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The actions of CBD on anxiety and other effects produced by Δ1-THC in normal subjects
Abstract
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.
... The first clinical evidence that CBD reduces the stress response was from the studies of CBD's ability to reduce the adverse effects of THC in healthy volunteers [94,95]. THC is known to induce stress in healthy people as demonstrated by an increase in cortisol and transient anxiety-like behavior in people with no anxiety disorders [13]. ...
... Karniol et al. reported that a single dose of CBD of 15-60 mg significantly reduced THC-induced anxiety, and CBD doses of 30-60 mg significantly reduced THC-induced tachycardia, which like anxiety is part of the stress response [94]. These results were supported by Zuardi et al. (1982), who showed that a single CBD dose of 1 mg/kg (50-80 mg; average of 67 mg) significantly lowered THC-induced anxiety as measured by the State-Trait Anxiety Inventory (STAI) [95]. In both studies, CBD alone did not change the pulse rate or anxiety levels, indicating that its effects were stress specific [94,95]. ...
... Karniol et al. reported that a single dose of CBD of 15-60 mg significantly reduced THC-induced anxiety, and CBD doses of 30-60 mg significantly reduced THC-induced tachycardia, which like anxiety is part of the stress response [94]. These results were supported by Zuardi et al. (1982), who showed that a single CBD dose of 1 mg/kg (50-80 mg; average of 67 mg) significantly lowered THC-induced anxiety as measured by the State-Trait Anxiety Inventory (STAI) [95]. In both studies, CBD alone did not change the pulse rate or anxiety levels, indicating that its effects were stress specific [94,95]. ...
The stress response is a well-defined physiological function activated frequently by life events. However, sometimes the stress response can be inappropriate, excessive, or prolonged; in which case, it can hinder rather than help in coping with the stressor, impair normal functioning, and increase the risk of somatic and mental health disorders. There is a need for a more effective and safe pharmacological treatment that can dampen maladaptive stress responses. The endocannabinoid system is one of the main regulators of the stress response. A basal endocannabinoid tone inhibits the stress response, modulation of this tone permits/curtails an active stress response, and chronic deficiency in the endocannabinoid tone is associated with the pathological complications of chronic stress. Cannabidiol is a safe exogenous cannabinoid enhancer of the endocannabinoid system that could be a useful treatment for stress. There have been seven double-blind placebo controlled clinical trials of CBD for stress on a combined total of 232 participants and one partially controlled study on 120 participants. All showed that CBD was effective in significantly reducing the stress response and was non-inferior to pharmaceutical comparators, when included. The clinical trial results are supported by the established mechanisms of action of CBD (including increased N-arachidonylethanolamine levels) and extensive real-world and preclinical evidence of the effectiveness of CBD for treating stress.
... As a result, studies on CBD lagged. However, in the 1980s, a plethora of work emerged highlighting its therapeutic potential, and CBD research accelerated [5][6][7][8][9]. Many of these papers focused on the anxiolytic [5], antiepileptic [6,7], anti-convulsive [8], and anti-psychotic [5,9] effects of CBD treatment. ...
... However, in the 1980s, a plethora of work emerged highlighting its therapeutic potential, and CBD research accelerated [5][6][7][8][9]. Many of these papers focused on the anxiolytic [5], antiepileptic [6,7], anti-convulsive [8], and anti-psychotic [5,9] effects of CBD treatment. ...
... However, in the 1980s, a plethora of work emerged highlighting its therapeutic potential, and CBD research accelerated [5][6][7][8][9]. Many of these papers focused on the anxiolytic [5], antiepileptic [6,7], anti-convulsive [8], and anti-psychotic [5,9] effects of CBD treatment. ...
Cannabidiol (CBD) is part of a group of phytocannabinoids derived from Cannabissativa. Initial work on CBD presumed the compound was inactive, but it was later found to exhibit antipsychotic, anti-depressive, anxiolytic, and antiepileptic effects. In recent decades, evidence has indicated a role for CBD in the modulation of mitochondrial processes, including respiration and bioenergetics, mitochondrial DNA epigenetics, intrinsic apoptosis, the regulation of mitochondrial and intracellular calcium concentrations, mitochondrial fission, fusion and biogenesis, and mitochondrial ferritin concentration and mitochondrial monoamine oxidase activity regulation. Despite these advances, current data demonstrate contradictory findings with regard to not only the magnitude of effects mediated by CBD, but also to the direction of effects. For example, there are data indicating that CBD treatment can increase, decrease, or have no significant effect on intrinsic apoptosis. Differences between studies in cell type, cell-specific response to CBD, and, in some cases, dose of CBD may help to explain differences in outcomes. Most studies on CBD and mitochondria have utilized treatment concentrations that exceed the highest recorded plasma concentrations in humans, suggesting that future studies should focus on CBD treatments within a range observed in pharmacokinetic studies. This review focuses on understanding the mechanisms of CBD-mediated regulation of mitochondrial functions, with an emphasis on findings in neural cells and tissues and therapeutic relevance based on human pharmacokinetics.
... CBD is known to interact with 5HT 1A and 5HT 2A receptors subtypes in the basal ganglia to ameliorate the EPS induced by D 2 receptor occupation 84,85 . CBD also influences phosphoinositide metabolism stimulated by activation of muscarinic receptors 86 . These factors may explain the effects of CBD in our experiment. ...
... This contrasts with a study which showed that risperidone at low dose induced an anxiolytic effect 87 . CBD at a higher dose than what we used in this study has reported anxiolytic effects 47,86 . We may not have observed an anxiolytic effect of different combinations of risperidone and CBD in our work because of the relatively low dose of CBD and high dose of risperidone. ...
Atypical antipsychotics, despite their rapid dissociation from dopamine receptors and reduced tendency to induce oxidative stress, have been associated with difficult-to-manage movement disorders, including tardive dyskinesia (TD). The study set out to investigate the effects of cannabidiol (CBD), a potent antioxidant, on risperidone-induced behavioural and motor disturbances; namely vacuous chewing movements (VCM), and oxidative stress markers (e.g. superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), malondialdehyde (MDA), Nitric oxide (NO), and DPPH (2,2-diphenyl-1-picrylhydrazyl)). Oral risperidone (10 mg/kg) or oral CBD (5 mg/kg) were administered to six experimental groups. While risperidone alone was administered for 28 days, CBD concomitantly or in sequential order with risperidone, was administered for 28 days; and CBD alone was administered for 21 days. Behavioural, motor, and specific biochemical parameters, which included VCM, muscle tone, fasting blood sugar (FBS), and oxidative stress markers were assessed at different time points after the last dose of medication. Oral CBD (5 mg/kg) significantly reduced risperidone-induced elevated FBS when given after the administration of risperidone. Oral CBD also had effects on VCM when administered before risperidone and similarly, attenuated risperidone-induced increased muscle tone. It was also established that concomitant or sequential administration of CBD and risperidone did not have any adverse effects on cognition or locomotion. Both CBD and risperidone increased the activity of antioxidant enzymes and decreased the activity of pro-oxidant enzymes. This study suggests CBD could mitigate metabolic dysregulation and extrapyramidal side effects associated with risperidone without producing cognitive impairments.
... monomers. As for cannabinoids, they can be also classified as terpenophenolic compounds, which are biosynthesized from the phenolic acid, olivetolitic acid and the monoterpene geranylpyrophosphate. Until now, more than 100 phytocannabinoids have been identified, most of them have demonstrated potential benefits, such as antiepileptic, analgesic, neuroprotective and anticonvulsant efficacy (Harris et al., 2016;Reddy, 2016;Yamaori et al., 2011;Zuardi et al., 1982). In particular, due to the larger number of cannabinoids involved in real samples, the fast and sustainable approach reported in the previous section can be considered just preliminary and an untargeted characterization is needed, by exploiting the MS signals for the identification of unknown peaks for which commercial standards are not available. ...
... While previous reports of THC-CBD synergy demonstrated reduced tumor growth [39,48,49], some studies suggested combining THC with CBD mainly modulated the adverse effects of THC [13,50,51]. This research points out CBD as the main API, and combining it with either CBC or THC at a ratio of 2:1 maximizes the cytotoxicity on HNSCC cells. ...
Cannabis sativa plants have a wide diversity in their metabolite composition among their different chemovars, facilitating diverse anti-tumoral effects on cancer cells. This research examined the anti-tumoral effects of 24 cannabis extracts representative of three primary types of chemovars on head and neck squamous cell carcinoma (HNSCC). The chemical composition of the extracts was determined using High-Performance Liquid Chromatography (HPLC) and Mass Spectrometry (MS). The most potent anti-tumoral extracts were type III decarboxylated extracts, with high levels of Cannabidiol (CBD). We identified extract 296 (CAN296) as the most potent in inducing HNSCC cell death via proapoptotic and anti-proliferative effects. Using chemical fractionation of CAN296, we identified the CBD fraction as the primary inducer of the anti-tumoral activity. We succeeded in defining the combination of CBD with cannabichromene (CBC) or tetrahydrocannabinol (THC) present in minute concentrations in the extract, yielding a synergic impact that mimics the extract’s full effect. The cytotoxic effect could be maximized by combining CBD with either CBC or THC in a ratio of 2:1. This research suggests using decarboxylated CBD-type extracts enriched with CBC for future preclinical trials aimed at HNSCC treatment.
... An allosteric binding activity of CBD on these two receptors has been reported, resulting in CBD binding to CB1 as an inverse agonist/antagonist and CB2 as an antagonist [14,30,33,34]. In line with that, preclinical and clinical evidence indicates that CBD not only lacks abuse potential but it also attenuates the psychotomimetic and anxiogenic effects induced by THC [35,36]. ...
Cannabidiol (CBD) is a non-psychotomimetic compound present in cannabis sativa. Many recent studies have indicated that CBD has a promising therapeutic profile for stress-related psychiatric disorders, such as anxiety, schizophrenia and depression. Such a diverse profile has been associated with its complex pharmacology, since CBD can target different neurotransmitter receptors, enzymes, transporters and ion channels. However, the precise contribution of each of those mechanisms for CBD effects is still not yet completely understood. Considering that epigenetic changes make the bridge between gene expression and environment interactions, we review and discuss herein how CBD affects one of the main epigenetic mechanisms associated with the development of stress-related psychiatric disorders: DNA methylation (DNAm). Evidence from in vivo and in silico studies indicate that CBD can regulate the activity of the enzymes responsible for DNAm, due to directly binding to the enzymes and/or by indirectly regulating their activities as a consequence of neurotransmitter-mediated signaling. The implications of this new potential pharmacological target for CBD are discussed in light of its therapeutic and neurodevelopmental effects.
... The human literature has diverged from preclinical findings -as well as epidemiological and consumer survey data -in reporting exclusively anxiogenic effects of THC administration [14••]. Nonetheless, some data suggest that the anxiogenic effects of THC may be blunted among regular cannabis users [21], and when THC is co-administered with CBD [22]. ...
Purpose of Review
In the context of ongoing decriminalization and legalization of cannabis, a better understanding of how THC and CBD impact anxiety is critical to elucidate the risks of recreational cannabis use as well as to establish the therapeutic potential of cannabis products for anxiety-related applications.
Recent Findings
Recent literature supports anxiogenic effects of THC administration, which may be attenuated among regular cannabis users. Data regarding anxiolytic effects of CBD administration are mixed. Most newer studies contradict earlier findings in reporting no effects of CBD on anxiety in healthy participants, whereas inconsistent results have been reported among individuals with anxiety disorders, substance use disorders, and other clinical populations.
