded that negative consequences for participants of a drug testing program due to a conversion of CBD into THC in human gastric fluid appear unlikely, especially considering a single intake of dosages of less than 400 mg. Nevertheless, there is a reasonable risk for consumers of CBD products being tested positive for THC or THC metabolites. However, this is probably not caused by CBD cyclization into THC in human gastric fluid but is most likely due to THC being present as an impurity of CBD products.
... The two main constituents of the Cannabis sativa plant, delta-9 tetrahydrocannabinol (delta-9 THC) and cannabidiol (CBD), have unique clinical and behavioral effects, including experiencing a "high" sensation and tranquility/relaxation [12]. CBD has sedative properties [12] and can reduce the acute psychotic symptoms caused by delta-9 THC [13]. The main psychoactive ingredient of the Cannabis sativa plant, delta-9 THC, is thought to be responsible for the plant's cognitive effects, psychiatric symptoms, and anxiety, as well as for the addictive potential of smoked cannabis [14,15]. ...
... The amount of delta-9 THC found in different countries, cannabis products, and genetic variants varies widely. These chemicals may have opposing effects on regional brain functions, which could explain their opposing symptomatic and behavioral effects, as well as the ability of CBD to block the psychotogenic effects of delta-9 THC [12][13][14][15][16]. Medical cannabis has many potential benefits but also a number of drawbacks. ...
Full-text available
Article
Background and objectives: Cannabinoids are currently used in cancer patients primarily for their pain-relieving and antiemetic properties. The aim of our review was to synthesize all available data of studies evaluating the therapeutic efficacy of cannabis in combination with oncological treatments in cancer patients and to explore ongoing studies with different goals and medical areas registered in the field of oncology worldwide. Materials and methods: This study was performed in accordance with the PRISMA guidelines. A search using MEDLINE/PubMed database was performed between 1 January 2006 and 1 March 2022. Search terms included the following: cannabidiol, cannabis, CBD, dronabinol, endocannabinoids, medical marijuana, nabiximols, nabilone, THC, and cancer. All studies that examined the efficacy of cannabis administered during oncological treatments, regardless of cancer localization, subtype, and sample size, were considered eligible. Results: In three studies, cannabis was administered to patients with glioblastoma, and in two other studies, cannabis was used in combination with immunotherapy in various cancer subgroups. The results of the clinical trials in cancer patients are not sufficient to draw conclusions at this time. Interestingly, several other studies addressing the systemic effects of cannabinoids in cancer patients are currently listed in the U.S. National Library of Medicine's registry on the ClinicalTrials.gov website. However, only one of the registered studies examined the efficacy of cannabinoids as a potential option for systemic cancer treatment. Conclusions: Although cannabis is touted to the public as a cancer cure, clinical trials need to clarify which combinations of chemotherapeutic agents with cannabinoids are useful for cancer patients.
... ASD children were chronically exposed (up to 6 months) to THC (up to 21 mg/day). For comparison, in previous studies, an oral dose of 10 mg of THC acutely induced psychosis in healthy adults (Martin-Santos et al. 2012;Bhattacharyya et al. 2009). The THC exposure during the neurodevelopmental phase may increase the risk of later behavioral sequelae, including cognition, motivation, impulsivity, mood, anxiety, psychosis, intelligence, and psychosocial functioning (Sorkhou et al. 2021). ...
Full-text available
Article
Rationale Autism spectrum disorder (ASD) is defined as a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction, restricted and repetitive patterns of behavior, and varying levels of intellectual disability. ASD is observed in early childhood and is one of the most severe chronic childhood disorders in prevalence, morbidity, and impact on society. It is usually accompanied by attention deficit hyperactivity disorder, anxiety, depression, sleep disorders, and epilepsy. The treatment of ASD has low efficacy, possibly because it has a heterogeneous nature, and its neurobiological basis is not clearly understood. Drugs such as risperidone and aripiprazole are the only two drugs available that are recognized by the Food and Drug Administration, primarily for treating the behavioral symptoms of this disorder. These drugs have limited efficacy and a high potential for inducing undesirable effects, compromising treatment adherence. Therefore, there is great interest in exploring the endocannabinoid system, which modulates the activity of other neurotransmitters, has actions in social behavior and seems to be altered in patients with ASD. Thus, cannabidiol (CBD) emerges as a possible strategy for treating ASD symptoms since it has relevant pharmacological actions on the endocannabinoid system and shows promising results in studies related to disorders in the central nervous system. Objectives Review the preclinical and clinical data supporting CBD’s potential as a treatment for the symptoms and comorbidities associated with ASD, as well as discuss and provide information with the purpose of not trivializing the use of this drug.