Summary
Future research is needed to reconcile heterogenous findings, explore sex differences in the effects of THC and CBD on anxiety, and to assess how effects change with extended exposure; the impact of different CBD doses, and the interactions between THC, CBD, and other cannabis compounds.
... Cannabidiol (CBD) is one of the most abundant phytocannabinoids present in the Cannabis sativa plant, devoid of psychotomimetic effects [1]. In addition, CBD antagonizes several of the psychoactive effects of the ∆9-tetrahydrocannabinol (∆9-THC), the major psychoactive compound of Cannabis sativa [2,3]. CBD exhibits a broad-spectrum pharmacological profile that makes it a potential treatment for several psychiatric and neurodegenerative disorders [4,5]. ...
Cannabidiol (CBD) is a phytocannabinoid contained in the Cannabis sativa plant, devoid of psychotomimetic effects but with a broad-spectrum pharmacological activity. Because of its pharmacological profile and its ability to counteract the psychoactive Δ9-tetrahydrocannabinol (Δ9THC), CBD may be a potential treatment for several psychiatric and neurodegenerative disorders. In this study, we performed a doseresponse evaluation of CBD modulatory effects on BDNF, a neurotrophin subserving pleiotropic effects on the brain, focusing on the cortico-striatal pathway for its unique role in the brain trafficking of BDNF. Male adult rats were exposed to single and repeated CBD treatments at different dosing regimen (5, 15, and 30 mg/kg), to investigate the rapid modulation of the neurotrophin (1 h after the single treatment) as well as a potential drug-free time point (24 h after the repeated treatment). We show here, for the first time, that CBD can be found in the rat brain and, specifically, in the medial prefrontal cortex (mPFC) following single or repeated exposure. In fact, we found that CBD is present in the mPFC of rats treated either acutely or repeatedly with the phytocannabinoid, with a clear doseresponse profile. From a molecular standpoint, we found that single, but not repeated, CBD exposure upregulates BDNF in the mPFC, while the repeated exposure increased BDNF only in the striatum, with a slight decrease in the mPFC. Together, these data reveal a CBD dose-dependent and anatomically specific modulation of BDNF, which may be functionally relevant and may represent an added value for CBD as a supplement.
... Interestingly, several studies that examined the pharmacological characteristics of CBD noted its antagonistic effect on CB1R (Pertwee, 2008;Thomas et al., 2007). Moreover, CBD was found to inhibit several CB1-mediated THC effects (Zuardi et al., 1982). ...
Introduction
Cannabidiol (CBD) is a phytocannabinoid found in the Cannabis plant. CBD has received significant medical attention in relation to its anticonvulsant, anxiolytic, and antipsychotic characteristics. An increasing number of studies focusing on the anti-addictive properties of CBD have recently been published. In this systematic review, we aim to offer a comprehensive overview of animal and human studies regarding the impact of CBD on substance use disorders (SUDs).
Methods
A systematic search was performed on the PubMed database in February 2021. We included all articles assessing the effects of CBD on substance use disorders.
Results
The current systematic review suggests that CBD might offer promising therapeutic potential for the treatment of SUD, based on available animal and human studies. Animal studies showed a positive impact of CBD in the context of alcohol, opioids, and methamphetamine use (e.g., diminishing of drug-seeking behaviors). The results for cocaine use were mixed among reviewed studies, and CBD was not found to have an effect in animal studies on cannabis use, No animal study was identified that focused on the impact of CBD on nicotine use. Human studies showed a positive impact of CBD in the context of nicotine, cannabis, and opioid use (e.g., frequency and quantity of consumption). In contrast, CBD was not found to have an effect in human studies on cocaine or alcohol use. No human study was identified that investigated the impact of CBD on methamphetamine use.
Conclusions
CBD might offer promising therapeutic potential for the treatment of SUD, especially for nicotine, cannabis, and opioid use disorders, based on available human studies. The available research evidence is, however, sparse and more research on humans is needed.
... However, since the approval in Canada of Sativex R , an oromucosal spray that contains 27 mg of THC and 25 mg of CBD per mL, for the management of neuropathic pain associated with multiple sclerosis (MS), the notion of dronabinol (isolated THC) being too aversive has favored the utilization of balanced formulations that include equimolar amounts of CBD (14). This approach has been proposed to reduce unwanted neurological and psychological side effects associated with unabated THC (29). Further, Sativex R demonstrated superior efficacy compared to both THC-predominant extracts and placebo at reducing pain in RCTs thus suggesting that the CBD component contributes an analgesic effect (21). ...
To date, the therapeutic use of cannabinoids in chronic pain management remains controversial owing to the limited clinical evidence found in randomized clinical trials (RCTs), the heterogeneous nature of the clinical indication, and the broad range of cannabis-based medicinal products (CBMPs) used in both experimental and observational clinical studies. Here we evaluate patient-reported clinical outcomes (PROMS) in a cohort of adult patients, diagnosed with chronic pain of diverse etiology, who received adjuvant treatment with oral, cannabis-based, magistral formulations between May and September 2021 at the Latin American Institute of Neurology and Nervous System (ILANS-Zerenia) in Bogotá, Colombia. During this period, 2,112 patients completed a PROMS questionnaire aimed at capturing the degree of clinical improvement of their primary symptom and any potential side effects. Most participants were female (76.1%) with an average age of 58.7 years old, and 92.5% (1,955 patients) reported some improvement in their primary symptom (p < 0.001). Two monovarietal, full-spectrum, cannabis formulations containing either cannabidiol (CBD 30 mg/mL; THC <2 mg/mL) or a balanced composition (THC 12 mg/mL; CBD 14 mg/mL) accounted for more than 99% of all prescriptions (59.5 and 39.8%, respectively). The degree of improvement was similar between both formulations, although males reported less effectiveness in the first 4 weeks of treatment. Sex-specific differences were also found in prescription patterns, with male patients increasing the intake of the balanced chemotype overtime. For many patients (71.7%) there were no adverse side effects associated to the treatment and those most reported were mild, such as somnolence (13.0%), dizziness (8.1%) and dry mouth (4.2%), which also appeared to fade over time. Our results constitute the first real-world evidence on the clinical use of medicinal cannabis in Colombia and suggest that cannabis-based oral magistral formulations represent a safe and efficacious adjuvant therapeutic option in the management of chronic pain.
... The results suggested that CBD's effects, contrary to those of Δ9-THC, are possibly connected to the antagonism of effects between the two cannabinoids. Further, it was found that the volunteers experienced a noticeable elevation in their anxiety level upon Δ9-THC ingestion [50]. ...
The rising popularity of medical marijuana and its potential therapeutic uses has resulted in passionate discussions that have mainly focused on its possible benefits and applications. Although the concept itself seems promising, the multitude of presented information has noticeable ramifications-terminological chaos being one. This work aimed to synthesize and critically analyze scientific evidence on the therapeutic uses of cannabinoids in the field of psychiatry. Emphasis was placed on the anxiolytic effects of cannabis constituents and their effects on post-traumatic stress disorder, anxiety disorders, schizophrenia spectrum, and other psychotic disorders. The review was carried out from an addictological perspective. A database search of interchangeably combined keywords resulted in the identification of subject-related records. The data were then analyzed in terms of relevance, contents, methodologies, and cited papers. The results were clear in supporting one common conclusion: while most findings provide support for beneficial applications of medical marijuana in psychiatry, no certain conclusions can be drawn until larger-scaled, more methodo-logically rigorous, and (preferably) controlled randomized trials verify these discoveries.
... There are a few studies including case reports [139,168], case series [140], and randomized controlled trials [169,170] that indicate that CBD may be efficacious in promoting sleep. Yet, there is some contention in the literature, with some studies suggesting CBD has a stimulating or alerting effect [171,172], and others suggest CBD has a sedating effect [169,170] and one which found no effect in terms of sleepiness [173]. There is a need for research into the potential effects of CBD on sleep in cancer patients, since the benefits of improved sleep would be tremendous. ...
The plant Cannabis sativa has been in use medicinally for several thousand years. It has over 540 metabolites thought to be responsible for its therapeutic effects. Two of the key phytocannabinoids are cannabidiol (CBD) and tetrahydrocannabinol (THC). Unlike THC, CBD does not have potentially intoxicating effects. Preclinical and clinical research indicates that CBD has a wide range of therapeutic effects, and many of them are relevant to the management of cancer. In this article, we explore some of the potential mechanisms of action of CBD in cancer, and evidence of its efficacy in the integrative management of cancer including the side effects associated with its treatment, demonstrating its potential for integration with orthodox cancer care.
... Research evaluating the anxiolytic or antidepressant effects of products with a more balanced THC:CBD ratio is limited. Some studies in humans indicate that concurrent CBD/THC administration attenuates anxiogenic effects produced by THC (64,65), but this has not been observed consistently (66,67) and may be dose-dependent (68). This inconsistency is mirrored in the preclinical literature (69)(70)(71), making it difficult to determine a responsible mechanism given the diverse pharmacological activity of CBD (72,73). ...
Background: Anxiety and depressive disorders are highly prevalent. Patients are increasingly using medicinal cannabis products to treat these disorders, but little is known about the effects of medicinal cannabis use on symptoms of anxiety and depression. The aim of the present observational study was to assess general health in medicinal cannabis users and non-using controls with anxiety and/or depression.
Methods: Participants (368 Cannabis Users; 170 Controls) completed an online survey assessing anxiety and depressive symptoms, cannabis product use, sleep, quality of life, and comorbid chronic pain. Participants that completed this baseline survey were then invited to complete additional follow-up surveys at 3-month intervals. Baseline differences between Cannabis Users and Controls were assessed using independent-samples t -tests and generalized linear mixed effects models were used to assess the impact of initiating cannabis product use, sustained use, or discontinuation of use on anxiety and depressive symptoms at follow-up.
Results: Medicinal cannabis use was associated with lower self-reported depression, but not anxiety, at baseline. Medicinal cannabis users also reported superior sleep, quality of life, and less pain on average. Initiation of medicinal cannabis during the follow-up period was associated with significantly decreased anxiety and depressive symptoms, an effect that was not observed in Controls that never initiated cannabis use.
Conclusions: Medicinal cannabis use may reduce anxiety and depressive symptoms in clinically anxious and depressed populations. Future placebo-controlled studies are necessary to replicate these findings and to determine the route of administration, dose, and product formulation characteristics to optimize clinical outcomes.
... THC is the main intoxicating phytochemical, however its main active metabolite after absorption is 11-hydroxy-D 9 -tetrahydroxannabinol (11-OH-THC), which has higher therapeutic potency (24,29) and blood brain barrier (BBB) permeability. CBD is an antagonist of cannabinoid receptor agonists, and may offset the psychoactivity of THC when co-administered -reducing symptoms such as paranoia, dysphoria and anxiety (30)(31)(32)(33)(34)(35) while also potentiating cannabis tolerability (36,37). CBD is anti-inflammatory (38), but also exhibits other diverse effects including neuroprotective (39), anticonvulsive (40), antipsychotic (27,(41)(42)(43), anxiolytic (44), antidepressant (45), hypnotic, sedative, anticancer (46-51), analgesic and antiemetic activity (27). ...
Background
Cannabis for cancer is very topical and, given the use of illicit cannabis preparations used in this vulnerable population, research investigating standardised, quality-assured medicinal cannabis is critical to inform clinicians and assist patient safety.
Methods
A randomized trial involving adult patients diagnosed with a high-grade glioma, no history of substance abuse, liver or kidney damage or myocardial infarction were eligible for inclusion in a tolerability study on two different ratios of medicinal cannabis. Baseline screening of brain morphology, blood pathology, functional status, and cognition was conducted. A retrospective control group was used for comparison for secondary outcomes.
Results
Participants (n=88) were on average 53.3 years old. A paired t-test assessed the Functional Assessment of Cancer Therapy for Brain Cancer (FACT-Br) between groups from baseline to week 12 found that the 1:1 ratio favoured both physical (p=0.025) and functional (p=0.014) capacity and improved sleep (p=0.009). Analysis of changes from baseline to week 12 also found 11% of 61 participants had a reduction in disease, 34% were stable, 16% had slight enhancement, and 10% had progressive disease. No serious adverse events occurred. Side effects included dry mouth, tiredness at night, dizziness, drowsiness.
Conclusion
This study demonstrated that a single nightly dose of THC-containing medicinal cannabis was safe, had no serious adverse effects and was well tolerated in patients. Medicinal cannabis significantly improved sleep, functional wellbeing, and quality of life.
Clinical Trial Registration
Australian New Zealand Clinical Trials Registry (ANZCTR) http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373556&isReview=true , identifier ACTRN12617001287325.
... In C57BL/6J mice, CBD (3 mg/kg) significantly blunted the cognitive alterations induced by THC (1 mg/kg) administration in an object recognition task (Aso et al., 2019). In the clinical setting, CBD (1 mg/kg) blocked the anxiety induced by THC (0.5 mg/kg) (Zuardi et al., 1982). Furthermore, CBD pre-treatment (600 mg) inhibited THC (1.5 mg)-induced paranoia, inhibited the detrimental effects of THC on episodic memory and decreased the proportion of participants experiencing clinically significant acute THC psychosis (Englund et al., 2013). ...
Drug treatments available for the management of substance use disorders (SUD) present multiple limitations in efficacy, lack of approved treatments or alarming relapse rates. These facts hamper the clinical outcome and the quality of life of the patients supporting the importance to develop new pharmacological agents. Lately, several reports suggest that cannabidiol (CBD) presents beneficial effects relevant for the management of neurological disorders such as epilepsy, multiple sclerosis, Parkinson’s, or Alzheimer’s diseases. Furthermore, there is a large body of evidence pointing out that CBD improves cognition, neurogenesis and presents anxiolytic, antidepressant, antipsychotic, and neuroprotective effects suggesting potential usefulness for the treatment of neuropsychiatric diseases and SUD. Here we review preclinical and clinical reports regarding the effects of CBD on the regulation of the reinforcing, motivational and withdrawal-related effects of different drugs of abuse such as alcohol, opioids (morphine, heroin), cannabinoids, nicotine, and psychostimulants (cocaine, amphetamine). Furthermore, a special section of the review is focused on the neurobiological mechanisms that might be underlying the ‘anti-addictive’ action of CBD through the regulation of dopaminergic, opioidergic, serotonergic, and endocannabinoid systems as well as hippocampal neurogenesis. The multimodal pharmacological profile described for CBD and the specific regulation of addictive behavior-related targets explains, at least in part, its therapeutic effects on the regulation of the reinforcing and motivational properties of different drugs of abuse. Moreover, the remarkable safety profile of CBD, its lack of reinforcing properties and the existence of approved medications containing this compound (Sativex®, Epidiolex®) increased the number of studies suggesting the potential of CBD as a therapeutic intervention for SUD. The rising number of publications with substantial results on the valuable therapeutic innovation of CBD for treating SUD, the undeniable need of new therapeutic agents to improve the clinical outcome of patients with SUD, and the upcoming clinical trials involving CBD endorse the relevance of this review.
Background:
Despite being added to numerous products, little is known about cannabidiol. Drowsiness is a self-reported side effect, which could impact cognitive functioning.
Objectives:
To determine whether cannabidiol impacts cognition and psychomotor function.
Methods:
A volunteer sample of healthy, college students were recruited for this randomized, parallel-group, double-blind, feasibility trial from April-November 2021. Participants completed a baseline survey, the Stanford Sleepiness Scale, Visual Analog Mood Scale, Digit Symbol Substitution Test, Trail Making Test, Psychomotor Vigilance Test, and Simple Reaction Time tests. Participants were then randomized and allocated to receive 300mg cannabidiol oil (N=21) or placebo (N=19). After 120 minutes, participants retook the tests. Performance between groups was compared using Analysis of Covariance and multi-level Negative Binomial regression.
Results:
Participants averaged 21 ± 3 years of age and 52% were female. Self-reported anxiety did not change post-treatment. Performances on the Stanford Sleepiness Scale, Visual Analog Mood Scale, and Psychomotor Vigilance test increased for both groups. After accounting for baseline scores, attention lapse duration significantly increased for those receiving cannabidiol compared to placebo in the Psychomotor Vigilance Test (76 msec vs. 66 msec; p=0.02). Auditory reaction time improved in the cannabidiol group versus placebo for one sound emitted during the Simple Reaction Time test (241 vs. 245 msec; p=0.02), but the number of early responses increased from 0.3 to 0.8 for those receiving cannabidiol.
Conclusions:
While performance on most tests were similar between those receiving cannabidiol or placebo, cannabidiol might affect certain aspects of vigilance. More research and larger trials are needed.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder, onset in early childhood and associated with cognitive, social, behavioral, and sensory impairments. The pathophysiology is still unclear, and it is believed that genetic and environmental factors are fully capable of influencing ASD, especially cell signaling and microglial functions. Furthermore, the endocannabinoid system (ECS) participates in the modulation of various brain processes and is also involved in the pathophysiological mechanisms of this condition. Due to the health and quality of life impacts of autism for the patient and his/her family and the lack of effective medications, the literature has elucidated the possibility that Cannabis phytocannabinoids act favorably on ASD symptoms, probably through the modulation of neurotransmitters, in addition to endogenous ligands derived from arachidonic acid, metabolizing enzymes and even transporters of the membrane. These findings support the notion that there are links between key features of ASD and ECS due to the favorable actions of cannabidiol (CBD) and other cannabinoids on symptoms related to behavioral and cognitive disorders, as well as deficits in communication and social interaction, hyperactivity, anxiety and sleep disorders. Thus, phytocannabinoids emerge as therapeutic alternatives for ASD.
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.
Background
Evidence suggests cannabidiol (CBD) has anxiolytic properties, indicating potential for novel treatment strategies. However, few clinical trials of CBD-based products have been conducted, and none thus far have examined the impact of these products on cognition.
Methods
For the open-label stage of clinical trial NCT02548559, autoregressive linear modeling assessed efficacy and tolerability of four-weeks of 1 mL t.i.d. treatment with a full-spectrum, high-CBD sublingual solution (9.97 mg/mL CBD, 0.23 mg/mL Δ−9-tetrahydrocannabinol) in 14 outpatients with moderate-to-severe anxiety, defined as ≥16 on the Beck Anxiety Inventory (BAI) or ≥11 on the Overall Anxiety Severity and Impairment Scale (OASIS).
Results
Findings suggest significant improvement on primary outcomes measuring anxiety and secondary outcomes assessing mood, sleep, quality of life, and cognition (specifically executive function) following treatment. Anxiety is significantly reduced at week 4 relative to baseline (BAI: 95% CI = [−21.03, −11.40], p < 0.001, OASIS: 95% CI = [−9.79, −6.07], p < 0.001). Clinically significant treatment response (≥15% symptom reduction) is achieved and maintained as early as week 1 in most patients (BAI = 78.6%, OASIS = 92.7%); cumulative frequency of treatment responders reached 100% by week 3. The study drug is well-tolerated, with high adherence/patient retention and no reported intoxication or serious adverse events. Minor side effects, including sleepiness/fatigue, increased energy, and dry mouth are infrequently endorsed.
Conclusions
Results provide preliminary evidence supporting efficacy and tolerability of a full-spectrum, high-CBD product for anxiety. Patients quickly achieve and maintain symptom reduction with few side effects. A definitive assessment of the impact of this novel treatment on clinical symptoms and cognition will be ascertained in the ongoing double-blind, placebo-controlled stage.
Rationale
Delta-9-tetrahydrocannabinol (THC), an active component of cannabis, can cause anxiety in some users during intoxication. Cannabidiol (CBD), another constituent of cannabis, has anxiolytic properties suggesting that cannabis products containing CBD in addition to THC may produce less anxiety than THC-only products. Findings to date around this issue have been inconclusive and could conceivably depend on moderating factors such as baseline anxiety levels in users.
Objective
The present study examined whether anxiety following single doses of vaporised THC, CBD and THC/CBD might be explained by state and trait anxiety levels at baseline.
Methods
A placebo-controlled, randomised, within-subjects study including 26 healthy recreational cannabis users tested the effects of vaporised THC-dominant cannabis (13.75 mg THC), CBD-dominant cannabis (13.75 mg CBD), THC/CBD-equivalent cannabis (13.75 mg THC/13.75 mg CBD) and placebo cannabis on anxiety. Self-rated trait anxiety was assessed with the State-Trait Anxiety Inventory (STAI). State levels of anxiety were objectively assessed with a computer-based emotional Stroop task (EST) and subjectively rated with the STAI-state questionnaire and a visual analogue scale.
Results
Both THC and THC/CBD significantly increased self-rated state anxiety compared to placebo. State anxiety after THC/CBD was significantly lower than after THC alone. THC-induced anxiety was independent of anxiety at baseline. When baseline anxiety was low, CBD completely counteracted THC-induced anxiety; however, when baseline anxiety was high, CBD did not counteract THC-induced anxiety. There were no effects of any treatment condition on the EST.
Conclusion
Overall, the study demonstrated that the THC/CBD-equivalent cannabis induces less state anxiety than THC-dominant cannabis.
Background: Cannabis is associated with a range of therapeutic and non-therapeutic, positive and negative effects.
While some benefits and harms may be specific to individual cannabinoid constituents (THC, CBD), individual
expectancies may also play a role.
Objectives: Evaluate the extent to which individuals hold expectancies about the effects of CBD, THC, and THC &
CBD combined, and whether this differs with prior cannabis experience.
Methods: Canadian adults (N = 345; n = 58 no prior cannabis use, n = 287 prior cannabis use) completed
a Qualtrics survey. Participants provided information regarding their expectancies about the effects of
cannabinoids (THC, CBD, THC & CBD combined) via a 15-item questionnaire, which included various therapeutic
(e.g., helps with pain) and non-therapeutic positive (e.g., enhances positive feelings) and negative
(e.g., risk for addiction) effects. They recorded their perceptions about the effects of each cannabinoid on a
scale (0=“definitely not true”, 10=“definitely true”). Data was analyzed using linear mixed models.
Results: For most therapeutic effects, CBD-containing products (CBD, THC & CBD) were rated higher than THC.
For most positive and negative non-therapeutic effects, THC-containing products (THC, THC & CBD) were rated
higher than CBD. Those with prior cannabis use (vs no prior use) rated all cannabinoids higher regarding their
association with many therapeutic and positive effects, while endorsing weaker expectancies about their role in
some negative effects.
Conclusions: Adults endorsed stronger expectancies that CBD-containing products are responsible for producing
a rage of therapeutic effects. Those with prior cannabis use experience tended to emphasize the benefits and
minimize potential harmful effects of cannabinoids.
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.