... A biphasic effect for THC has been established in both pre-clinical and clinical studies: depending on the dose, THC seems to increase as well as decrease psychological complaints such as anxiety. [63][64][65][66] In this meta-analysis, doses ranging from 1 mg to max 120 mg were investigated. Contrary to THC, CBD attenuates anxiety in both pre-clinical and clinical studies. ...
Full-text available
Article
Background: Cannabinoids have been suggested to alleviate frequently experienced symptoms of reduced mental well-being such as anxiety and depression. Mental well-being is an important subdomain of health-related quality of life (HRQoL). Reducing symptoms and maintaining HRQoL are particularly important in malignant primary brain tumor patients, as treatment options are often noncurative and prognosis remains poor. These patients frequently report unprescribed cannabinoid use, presumably for symptom relieve. As studies on brain tumor patients specifically are lacking, we performed a meta-analysis of the current evidence on can-nabinoid efficacy on HRQoL and mental well-being in oncological and neurological patients. Methods: We performed a systematic PubMed, PsychINFO, Embase, and Web of Science search according to PRISMA guidelines on August 2 and 3, 2021. We included randomized controlled trials (RCTs) that assessed the effects of tetrahydrocannabinol (THC) or cannabidiol (CBD) on general HRQoL and mental well-being. Pooled effect sizes were calculated using Hedges g. Risk of bias of included studies was assessed using Cochrane's Risk of Bias tool. Results: We included 17 studies: 4 in oncology and 13 in central nervous system (CNS) disease. Meta-analysis showed no effect of cannabinoids on general HRQoL (g = À0.02 confidence interval [95% CI À0.11 to 0.06]; p = 0.57) or mental well-being (g = À0.02 [95% CI À0.16 to 0.13]; p = 0.81). Conclusions: RCTs in patients with cancer or CNS disease showed no effect of cannabinoids on HRQoL or mental well-being. However, studies were clinically heterogeneous and since many glioma patients currently frequently use cannabinoids, future studies are necessary to evaluate its value in this specific population.
Article
Background: The popularity of edible cannabis products continues to grow in states with legal cannabis access, but few studies have investigated the acute effects of these commercially available products. The present study sought to explore the effects of three commercially available edible products with different levels of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Methods: A sample of regular cannabis users (N=99) were evaluated. Fifty participants completed the study procedures in-person, whereas 49 participants completed the study procedures remotely via Zoom. Subjective effects and plasma cannabinoid levels (in-person participants only) were assessed before and 2 h after participants self-administered one of three products ad libitum: a THC-dominant edible product, a CBD-dominant edible product, or a THC+CBD edible product. Results: At the 2-h post-use assessment, among in-person participants, plasma THC and CBD levels were robustly correlated with self-reported milligrams of THC and CBD consumed, respectively. Across all three conditions, in-person and remote participants experienced (1) an increase in subjective intoxication and elation, (2) a decrease in tension, and (3) no change in paranoia from pre-use to post-use. At post-use, participants who used a CBD product reported less intoxication relative to participants who used a THC+CBD or THC-only product. Participants who used a THC+CBD product reported consuming less THC-and displayed lower plasma THC levels (in-person participants)-relative to participants who used a THC-only product, despite reporting similar levels of positive (intoxication, elation, liking) and psychotomimetic (paranoia, tension) effects. Psychotomimetic effects were very low among both in-person and remote participants across all three conditions, and there were no post-use differences across conditions. Conclusions: Findings suggest that experienced users who consumed a THC+CBD product reported similar levels of positive and psychotomimetic effects relative to those who consumed a THC-only product, despite consuming less THC and displaying lower plasma THC concentrations. Given the potential harms associated with acute cannabis reward and long-term THC exposure, further research is needed to establish whether edible cannabis products with CBD pose less risk to users. Future studies should examine whether these effects generalize to samples of infrequent users, who may have less experience with edible cannabis use. ClinicalTrials.gov ID: NCT03522103.