Combination tetrahydrocannabinol (THC)/cannabidiol (CBD) medicines or CBD-only medicines are prospective treatments for chronic pain, stress, anxiety, depression, and insomnia. THC and CBD increase signaling from cannabinoid receptors, which reduces synaptic transmission in parts of the central and peripheral nervous systems and reduces the secretion of inflammatory factors from immune and glial cells. The overall effect of adding CBD to THC medicines is to enhance the analgesic effect but counteract some of the adverse effects. There is substantial evidence for the effectiveness of THC/CBD combination medicines for chronic pain, especially neuropathic and nociplastic pain or pain with an inflammatory component. For CBD-only medication, there is substantial evidence for stress, moderate evidence for anxiety and insomnia, and minimal evidence for depression and pain. THC/CBD combination medicines have a good tolerability and safety profile relative to opioid analgesics and have negligible dependence and abuse potential; however, should be avoided in patients predisposed to depression, psychosis and suicide as these conditions appear to be exacerbated. Non-serious adverse events are usually dose-proportional, subject to tachyphylaxis and are rarely dose limiting when patients are commenced on a low dose with gradual up-titration. THC and CBD inhibit several Phase I and II metabolism enzymes, which increases the exposure to a wide range of drugs and appropriate care needs to be taken. Low-dose CBD that appears effective for chronic pain and mental health has good tolerability and safety, with few adverse effects and is appropriate as an initial treatment.
Cannabis legalization continues to progress in many US states and other countries. Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is the major psychoactive constituent in cannabis underlying both its abuse potential and the majority of therapeutic applications. However, the neural mechanisms underlying cannabis action are not fully understood. In this chapter, we first review recent progress in cannabinoid receptor research, and then examine the acute CNS effects of Δ⁹-THC or other cannabinoids (WIN55212-2) with a focus on their receptor mechanisms. In experimental animals, Δ⁹-THC or WIN55212-2 produces classical pharmacological effects (analgesia, catalepsy, hypothermia, hypolocomotion), biphasic changes in affect (reward vs. aversion, anxiety vs. anxiety relief), and cognitive deficits (spatial learning and memory, short-term memory). Accumulating evidence indicates that activation of CB1Rs underlies the majority of Δ⁹-THC or WIN55121-2’s pharmacological and behavioral effects. Unexpectedly, glutamatergic CB1Rs preferentially underlie cannabis action relative to GABAergic CB1Rs. Functional roles for CB1Rs expressed on astrocytes and mitochondria have also been uncovered. In addition, Δ⁹-THC or WIN55212-2 is an agonist at CB2R, GPR55 and PPARγ receptors and recent studies implicate these receptors in a number of their CNS effects. Other receptors (such as serotonin, opioid, and adenosine receptors) also modulate Δ⁹-THC's actions and their contributions are detailed. This chapter describes the neural mechanisms underlying cannabis action, which may lead to new discoveries in cannabis-based medication development for the treatment of cannabis use disorder and other human diseases.
Objectives:
We assessed whether administering cannabidiol (CBD) before recalling the traumatic event that triggered their disorder attenuates anxiety in patients with post-traumatic stress disorder (PTSD). As an exploratory pilot analysis, we also investigated whether this effect depends on the nature of the event (sexual vs. nonsexual trauma).
Methods:
Thirty-three patients of both sexes with PTSD were recruited and randomized 1:1 into two groups. One group received oral CBD (300 mg), and the other received a placebo before listening to a digital audio playback of their previously recorded report of the trigger event. Subjective and physiological measurements were taken before and after recall. We analyzed the data in two subsamples: trigger events involving sexual and nonsexual trauma.
Results:
In the nonsexual trauma group, the differences between measurements before and after recall were significantly smaller with CBD than placebo; this held true for anxiety and cognitive impairment. However, in the sexual trauma group, the differences were non-significant for both measurements.
Conclusion:
A single dose of CBD (300mg) attenuated the increased anxiety and cognitive impairment induced by recalling a traumatic event in patients with PTSD when the event involved nonsexual trauma.
Aim
We undertook this systematic review to determine the efficacy and safety of cannabis-based medicine as a treatment for behavioral, psychological, and motor symptoms associated with neurocognitive disorders.
Methods
We conducted a PRISMA-guided systematic review to identify studies using cannabis-based medicine to treat behavioral, psychological, and motor symptoms among individuals with Alzheimer's disease (AD) dementia, Parkinson’s disease (PD), and Huntington’s disease (HD). We considered English-language articles providing original data on three or more participants, regardless of design.
Findings
We identified 25 studies spanning 1991 to 2021 comprised of 14 controlled trials, 5 pilot studies, 5 observational studies, and 1 case series. In most cases, the cannabinoids tested were dronabinol, whole cannabis, and cannabidiol, and the diagnoses included AD ( n = 11), PD ( n = 11), and HD ( n = 3). Primary outcomes were motor symptoms (e.g., dyskinesia), sleep disturbance, cognition, balance, body weight, and the occurrence of treatment-emergent adverse events.
Conclusions
A narrative summary of the findings from the limited number of studies in the area highlights an apparent association between cannabidiol-based products and relief from motor symptoms in HD and PD and an apparent association between synthetic cannabinoids and relief from behavioral and psychological symptoms of dementia across AD, PD, and HD. These preliminary conclusions could guide using plant-based versus synthetic cannabinoids as safe, alternative treatments for managing neuropsychiatric symptoms in neurocognitive vulnerable patient populations.
Cannabidiol (CBD) is one of the most abundant components of Cannabis and has long been used in Cannabis-based preparations. Recently, CBD has become a promising pharmacological agent because of its beneficial properties in the pathophysiology of several diseases. Although CBD is a kind of cannabinoid and acts on cannabinoid receptors (CB1 and CB2), molecular targets involved in diverse therapeutic properties of CBD have not been identified because CBD also interacts with other molecular targets. Considering that CBD alters the intracellular calcium level by which calpain activity is controlled, and both CBD and calpain are associated with various diseases related to calcium signaling, including neurological disorders, this review provides an overview of calpain and calcium signaling as possible molecular targets of CBD. As calpain is known to play an important role in the pathophysiology of neurological disease, a deeper understanding of its relationship with CBD will be meaningful. To understand the role of CBD as a calpain regulator, in silico structural analysis on the binding mode of CBD with calpain was performed.
An Acute Reference Dose (ARfD) of 1 µg of delta-9-tetrahydrocannabinol (THC) per kilogram (kg) of body weight (bw) per day was recommended by the European Food Safety Authority (EFSA) for its assessment of possible acute health risks from the intake of industrial hemp food products. The scientific basis for this opinion, such as their choice of a Point of Departure for identification of the Lowest Observed Adverse Effect Level (LOAEL) for THC on the central nervous system, and the seeming absence of an experimental No Observed Adverse Effect Level (NOAEL), is critically reviewed. Moreover, the risk assessment for an ARfD derivation for THC is then reconsidered. In contrast to the EFSA Scientific Opinion of 2015, a higher LOAEL is presently identified from pharmacokinetic and pharmacodynamic studies, and forensic data, in representative cohorts of healthy humans after oral administrations of low THC doses. A NOAEL for THC is derived through this combination of results, demonstrating a threshold for impairment of psychomotor function only after intake of an oral THC bolus beyond 2.5 mg for the average healthy adult. This 2.5 mg dose produces mean THC blood serum levels of <2 ng/mL, as well as do two doses when taken daily within a time interval of ≥6 h. The forensic threshold of THC that is correlated with the impairment of psychomotor function is known to be between 2 and 5 ng/mL in blood serum for adults. For an appropriately spaced intake of 2 × 2.5 mg THC per day, an adult can therefore be regarded as being at the NOAEL. Applying a default uncertainty factor of 10 for intraspecies variability to a NOAEL of 2 × 2.5 mg (over ≥6 hours) for THC, yields a "daily dose of no concern" or a "tolerable upper intake level" of 0.50 mg, corresponding to 7 µg/kg bw. Starting with a NOAEL of only 2.5 mg, consumed as a single bolus, the lowest possible daily THC Acute Reference Dose would therefore be 0.25 mg, or 3.5 µg/kg bw for healthy adults, as the absolutely most conservative estimate. Other justifiable estimates have ranged up to 14 µg/kg bw per day.
ZUSAMMENFASSUNG
Hintergrund Bei Patienten mit Störungen aus dem schizophrenen Formenkreis ist der Konsum von Cannabis und anderen psychoaktiven Substanzen weit verbreitet. Es besteht eine wissenschaftliche Evidenz, dass der hochdosierte und regelmäßige Freizeitkonsum von Cannabis mit nachteiligen Langzeitfolgen assoziiert ist. Und dennoch könnte die physiologische Bedeutung des Endocannabinoidsystems (ECS) den Einsatz von Cannabispräparaten – womöglich mit einem hohen Gehalt an Cannabidiol (CBD) – zur Therapie neuropsychiatrischer Erkrankungen als nützlich erscheinen lassen.
Ziel Darstellung der Grundlagen für die Wirksamkeit von medizinischem Cannabis bei neuropsychiatrischen Erkrankungen – insbesondere Störungen aus dem schizophrenen Formenkreis – und kritische Nutzen-Risiko-Bewertung.
Ergebnisse und Diskussion Die beiden wichtigsten neuroaktiven Bestandteile von Cannabis sind CBD und Tetrahydrocannabinol (THC). THC scheint psychose- und angstfördernd zu wirken und die Kognition zu beeinträchtigen. Basierend auf einer Recherche aktueller Literatur ist anzunehmen, dass CBD im Gegensatz zu THC nicht euphorisierend, sondern antikonvulsiv, analgetisch, angstlösend und antipsychotisch wirken könnte und möglicherweise die kognitive Leistungsfähigkeit verbessern kann. Somit wäre CBD ein natürlicher Antagonist von THC. Während es eine hinreichende Evidenz gibt, dass der Freizeitkonsum von meist THC-lastigem Cannabis die psychische Gesundheit nachteilig beeinflusst und Psychosen fördert, gibt es Studien, die darauf hindeuten, dass CBD protektiv sein könnte. Allerdings mangelt es an hochwertigen kontrollierten klinischen Studien mit größeren Patientenzahlen und guter Methodik, um eine ausreichende Evidenz für den Einsatz von Cannabidiol in der klinischen Praxis zu begründen.
Objectives:
Individuals with a cocaine use disorder (CUD) are more likely to present anxiety, which in turn negatively impacts substance use outcomes. Some evidence suggests that cannabidiol (CBD) presents anxiolytic properties and could be a treatment for substance use disorders. This study explores CBD's effect on stress biomarker (cortisol) and anxiety symptoms in people with CUD.
Methods:
Exploratory analyses were conducted using data from a randomized, double-blind, placebo-controlled trial evaluating CBD's efficacy to treat CUD. We randomized 78 individuals with CUD into receiving a daily oral dose up to 800 mg CBD (n = 40) or placebo (n = 38). The trial was divided into 2 phases: an inpatient detoxification lasting 10 days and an outpatient follow-up lasting 12 weeks. Anxiety symptoms and stress response were assessed using a visual analog scale, the Beck Anxiety Inventory, and cortisol levels at multiple time points throughout the study. We also measured anxiety after a stressful and a cocaine-cue scenarios. We used generalized estimating equations models and multiple linear regression to assess CBD's effects on anxiety and cortisol levels.
Results:
Both treatment groups had similar mean anxiety scores according to the Beck Anxiety Inventory (P = 0.27) and the visual analog scale (P = 0.18). CBD did not decrease anxiety after a stressful (P = 0.14) and a cocaine (P = 0.885) scenarios compared with placebo. No statistically significant group difference was found in cortisol levels (P = 0.76).
Conclusions:
We found no evidence for 800 mg of CBD to be more efficacious than placebo for modulating anxiety symptoms and cortisol levels in individuals with CUD.
Background:
There is a growing interest in the use of cannabis (and its extracts), as well as CBD oil (hemp extracts containing cannabidiol), for therapeutic purposes. While there is reason to believe that cannabinoids may be efficacious for a number of different diseases and syndromes, there exist limited objective data supporting the use of crude materials (CBD oil, cannabis extracts, and/or cannabis itself).
Summary:
In the present review, we examined data for pure cannabinoid compounds (dronabinol, nabilone, and CBD), as well as partially purified medicinal cannabis extracts (nabiximols), to provide guidance on the potential therapeutic uses of high-THC cannabis and CBD oil. In general, data support a role for cannabis/cannabinoids in pain, seizure disorders, appetite stimulation, muscle spasticity, and treatment of nausea/vomiting. Given the biological activities of the cannabinoids, there may be utility in treatment of central nervous system disorders (such as neurodegenerative diseases, PTSD, and addiction) or for the treatment of cancer. However, those data are much less compelling. Key Message: On balance, there are reasons to support the potential use of medical cannabis and cannabis extract (Δ9-THC-dominant or CBD-dominant), but much more careful research is required.
Studies with cannabidiol (CBD) suggest that this compound has anxiolytic properties and may mediate the reconsolidation and extinction of aversive memories. The objective of this study was to test whether the administration of CBD 300 mg before the recall of traumatic events attenuated symptoms usually induced by recall in subjects diagnosed with posttraumatic stress disorder (PTSD) and if its potential effects interfere with the reconsolidation of aversive memories. The double-blind trial included 33 participants of both sexes, aged between 18 and 60 years, diagnosed with PTSD according to the SCID-5 and randomly allocated to two groups treated with CBD (n = 17) and placebo (n = 16). In the first experimental section, participants were matched by sex, age, body mass index (BMI), and PTSD symptoms as assessed with the Posttraumatic Stress Disorder Checklist (PCL-5). On the same day, participants prepared the behavior test, recording accounts of their traumas in digital audio for a minute and a half and then imagining the trauma for 30 s. After 7 days, participants received CBD (300 mg) or placebo and performed the behavioral test, listening to the trauma account and imagining themselves in that situation. Before and after the behavioral test, subjective changes in mood and anxiety were recorded (Visual and Analogical Mood Scale — VAMS and STAI-state), along with physiological correlates of anxiety blood pressure (BP), heart rate (HR), and salivary cortisol (SC). Seven days later, participants underwent the same procedures as the previous session, but without the pharmacological intervention, to assess the effect on reconsolidation of traumatic memories. We found that CBD significantly attenuated the increase in the VAMS scale cognitive impairment factor scores, under the CBD’s effect, with this effect remaining 1 week after drug administration. No significant differences between the effects of CBD and placebo on anxiety, alertness, and discomfort induced by the recall of the traumatic event during the pharmacological intervention and in the subsequent week, in the absence of it. There were no significant differences between the CBD and placebo groups regarding physiological data (BP, HR, and SC). The attenuation of cognitive impairments during trauma recall under the effect of CBD may have interfered with the reconsolidation of traumatic memories concerning its association with cognitive impairments.
Objectives
Anxiety disorders are one of the most common reasons for seeking treatment with cannabis-based medicinal products (CBMPs). Current pharmacological treatments are variable in efficacy and the endocannabinoid system has been identified as a potential therapeutic target. This study aims to detail the changes in health-related quality-of-life (HRQoL) and clinical safety following CBMP therapy for generalised anxiety disorder.
Methods
A case series of the UK Medical Cannabis Registry was performed. Primary outcomes included change from baseline in patient-reported outcome measures (the General Anxiety Disorder Scale (GAD-7), EQ-5D-5L (a measure of health-related quality of life), and Sleep Quality Scale (SQS)) at 1, 3 and 6 months. Statistical significance was defined as p<0.050.
Results
67 patients were treated for generalised anxiety disorder. Statistically significant improvements were observed in GAD-7, EQ-5D-5L Index Value, EQ5D Visual Analogue Scale, and SQS scores at 1, 3 and 6 months (p<0.050). 25 (39.1%) patients reported adverse events during the follow-up period.
Conclusion
This study suggests that CBMPs may be associated with improvement in HRQoL outcomes when used as a treatment for generalised anxiety disorder. These findings must be treated with caution considering limitations of study design; however this data may help inform future clinical studies and practice.
Keine Droge führt derzeit zu so intensiven, teilweise leidenschaftlich geführten Diskussionen wie Cannabis. Welche gesundheitlichen und sozialen Risiken birgt die Substanz, wenn sie zu Rauschzwecken gebraucht wird? Dieser Beitrag beschreibt die wichtigsten Cannabinoide, das endogene Cannabissystem sowie mögliche kurzund langfristige Risiken. Er zeigt zudem psychotherapeutische Behandlungsoptionen von Cannabismissbrauch und -abhängigkeit auf.
Good sleep is vital for good health, and poor sleep, in particular insomnia, is associated with a range of poor health outcomes. Sleep disorders are common and a key reason why people self-medicate with cannabis. We have two key biological mechanisms which work together to regulate our sleep-wake cycle, the processes of sleep-wake homeostasis and our circadian rhythms. The endocannabinoid system is involved in the circadian sleep-wake cycle, including maintenance and promotion of sleep, and may provide the link between the circadian regulation systems and the physiological process of sleep. Cannabis has been used for centuries to treat sleep disorders. Preclinical and clinical evidence indicate that cannabidiol and tetrahydrocannabinol may have a role to play in the treatment of sleep disorders.
Anxiety is a common condition for which people have been found to self-medicate with cannabis. Anxiety is often comorbid with other conditions, including depression, sleep disorders and chronic pain. The pathomechanisms underpinning anxiety are complex. Animal and human research indicates that the endocannabinoid system is involved in our stress response and in anxiety. Evidence from preclinical studies has elucidated some of the potential mechanisms by which cannabidiol (CBD) is anxiolytic. Clinical research also supports the notion that CBD is anxiolytic, though the majority of studies have been studies of acute use rather than chronic use. There is evidence that tetrahydrocannabinol (THC) may have a bimodal effect, being anxiolytic in lower doses and anxiogenic in higher doses. The majority of studies of CBD and THC, in particular in animal studies, have utilised purified CBD or THC. Whole plant medicines that contain multiple phytocannabinoids, terpenes, polyphenols, flavonoids and other plant nutrients appear to act more potently, with different pharmacophysiologic relationships and reduced adverse effect profiles than purified isolates.
Background: To date, no studies have directly assessed potential cannabis use disorder (CUD) in medical cannabis (MC) patients pre- vs post-MC treatment. Given that MC patients use cannabis for symptom alleviation rather than intoxication, we hypothesized that MC patients would exhibit few symptoms of CUD after initiating MC treatment. Methods: As part of an ongoing observational, longitudinal study, 54 MC patients completed baseline assessments prior to initiating MC use and returned for at least one follow-up assessment after three, six, and/or twelve months of a self-selected MC treatment regimen; detailed MC treatment information was collected and quantified. All patients completed the Cannabis Use Disorder Identification Test - Revised (CUDIT-R) at each visit. Changes in individual items scores and total scores were assessed over time, and we examined whether total CUDIT-R scores correlated with frequency of MC use, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) exposure. Further, Cronbach’s alpha analyses were conducted to provide preliminary data regarding the psychometric properties of the CUDIT-R when used among MC patients. Results: Although total CUDIT-R scores increased relative to baseline, on average, ratings fell below the ‘hazardous use’ threshold at each visit. Analyses of individual items revealed that increases in total scores were primarily attributable to increases in frequency of use and not necessarily other aspects of problematic use. Total CUDIT-R scores were not associated with number of MC uses or CBD exposure, but a significant relationship was detected between increased THC exposure and higher CUDIT-R scores. Importantly however, analyses revealed that the CUDIT-R does not appear to be an appropriate tool for identifying CUD in MC patients. Conclusions: Screening tools specifically designed to assess CUD in MC patients are needed and should distinguish between frequent use and problematic use; exposure to individual cannabinoids must also be considered.
To investigate effects of smoking cannabidiol (CBD)-rich marijuana on driving ability and determine free CBD and Δ⁹-tetrahydrocannabinol (THC) concentrations in capillary blood samples, a randomised, double-blind, placebo-controlled, two-way crossover pilot study was conducted with 33 participants. Participants smoked a joint containing 500 mg of tobacco and either 500 mg of CBD-rich marijuana (16.6% total CBD; 0.9% total THC) or 500 mg of a placebo substance, then performed three different dimensions of the Vienna Test System TRAFFIC examining reaction time, behaviour under stress, and concentration performance. For further assessment of participants’ fitness to drive, three tests of balance and coordination were evaluated and vital signs (blood pressure and pulse) were measured. Dried blood spot samples of capillary blood were taken after smoking and after completion of the tests to determine the cannabinoid concentrations (CBD, THC and THC-metabolites). The results revealed no significant differences between the effects of smoking CBD-rich marijuana and placebo on reaction time, motor time, behaviour under stress, or concentration performance. Maximum free CBD and THC concentrations in capillary blood were detected shortly after smoking, ranging between 2.6–440.0 ng/mL and 6.7–102.0 ng/mL, respectively. After 45 min, capillary blood concentrations had already declined and were in the range of 1.9–135.0 ng/mL (free CBD) and 0.9–38.0 ng/mL (free THC). Although the observed levels of free THC concentrations have been reported to cause symptoms of impairment in previous studies in which THC-rich marijuana was smoked, no signs of impairment were found in the current study. This finding suggests that higher CBD concentrations cause a negative allosteric effect in the endocannabinoid system, preventing the formation of such symptoms. Nevertheless, it is recommended that consumers refrain from driving for several hours after smoking CBD-rich marijuana, as legal THC concentration limits may be exceeded.
Supplemental data for this article is available online at https://doi.org/10.1080/20961790.2021.1946924 .
Context:
Depression is a severe mental illness caused by a deficiency of dopamine and serotonin. Cannabis sativa L. (Cannabaceae) has long been used to treat pain, nausea, and depression.
Objective:
This study investigates the anti-depressant effects of C. sativa (hemp) seed ethanol extract (HE) in chlorpromazine (CPZ)-induced Drosophila melanogaster depression model.
Materials and methods:
The normal group was untreated, and the control group was treated with CPZ (0.1% of media) for 7 days. The experimental groups were treated with a single HE treatment (0.5, 1.0, and 1.5% of media) and a mixture of 0.1% CPZ and HE for 7 days. The locomotor activity, behavioural patterns, depression-related gene expression, and neurotransmitters level of flies were investigated.
Results:
The behavioural patterns of individual flies were significantly reduced with 0.1% CPZ treatment. In contrast, combination treatment of 1.5% HE and 0.1% CPZ significantly increased subjective daytime activity (p < 0.001) and behavioural factors (p < 0.001). These results correlate with increased transcript levels of dopamine (p < 0.001) and serotonin (p < 0.05) receptors and concentration of dopamine (p < 0.05), levodopa (p < 0.001), 5-HTP (p < 0.05), and serotonin (p < 0.001) compared to those in the control group.