Article
Cannabidiol’s (CBD) safety profile and broad action has made it a popular treatment option for anxiety and co-occurring sleep disturbance. However, its efficacy in healthy and clinical populations, treatment duration, formulation and doses for optimal therapeutic benefits remains unclear. Selected databases were examined from inception to October 2022. Study selection, data extraction and Cochrane Risk of Bias assessments were conducted according to PRISMA guidelines and registered on the PROSPERO database (CRD42021247476) with 58 full-text studies meeting the eligibility criteria and administered CBD only or with Δ-9-tetrahydrocannabinol (THC) across healthy and clinical populations. In healthy populations and certain non-cannabis using clinical populations, CBD had greater anxiolytic effects without prominent effects on sleep. An inverted U-shaped dose relationship, and CBD ratio to THC in combined treatments likely moderated these effects. Mechanistically, observed CBD effects occurred via primary modulation of the endocannabinoid system and secondary regulation of neuroendocrine function. Additional research is needed to understand CBD mechanisms of action across diverse groups.
Article
Introduction: Opioid use disorder (OUD) is a major public health crisis worldwide. Patients with OUD inevitably experience withdrawal symptoms when they attempt to taper down on their current opioid use, abstain completely from opioids, or attempt to transition to certain medications for opioid use disorder. Acute opioid withdrawal can be debilitating and include a range of symptoms such as anxiety, pain, insomnia, and gastrointestinal symptoms. Whereas acute opioid withdrawal only lasts for 1-2 weeks, protracted withdrawal symptoms can persist for months after the cessation of opioids. Insufficient management of opioid withdrawal often leads to devastating results including treatment failure, relapse, and overdose. Thus, there is a critical need for cost-effective, nonopioid medications, with minimal side effects to help in the medical management of opioid withdrawal syndrome. We discuss the potential consideration of cannabidiol (CBD), a nonintoxicating component of the cannabis plant, as an adjunctive treatment in managing the opioid withdrawal syndrome. Materials and Methods: A review of the literature was performed using keywords related to CBD and opioid withdrawal syndrome in PubMed and Google Scholar. A total of 144 abstracts were identified, and 41 articles were selected where CBD had been evaluated in clinical studies relevant to opioid withdrawal. Results: CBD has been reported to have several therapeutic properties including anxiolytic, antidepressant, anti-inflammatory, anti-emetic, analgesic, as well as reduction of cue-induced craving for opioids, all of which are highly relevant to opioid withdrawal syndrome. In addition, CBD has been shown in several clinical trials to be a well-tolerated with no significant adverse effects, even when co-administered with a potent opioid agonist. Conclusions: Growing evidence suggests that CBD could potentially be added to the standard opioid detoxification regimen to mitigate acute or protracted opioid withdrawal-related symptoms. However, most existing findings are either based on preclinical studies and/or small clinical trials. Well-designed, prospective, randomized-controlled studies evaluating the effect of CBD on managing opioid withdrawal symptoms are warranted.
Article
Background: Preclinical research suggests that cannabidiol (CBD) may have therapeutic potential in pathological anxiety. Dosing guidelines to inform future human studies are however lacking. Aim: We aimed to predict the therapeutic window for anxiety-reducing effects of CBD in humans based on preclinical models. Methods: We conducted two systematic searches in PubMed and Embase up to August 2021, into pharmacokinetic (PK) and pharmacodynamic (PD) data of systemic CBD exposure in humans and animals, which includes anxiety-reducing and potential side effects. Risk of bias was assessed with SYRCLE's RoB tool and Cochrane RoB 2.0. A control group was an inclusion criterion in outcome studies. In human outcome studies, randomisation was required. We excluded studies that co-administered other substances. We used the IB-de-risk tool for a translational integration of outcomes. Results: We synthesised data from 87 studies. For most observations (70.3%), CBD had no effect on anxiety outcomes. There was no identifiable relation between anxiety outcomes and drug levels across species. In all species (humans, mice, rats), anxiety-reducing effects seemed to be clustered in certain concentration ranges, which differed between species. Discussion: A straightforward dosing recommendation was not possible, given variable concentration-effect relations across species, and no consistent linear effect of CBD on anxiety reduction. Currently, these results raise questions about the broad use as a drug for anxiety. Meta-analytic studies are needed to quantitatively investigate drug efficacy, including aspects of anxiety symptomatology. Acute and (sub)chronic dosing studies with integrated PK and PD outcomes are required for substantiated dose recommendations.