Discussion and conclusions:
Collectively, HE administration alleviates depression-like symptoms by modulating the circadian rhythm-related behaviours, transcript levels of neurotransmitter receptors, and neurotransmitter levels in the CPZ-induced Drosophila model. However, additional research is needed to investigate the role of HE administration in behavioural patterns, reduction of the neurotransmitter, and signalling pathways of depression in a vertebrate model system.
Post-Traumatic Stress Disorder (PTSD), characterized by re-experiencing, avoidance, negative affect, and impaired memory processing, may develop after traumatic events. PTSD is complicated by impaired plasticity and medial prefrontal cortex (mPFC) activity, hyperactivity of the amygdala, and impaired fear extinction. Cannabidiol (CBD) is a promising candidate for treatment due to its multimodal action that enhances plasticity and calms hyperexcitability. CBD’s mechanism in the mPFC of PTSD patients has been explored extensively, but literature on the mechanism in the dorsal raphe nucleus (DRN) is lacking. Following the PRISMA guidelines, we examined current literature regarding CBD in PTSD and overlapping symptomologies to propose a mechanism by which CBD treats PTSD via corticoraphe circuit. Acute CBD inhibits excess 5-HT release from DRN to amygdala and releases anandamide (AEA) onto amygdala inputs. By first reducing amygdala and DRN hyperactivity, CBD begins to ameliorate activity disparity between mPFC and amygdala. Chronic CBD recruits the mPFC, creating harmonious corticoraphe signaling. DRN releases enough 5-HT to ameliorate mPFC hypoactivity, while the mPFC continuously excites DRN 5-HT neurons via glutamate. Meanwhile, AEA regulates corticoraphe activity to stabilize signaling. AEA prevents DRN GABAergic interneurons from inhibiting 5-HT release so the DRN can assist the mPFC in overcoming its hypoactivity. DRN-mediated restoration of mPFC activity underlies CBD’s mechanism on fear extinction and learning of stress coping.
Background and aims
The simultaneous use of alcohol and cannabis (“simultaneous alcohol and marijuana [SAM] use”) is common among young adults and associated with negative substance-related consequences. SAM use may be tied to fluctuating mood states such as negative affect and individual characteristics including trait level of anxiety and sex. However, little is understood about their collective role. In this study, we sought to understand the daily link between SAM use and negative affect and whether this link might differ by both trait anxiety and sex.
Method
Participants were 154 young adults (57.8% female, 72.7% White, M age = 20.2) who completed baseline surveys on trait anxiety symptoms and up to 14 consecutive daily surveys on their substance use and affective states.
Results
Multilevel models tested for associations of type of substance use day (i.e., alcohol-only days, cannabis-only days, and no use days relative to SAM use days) with next-day negative affect. Three-way and lower order interactions were tested for substance use day type, anxiety, and sex. Two three-way interactions between cannabis-only days, anxiety, and sex and between alcohol-only days, anxiety, and sex emerged such that SAM use was associated with greater next-day negative affect relative to single substance use days particularly among female participants with elevated anxiety.
Conclusions
Anxiety and sex are salient factors in the link between SAM use relative to single-substance use and daily negative affect. Study findings reinforce the need to account for all of these factors in order to develop maximally efficacious substance use interventions.
Objective:
Cannabis use has increased dramatically across the country; however, few studies have assessed the long-term impact of medical cannabis (MC) use on cognition. Studies examining recreational cannabis users generally report cognitive decrements, particularly in those with adolescent onset. As MC patients differ from recreational consumers in motives for use, product selection, and age of onset, we assessed cognitive and clinical measures in well-characterized MC patients over 1 year. Based on previous findings, we hypothesized MC patients would not show decrements and might instead demonstrate improvements in executive function over time.
Method:
As part of an ongoing study, MC patients completed a baseline visit prior to initiating MC and evaluations following 3, 6, and 12 months of treatment. At each visit, patients completed a neurocognitive battery assessing executive function, verbal learning/memory, and clinical scales assessing mood, anxiety, and sleep. Exposure to delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) was also quantified.
Results:
Relative to baseline, MC patients demonstrated significant improvements on measures of executive function and clinical state over the course of 12 months; verbal learning/memory performance generally remained stable. Improved cognitive performance was not correlated with MC use; however, clinical improvement was associated with higher CBD use. Analyses suggest cognitive improvements were associated with clinical improvement.
Conclusions:
Study results extend previous pilot findings, indicating that MC patients may exhibit enhanced rather than impaired executive function over time. Future studies should examine distinctions between recreational and MC use to identify potential mechanisms related to cognitive changes and the role of clinical improvement.
Cannabinoids are chemicals either derived from cannabis (phytocannabinoids) like cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC); synthetic medications like nabilone, dronabinol, and rimonabant; or endogenous chemicals that stimulate cannabinoid receptors. Phytocannabinoids consist of natural products capable of either interacting directly with cannabinoid receptors or sharing chemical similarity with endocannabinoids or both. The two most studied phytocannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD is a non-intoxicating phytocannabinoid and has low affinity to cannabinoid receptors. It acts as a partial antagonist of CB1R and as a weak inverse agonist of CB2R. CBD also interacts with other non-cannabinoid targets, including serotonin 1A receptor (or 5-TH1A), vanilloid receptor 1 (TRPV1), and adenosine A2A receptors, which regulates perception of pain. CBD has been associated with analgesic, anti-inflammatory, anticonvulsant, anxiolytic, and antipsychotic effects. CBD works synergistically with THC for its analgesic effect while decreasing its psychoactive and cognitive side effects such as sedation and memory impairment of THC. Further studies are required to validate the medicinal applications of CBD.
The prelimbic division (PrL) of the medial prefrontal cortex (mPFC) is a cerebral division that is putatively implicated in the chronic pain and depression. We investigated the activity of PrL cortex neurons in Wistar rats that underwent chronic constriction injury (CCI) of sciatic nerve and were further subjected to the forced swimming (FS) test and mechanical allodynia (by von Frey test). The effect of blockade of synapses with cobalt chloride (CoCl2), and the treatment of the PrL cortex with cannabidiol (CBD), the CB1 receptor antagonist AM251 and the 5-HT1A receptor antagonist WAY-100,635 were also investigated. Our results showed that CoCl2 decreased the time spent immobile during the FS test but did not alter mechanical allodynia. CBD (at 15, 30 and 60 nmol) in the PrL cortex also decreased the frequency and duration of immobility; however, only the dose of 30 nmol of CBD attenuated mechanical allodynia in rats with chronic NP. AM251 and WAY-100,635 in the PrL cortex attenuated the antidepressive and analgesic effect caused by CBD but did not alter the immobility and the mechanical allodynia when administered alone. These data show that the PrL cortex is part of the neural substrate underlying the comorbidity between NP and depression. Also, the previous blockade of CB1 cannabinoid receptors and 5-HT1A serotonergic receptors in the PrL cortex attenuated the antidepressive and analgesics effect of the CBD. They also suggest that CBD could be a potential medicine for the treatment of depressive and pain symptoms in patients with chronic NP/depression comorbidity.
Owing to its psychotropic effects, Cannabis has been stigmatized by its recreational use leading to a dramatic decline in the experimentations about its medical use in the twentieth century. The medical properties of the plant – known since ancient times – has received increased attention over recent years; yet, the research on its potential application in the field of psychiatry is still nascent. In this connection, the non-psychotropic cannabidiol (CBD) has emerged as a phytocannabinoid compound with promising antipsychotic effects. In addition, advances in our understanding of the endocannabinoid system, along with accumulating evidence implicating this system in the pathophysiology of schizophrenia, have stimulated research by the pharmaceutical industry to explore whether alteration of this system can be of medical benefit. This review examines the current state of evidence regarding the clinical potential of cannabinoid-based drugs as a treatment for schizophrenia, while discussing various limitations with the therapeutic approaches considered so far. In the second part, the author highlights the most promising strategies, as well as the most interesting directions one could follow, in the emerging field of cannabinoid therapies for schizophrenia.
Background:
Cannabidiol (CBD), a major nonintoxicating constituent of cannabis, exhibits anxiolytic properties in preclinical and human studies and is of interest as a novel intervention for treating anxiety disorders. Existing first-line pharmacotherapies for these disorders include selective serotonin reuptake inhibitor and other antidepressants. Cannabidiol has well-described inhibitory action on cytochrome P450 (CYP450) drug-metabolizing enzymes and significant drug-drug interactions (DDIs) between CBD and various anticonvulsant medications (eg, clobazam) have been described in the treatment of epilepsy. Here, we examined the likelihood of DDIs when CBD is added to medications prescribed in the treatment of anxiety.
Methods:
The effect of CBD on CYP450-mediated metabolism of the commonly used antidepressants fluoxetine, sertraline, citalopram, and mirtazapine were examined in vitro. Cannabidiol-citalopram interactions were also examined in vivo in patients (n = 6) with anxiety disorders on stable treatment with citalopram or escitalopram who received ascending daily doses of adjunctive CBD (200-800 mg) over 12 weeks in a recent clinical trial.
Results:
Cannabidiol minimally affected the metabolism of sertraline, fluoxetine, and mirtazapine in vitro. However, CBD significantly inhibited CYP3A4 and CYP2C19-mediated metabolism of citalopram and its stereoisomer escitalopram at physiologically relevant concentrations, suggesting a possible in vivo DDI. In patients on citalopram or escitalopram, the addition of CBD significantly increased citalopram plasma concentrations, although it was uncertain whether this also increased selective serotonin reuptake inhibitor-mediated adverse events.
Conclusions:
Further pharmacokinetic examination of the interaction between CBD and citalopram/escitalopram is clearly warranted, and clinicians should be vigilant around the possibility of treatment-emergent adverse effects when CBD is introduced to patients taking these antidepressants.
Cannabis has been used for hundreds of years, with its ability to dampen feelings of anxiety often reported as a primary reason for use. Only recently has the specific role cannabinoids play in anxiety been thoroughly investigated. Here we discuss the body of evidence describing how endocannabinoids and exogenous cannabinoids are capable of regulating the generation and termination of anxiety states. Disruption of the endogenous cannabinoid (eCB) system following genetic manipulation, pharmacological intervention or stress exposure reliably leads to the generation of an anxiety state. On the other hand, upregulation of eCB signaling is capable of alleviating anxiety-like behaviors in multiple paradigms. When considering exogenous cannabinoid administration, cannabinoid receptor 1 (CB1) agonists have a biphasic, dose-dependent effect on anxiety such that low doses are anxiolytic while high doses are anxiogenic, a phenomenon that is evident in both rodent models and humans. Translational studies investigating a loss of function mutation in the gene for fatty acid amide hydrolase, the enzyme responsible for metabolizing AEA, have also shown that AEA signaling regulates anxiety in humans. Taken together, evidence reviewed here has outlined a convincing argument for cannabinoids being powerful regulators of both the manifestation and amelioration of anxiety symptoms, and highlights the therapeutic potential of targeting the eCB system for the development of novel classes of anxiolytics.
This article is part of the special issue on ‘Cannabinoids'.
The concept of well-being is a common topic in both human and veterinary medicine with a wide-ranging and highly debated definition (Zainuddin and Russell-Bennett 2017; Charlemagne-Badal et al. 2015). In its broadest sense, “well-being” encompasses all aspects of an individual’s life and experiences. It can be viewed as a multi-dimensional coordination of “an intersecting triumvirate of emotional, physical, and cognitive self” (Charlemagne-Badal et al. 2015; Gillett-Swan and Sargeant 2015).