Full-text available
Article
Sativex(®), a cannabis extract oromucosal spray containing Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC's effects, but it is unclear if this is due to a pharmacokinetic and/or pharmacodynamic interaction. Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board-approved study. Participants received 5 and 15 mg synthetic oral THC, low-dose (5.4 mg THC and 5.0 mg CBD) and high-dose (16.2 mg THC and 15.0 mg CBD) Sativex, and placebo over 5 sessions. CBD, THC, 11-hydroxy-THC, and 11-nor- 9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS. Lower limits of quantification were ≤0.25 μg/L. Nine cannabis smokers completed all 5 dosing sessions. Significant differences (P < 0.05) in maximum plasma concentrations (C(max)) and areas under the curve from 0-10.5 h postdose (AUC(0→10.5)) for all analytes were found between low and high doses of synthetic THC and Sativex. There were no statistically significant differences in C(max), time to maximum concentration or in the AUC(0→10.5) between similar oral THC and Sativex doses. Relative bioavailability was calculated to determine the relative rate and extent of THC absorption; 5 and 15 mg oral THC bioavailability was 92.6% (13.1%) and 98.8% (11.0%) of low- and high-dose Sativex, respectively. These data suggest that CBD modulation of THC's effects is not due to a pharmacokinetic interaction at these therapeutic doses.
Article
The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by ?9-TCH in normal volunteers, and whether this effect occurs by a general block of the action of ?9-TCH or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg ?9-TCH, 1 mg/kg CBD, a mixture containing 0.5 mg/kg ?9-TCH and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by ?9-TCH, however this effect also extended to marihuanalike effects and to other subjective alterations induced by ?9-TCH. This antagonism does not appear to be caused by a general block of ?9-TCH effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of ?9-TCH.
Article
The pharmacological interaction between cannabidiol (CBD) and (−)δ 9-trans-tetrahydrocannabinol (δ 9-THC) has been studied in rabbits, mice and rats by administering mixtures containing varying amounts of both substances. CBD blocked the following effects of δ 9-THC: catatonia in mice, corneal areflexia in rabbits, the increased defecation and decreased ambulation after chronic treatment and exposures of rats in an open field arena, and the aggressiveness of rats previously stressed by REM sleep deprivation. On the other hand, CBD potentiated the δ 9-THC-induced analgesia in mice and the δ 9-THC-impairing effect on climbing rope performance of rats. These interactions are tentatively explained by postulating that CBD directly antagonizes the excitatory effects and/or indirectly potentiates the depressant effects of δ 9-THC.
Article
A dose-response study of the effect of orally administered Δ9-tetrahydrocannabinol (THC) on human mood and skills performance was conducted. Using five dose levels of THC (0, 5, 10, 15, 20 mg) with 16 volunteers per dosage group, mood and performance measures were recorded at five testing occasions, one before and four after drug administration. The slope of the linear regression of performance on the test battery was significant for up to 200 minutes after dosage. That is to say, oral THC, at the doses used, produced significant dose-dependent impairment of performance for a period in excess of three hours. A similar time course for the effect of THC on the subjective assessment of intoxication (‘stone’) suggested a correlation between drug-induced impairment skills and the effects on mood.
Article
Synopsis The reliability and validity of the Visual Analogue Mood Scale (VAMS) has been demonstrated in both a military and a private psychiatric hospital, inpatient population. The repeated and concurrent administration of the VAMS and the Digit-Symbol test identifies a mood-performance correlation which distinguishes patients with affective disorders, of manic or depressed type, from other psychiatric patients.