A person ingesting or smoking cannabis experiences a fairly predictable sequence of physiologic and psychologic changes that last a few hours and then gradually disappear. Although dose administered and individual differences in personality, expectations, setting, and past drug experience all contribute to varied consequences from a given dose of cannabis, the variability in acute effects from cannabis seems no greater than with any other psychoactive drug. Recently, a number of reviews and collections of papers have appeared that attempt to cover the vast amount of information accumulating about the acute and chronic effects of cannabis (Bech et al., 1974; Brecher, 1975; Committee on Drugs, 1975; Edwards, 1974; Hollister, 1974a; Kalant and Kalant, 1974; Kaymakcalan, 1975; Lemberger and Rubin, 1975; McGlothlin, 1975; Mechoulam et al., 1976; Miller, 1974; Nahas, 1975a, b). Some authors have attempted to consider the research findings in the context of political-social decisions (Edwards, 1974; Pillard, 1974) and point out the lacunae in the data as well as the well-established facts (Edwards, 1974). Other reviews tend to emphasize possible adverse effects (Nahas, 1975a, b; Kaymakcalan, 1975), legal versus health issues (Brecher, 1975), or the chemistry of cannabis (Lemberger and Rubin, 1975; Mechoulam et al., 1976). The continuing research efforts this past year have attempted to fill some of the gaps. Research papers on cannabis are appearing at an average rate of more than one per day and about a third of them deal with effects in humans. Thus, a single detailed review of the literature is becoming an almost impossible task.
A synthetic isomer of tetrahydrocannabinol (1-Δ'-3,4-transtetrahydrocannabinol), believed to be identical to the most active naturally occurring THC, was compared with a semisynthetic THC-like compound, synhexyl. Sixteen volunteer subiects received THC in doses ranging from 341 to 946 p.g per kilo gram (median 581). Thirteen subjects received synhexyl in doses ranging from 633 to 2,666 µg per kilogram (median 1,370). Clinical syndromes tram the 2 drugs were similar, although synhexyl was slower in onset and only about one third as potent. The clinical effects resembled those of psychotomimetics such as LSD, at least at the higher doses. These drugs differed from LSD in the following respects: sedation was prominent; euphoria was langer lasting; dreamlike sequences more pronounced; and physiological and biochemical effects were somewhat different, especially in the absence of sympathomimetic effects.
Forty Army volunteers were given a synthetic tetrahydrocannabinol (THC) compound similar in structure and physiological activity to the active component of marihuana. Significant relationships were found between the personalities of these volunteers as measured by the Minnesota Multiphasic Personality Inventory (MMPI) and the Army General Intelligence Test (GT), and performance on objective tests following administration of this compound. Several MMPI scales and the GT score appeared to be as strongly correlated with performance as was the dose level. MMPI and GT test interpretation of subjects resistant to the performance impairment caused by this compound showed them to be more intelligent, adventurous, and more hostile and aggressive than sensitive subjects. A possible explanation for continued use of marihuana by certain personality types is offered.
It is sometimes useful in an analysis of variance to split the treatments into reasonably homogeneous groups. Multiple comparison procedures are often used for this purpose, but a more direct method is to use the techniques of cluster analysis. This approach is illustrated for several sets of data, and a likelihood ratio test is developed for judging the significance of differences among the resulting groups.
Twelve chronic marijuana users received ▵9-tetrahydrocannabinol by smoking. The magnitude of their pulse increment was highly correlated with their subjective experiences.
Three of the 12 subjects subsequently received ▵9-tetrahydrocannabinol labeled with carbon-14; the time course of its concentration in plasma was highly correlated with the
pulse increment. Subjective symptoms, however, appeared later and dissipated more slowly.
The pharmacological activity of several doses of &karsi028;8-THC and &karsi028;9-TΗC was studied comparatively using rats (climbing rope test), mice (catatonia and spontaneous motor activity tests) and rabbits (Gayer test) and also human volunteers (pulse rate, time discrimination and subjective symptoms). &karsi028;9-TΗC was twice as active as &karsi028;8-THC in rats and mice; both compounds were equiactive in rabbits. In man &karsi028;9-THC revealed to be nearly twice as active as its isomer. There were no qualitative differences between both drugs neither in man nor in the laboratory animals.
The experiment was conducted on a double blind basis according to a completely randomized design. There were four groups consisting of six subjects each as follows: propranolol pretreatment plus marihuana; propranolol pretreatment plus placebo marihuana; placebo propranolol pretreatment plus marihuana; and placebo propranolol pretreatment plus placebo marihuana. Smoking of active marihuana resulted in a significant increase in heart rate. The prior administration of propranolol antagonized the marihuana induced tachycardia both in magnitude and duration. However, propranolol pretreatment neither decreased the number of responses on the Cornell Medical Index following the smoking of marihuana nor interfered with the subject's ability to distinguish active marihuana from placebo marihuana.
Cannabinol (CBN) and Cannabidiol (CBD) were tested in several test procedures known to be altered by
9-tetrahydrocannabinol (THC) or crude cannabis preparations. They were inactive in doses up to 80 mg/kg in tests on animal motility, food and water intake, body temperature and catalepsy. In contrast, CBD enhanced the hexobarbitone sleeping time more pronounced than
9-THC whereas CBN increased the sleeping time only slightly. When administered in combination CBD prolonged all actions of THC, whereas CBN selectively blocked the effect of THC on hexobarbitone sleeping time. The enhancement by CBD is best explained by an inhibition of THC-metabolism.
1.
The objective and subjective effects of 0.5 and 1.5 mcg/kg of LSD intramuscularly were compared with those of 75 and 225 mcg/kg of (-)-
9-trans-tetrahydrocannabinol by smoking in the same eight subjects.
2.
The objective effects of LSD and THC differed markedly. LSD increased body temperature, systolic and diastolic blood pressure, lowered the threshold for the knee-jerk, and dilated the pupils. THC had none of these effects but caused more marked tachycardia than did LSD.
3.
The subjective effects of the two drugs could not be readily distinguished by the methods used. Both LSD and THC are psychotomimetic drugs.
4.
Patients tolerant to LSD were not cross-tolerant to THC, indicating that the mental effects of the two drugs are probably mediated by different mechanisms.
Le cannabidiol administr dose de 100 mg par os et de 30 mg par injection i.v. fut inactif dans les sujets d'tude. Le cannabinol, dose orale de 400 mg, le fut aussi. Ces constituants du cannabis ne contribuent donc pas l'effet pharmacologique.
Se hizo un estudio comparativo de la actividad del
9-tetrahidrocannabinol, cannabinol, y cannabidiol en producir efectos similares a la marihuana cuando son inyectados i.v. a humanos. Estas substancias son los componentes predominantes de la marihuana o del hashish. Se encontro que a las dosis inyectados cannabidiol no tiene ninguna potencia, y que cannabinol es capaz de producir efectos tipicos de la marihuana, aunque a dosis varias veces mas grandes que las del
9-tetrahidrocannabinol.
A “custom-built” inventory for assessing subjective effects of drugs, the Addiction Research Center Inventory (ARCI), was
developed from the use of “sentence completion” and other association techniques on male subjects under drug and no-drug conditions.
In addition to demonstrated “drug-sentitive” questions, the final form of the inventory (550 “true-false” items) also contains
items which may delineate to some extent schizoid and “psychopathic” characteristics. The format is similar to that of the
MMPI and the content has a fairly wide range. Initial use indicates that the inventory is effective in differentiating various
subjective effects of drugs and in discriminating some similarities and differences of naturally occurring and experimentally
induced behavioral abnormalities. Results also indicate that the effectiveness of specially designed tests, whether in the
form of complete sentences or adjective check lists, chiefly depends upon assessment of the “activitysedation” continuum and
allied changes in motivation, alterations in mood such as in a “euphoria-dysphoric” continuum, alterations in sensation and
perception, and in reportable physiological processes.
Based on previous observations that cannabidiol (CBD) blocks some effects of Δ9-tetrahydrocannabinol (Δ9-THC) in laboratory animals, the present work was carried out to study possible interaction between CBD and Δ9-THC in human beings. In a double blind procedure, 40 healthy male volunteers were assigned to 1 of 8 experimental groups, receiving per oral route, placebe, 30 mg Δ9-THC, 15 30 or 60 mg of CBD, and mixtures of 30 mg of Δ9-THC plus either 15, 30 or 60 mg of CBD respectively. Pulse rate, time production tasks and psychological logical reactions were measured at several time intervals after drug ingestion. 30 mg Δ9-THC alone increased pulse rate, disturbed time tasks and induced strong psychological reactions in the subjects. 15–60 mg of CBD alone provoked no effects. On the other hand, CBD was efficient in blocking most of the effects of Δ9-THC when both drugs were given together. CBD also decreased the anxiety component of Δ9-THC effects, in such a way that the subjects reported more pleasurable effects.
Administered 16 visual analog scales to 8 normal Ss to test the validity of the scales in measuring drug effects; Ss received 150 mg of butobarbitone sodium, 15 and 30 mg of flurazepam, and a placebo. Results indicate that (a) there were no significant effects on Factor 1 (Alertness), but there was a tendency for Ss to rate themselves as more alert after placebo; (b) there was a significant Drug * Times interaction effect on Factor 2 (Contentedness); and (c) Factor 3 (Calmness) also showed a significant Drug * Times interaction effect which was caused by the anti-anxiety effect of flurazepam. (15 ref) (PsycINFO Database Record (c) 2004 APA, all rights reserved)
In the acute experiment six healthy volunteers were given orally two doses of lithium chloride, 16 and 32 mmol, and placebo sodium chloride 32 mmol in a double-blind standardized procedure, with a 1-week interval between treatments. Compared to sodium, lithium produced a decrease in subjective well-being, decrease of skin conductance fluctuations, and increase in plasma calcium concentrations. Dose-related effects were maximal at the first hour after ingestion, decreasing or disappearing at 3–5h. Most effects did not correlate with plasma or erythrocyte lithium concentrations, but drug effects and feelings of nausea were highly correlated. Accordingly, most acute effects seemed due to peripheral drug effects.
In the chronic experiment six healthy volunteers were given orally 16 mmol of lithium chloride or sodium chloride (placebo) twice a day for 1 week in a double-blind standardized procedure with a 2-week interval between treatment weeks. Compared to placebo, lithium produced feelings of subjective impairment, an increase in EEG slow waves and of auditory evoked response variability, a deficit in long-term memory, and an increase in plasma magnesium concentrations. Most lithium effects did not correlate with plasma or erythrocyte lithium concentrations.
The actions of cannabidiol (CBD), one of the cannabis constituents, were assessed on the sleep-wakefulness cycle of male Wistar rats.
During acute experiments, single doses of 20 mg/kg CBD decreased slow-wave sleep (SWS) latency. After 40 mg/kg SWS time was significantly increased while wakefulness was decreased. REM sleep was not significantly modified. Following the once-daily injections of 40 mg/kg CBD for a period of 15 days, tolerance developed to all the above-mentioned effects.
Fifteen adult male marihuana smokers volunteered to live on a hospital research ward for a 31-day study which included a five-day baseline, a 21-day marihuana smoking period and a concluding five-day baseline. Subjects rated their moods and level of intoxication each day at scheduled occasions. Analyses of variance indicated a significant trend in the mood ratings which increased slightly in the euphoric direction just before smoking marihuana (compared to routine ratings) and further increased slightly after smoking marihuana. Level of intoxication ratings and mood ratings were not significantly correlated, but an intoxicated subject's mood ratings were significantly correlated with the average mood ratings of other subjects intoxicated or not. The results suggest that marihuana may increase a person's susceptibility to the moods of others and the feeling of being in harmony with others may be a positive reinforcer.
The effect of marijuana on memory as measured by free recall and recognition, pulse rate and self ratings of intoxication was evaluated in 16 male volunteers. Marijuana containing 0, 5, 10 or 15 mg delta9-THC was administered to all subjects by smoking in 4 sessions separated by a 1 week interval. Free recall was reduced in a dose related manner by the drug, but recognition memory was unaffected. A 2 sec word presentation rate produced inferior recall in comparison to a 4 sec rate, but this variable did not interact with drug condition. Intrusion errors increased following intoxication but this effect was not systematically related to dosage of delta9-THC. Both pulse rate and self ratings of intoxication increased with dosage.
Experiments investigating the possible interaction of tetrahydrocannabinol (THC) and cannabidiol (CBD), two major components of marihuana, were conducted under controlled laboratory conditions in a double-blind manner. In one study, 15 male volunteers were given placebo or 25 mug/kg of THC together with either placebo or 150 mug/kg of CBD by inhalation of the smoke of a single cigarette. All four treatments were assigned to each subject according to a series of Latin-square designs. CBD significantly attenuated the subjective euphoria of THC. Psychomotor impairment due to THC was not significantly altered by the simultaneous administration of CBD, but a trend indicating a decrease in THC-like effects was observed after the combination. When administered alone CBD was inactive for all the parameters measured. In a second study, 8 male subjects were given CBD (0 or 150 mug/kg) by smoke inhalation 30 min before THC (0 or 25 mug/kg) in a second cigarette. In contrast to the simultaneous administration of both drugs, CBD pretreatment did not alter the effects of THC on the parameters observed.
To examine the interaction of marijuana and an induced state of stress, on both subjective and physiological measures, two groups of 15 subjects each were given a mental arithmetic task to perform. The sequence of events was 10 min each of pre-stress, stress, post-stress, intoxication (about 20 min), pre-stress, stress, post-stress. In the intoxication phase, one group smoked marijuana containing 14 mg Δ9-THC while the other group smoked a placebo. The dependent variables were forearm blood flow (FBF), heart rate (HR). and skin conductance (SC), and a subjective measure of stress–the Multiple Affect Adjective Checklist (MAACL).
The results revealed all physiological variables to be reactive to the stress task. In addition, marijuana intoxication produced reliable increases in both pre-stress HR and FBF, and yet the physiological response to the post-intoxication stress period showed no significant decrement when compared In the placebo group. Discussion of these results centered around marijuana's effects on tonic and phasic reactivity.
Ten healthy volunteers were given orally 0.33 and 0.67 mg/kg of trazodone, 0.50 mg/kg of imipramine, 0.067 mg/kg of diazepam and placebo in a double blind standardization procedure with a 2 wk interval between treatments. Compared to placebo, trazodone produced subjective feelings of impairment and decrement in motor performance. There were increases in the percentages of slow waves and total voltage of the EEG and in the amplitude (P2-N2) of the EEG evoked response. The skin conductance (sweating), the percentage of fast waves in the EEG, the peak frequency of finger tremor, the pupil size and the diastolic blood pressure decreased with trazodone. In most tests, dose related effects were present. In many, actions were maximal in the 1st hr, decreasing or disappearing by 3 hr. Diazepam was no different from placebo in most tests but any effects which did occur were opposite to those of trazodone, with increase, for example, in the proportion of fast wave activity in the EEG. Some central effects of imipramine resembled those of trazodone, e.g., the increase in some slow waves in the EEG. In most tests, however, it was less active, producing less subjective impairment; in others, it acted differently, e.g., increasing the peak frequency of finger tremor. These results indicate a profile of action in normal subjects for trazodone which is atypical of both anoxiolytic and antidepressant drugs.
The administration of delta9THC intravenously as a premedicant to oral surgery resulted in acute pronounced elevations in anxiety states, a predominance of dysphoria over euphoria, and varying degrees of psychotic-like paranoiac thought. Neural effects that appeared to promote these effects included distortions of perception with sensory delusions, and heightened sensory receptiveness including antalgesic impressions of surgery; autonomic and visceral arousal greater than control or placebo levels; lack of overt behavioral signals of distress due to depersonalization; and time disintegration leading to fear-inducing misinformation about real surgical events. Introverted subjects who generally were inclined to rely on drug solutions to their problems tended to respond poorly to surgical pain and anxiety with delta9THC. These results, obtained from subjects considered to have levels of presurgical apprehension that were average or below average, suggest that the environment in which high doses of cannabinols are experienced is a potent factor in determining the quality of the emotional response. A surgical environment containing even the mild stress of outpatient oral surgery appears to have the potential to precipitate undesirable emotional responses among cannabinol-intoxicated patients. There is continued high-level social use of cannabinols inour society, with an estimate of 40% to 55% among the college-age group seen frequently by oral surgeons. Results of this study suggest that clinicians should be prepared to detect the subtle signs of marijuana intoxication to protect their patients from further psychophysiologic complications during surgery.
Oral doses of delta-9-tetrahydrocannabinol (THC) 20 mg, combined with placebo or with 40 mg dses of cannabinol (CBN) and cannabidiol (CBD), were given to volunteers. The combination of THC with CBN produced no detectable changes in the quality, intensity, or duration of the effects of THC alone. The THC-CBD combination tended to delay onset and prolong effects of THC, while making them somewhat more intense. Even this interactive effect was slight, providing no reason to abandon the current practice of basing doses of marihuana for clinical studies solely on THC content.
Delta9-Tetrahydrocannabinol (THC), the active component of marijuana, was studies to determine whether it might be useful for preanesthetic medication. Ten healthy subjects received THC intravenously in logarithmically spaced incremental doses. Four subjects received a total cumulatine dose of 135 mug/kg and four others, 201 mug/kg, Two of the ten subjects discontinued the study because of anxiety reactions. Ventilatory minute volume at a controlled elevated CO2 tension, 48 plus or minus 2 (SD) torr, changed minimally with TCH, -0.49 1/min/50 per cent increase in dose. TCH shifted the ventilatory response to CO22.7 torr destrad at 20 1/min without a change in slope. Dose-related tachycardia was the most marked cardiovascular effect. Heart rates increased to more than 100/min in five of six subjects. Cardiac index increased from 4.04 plus or minus 0.62 1/min/m-2 before TCH to 6.92 plus or minus 2.34 1/min/m-2 after 134 mug/kg. Mean arterial pressure increased slightly, and total peripheral resistance fell. The cardiovascular changes suggest beta-adrenergic stimulation. Intense mental effects and anxiety prohibited higher THC doses.
Graded doses of marihuana were administered to five adults in a longitudinal repeated-measurements design. Speed of response was the basic parameter measured accross tests of increasing cognitive involvement. Marihuana produced significant dose-response effects of impaired performance in all test scores. However, single automatic motor abilities demonstrated greater sensitivity than tests of greater complexity. Evidence is presented for tolerance development.
A psychopharmacological review is given of cannabis and Δ1 tetrahydrocannabinol (THC). THC is probably the predominant psychoactive component in cannabis (or precursor of an active metabolite). Cannabis intoxication has specific characteristics, especially the increase in time and distance estimation. In high doses, cannabis and THC exert effects which cannot be distinguished from that of true hallucinogens, such as LSD; it is however, reasonable to place cannabis in a distinct category of its own due to the lack of cross tolerance with the hallucinogens, and the lack of (or very limited) development of tolerance. Brain damage or persisting psychic changes after prolonged cannabis use have not been proved at acceptable scientific standards, and these important problems are thus unsolved. Cannabis has its own distinct profile of action, and it is thus not possible to extrapolate from the effects of cannabis to the effects of other psychoactive substances, or vice versa.
Two experiments tested whether laboratory stressors induce greater or more variable anxiety in marijuana-intoxicated subjects. In experiment 1, marijuana and placebo subjects were shown a motion picture film depicting dental procedures. In experiment 2, they were subjected to the stress of giving a short videotaped speach. We found no significant difference between marijuana and placebo subjects in anxiety response to these two stressors, as measured by a mood adjective rating scale.
Studies were conducted into the effects of cannabidiol (CBD), a relatively inactive constituent of cannabis, on behavioral actions of Δ9 tetrahydrocannabinol (Δ9 THC). CBD pretreatment in both rat (25 mg/kg) and pigeon (50 mg/kg) significantly reduced the depressant effects of Δ9 THC (1 to 3 mg/kg) on variable interval and fixed interval schedules of food reinforced operant behavior. The doses of CBD employed had no effect on the behavioral parameters, although higher doses did produce behavioral inhibition. The data suggest that cannabidiol may function as a partial agonist in relation to certain effects of Δ9 THC.
Twelve chronic marijuana users received triangle up(9)-tetrahydrocannabinol by smoking. The magnitude of their pulse increment was highly correlated with their subjective experiences. Three of the 12 subjects subsequently received triangle up(9)-tetrahydrocannabinol labeled with carbon-14; the time course of its concentration in plasma was highly correlated with the pulse increment. Subjective symptoms, however, appeared later and dissipated more slowly.
Conducted 2 experiments with a total of 120 males (mean age = 23 yr.) to determine to what extent marihuana intoxication is the result of drug effects, expectancy, social setting, or an interaction of these factors. In Exp. I, Ss 1st swallowed a placebo pill and then smoked either 2 placebo cigarettes or two marihuana cigarettes containing a total of l5 mg. D9-tetrahydrocannabinol (THC). The cigarettes were smoked in a setting designed to either facilitate intoxication ("up night") or interfere with it ("down night") through manipulation of S's expectancy and through modeling. Results indicate that the amount of marihuana smoked impaired cognitive functioning and was rated as more intoxicating than the placebo. Manipulations of setting and belief had no effect. In Exp. II, Ss smoked 2 cigarettes containing either placebo, 7.5 mg. THC, or l5 mg. THC. Ss who smoked placebo cigarettes 1st swallowed a pill containing either 10 or 25 mg. librium (chlordiazepoxide). Ss who smoked cigarettes containing THC received placebo pills. Smoking was done in either "up night" or "down night" contexts. Results suggest that social setting and belief interact with smaller doses of marihuana but not with large doses nor with placebo.
The past 3 years of renewed research on the effects of marihuana in man has added little not previously known about the clinical syndromes produced by the drug. The major advance has been a quantification of dose in relation to clinical phenomena, and a beginning of an understanding of the drug's metabolism. The crucial clinical experiments in regard to the social questions about marihuana, such as the possible deleterious effects from chronic use, cannot be answered by laboratory experiments. These must be settled by close observations made on those who experiment on themselves. It should be possible, within a relatively short time, to determine whether marihuana has any medical utility, but the future would appear to be no more promising than the past in this regard. The mechanisms by which marihuana alters mental functions are not likely to be answered in man, nor even answered soon by animal studies. As marihuana may be unique among drugs in that more experimentation has been accomplished in man than in animals, it may be necessary to look to additional animal studies to provide leads for pertinent future studies in man.
Nitrazepam (7.5 mg and 10 mg) was compared with sodium phenobarbitone (200 mg orally) in man. Suppression of smooth tracking eye movement, subjective effects and performance on the digit-symbol substitution test were recorded. Nitrazepam (7.5 mg) had significantly less oculomotor effect but significantly more subjective effects than phenobarbitone. This finding is related to the evidence that smooth tracking suppression arises from drug action on brain stem systems, and the evidence that benzodiazepines affect brain stem systems less than the limbic system. The nature of the muscular effects of the drugs is discussed.