PURPOSE: Previous studies have shown that tetrahydrocannabinol (THC), the main psychoactive component of cannabis, can impair cognitive abilities. There is also some evidence that cannabidiol (CBD), the most abundant non-intoxicating constituent of cannabis, can attenuate these effects. The purpose of this study was to investigate the effects of THC, CBD oromucosal spray (with equal parts THC and CBD) on cognition compared with control conditions in human studies.
METHODS: A systematic literature search was performed on four major bibliographic databases. Studies were included in the present review if they evaluated the cognitive effects of THC, CBD oromucosal spray compared with a control condition.
RESULTS: Ten studies were identified (7 on patients with multiple sclerosis, 1 on those with Huntington, and 2 on healthy volunteers) with 510 participants in total. There was considerable heterogeneity among the studies in terms of dose and duration of administration. All studies have used an equal or nearly equal dose of THC and CBD.
CONCLUSIONS: Although the results across studies were somewhat inconsistent, most evidence revealed that there is no significant difference between THC, CBD oromucosal spray and control treatments in terms of cognitive outcomes. However, more trials are needed with longer follow-up periods, and dose considerations, particularly comparing lower and higher doses of the spray.
ABSTRACT: Background: Δ9-Tetrahydrocannabinol (THC), the main intoxicating component of cannabis, can cause cognitive and psychomotor impairment. Whether this impairment is still present many hours or even days after THC use requires clarification. Possible "next day" effects are of major significance in safety-sensitive workplaces. We therefore conducted a systematic review of studies investigating the "next day" effects of THC. METHODS: Studies that measured performance on safety-sensitive tasks (e.g., driving, flying) and/or neuropsychological tests >8 h after THC (or cannabis) use using interventional designs were identified by searching two online databases from inception until March 28, 2022. Risk of bias (RoB) was evaluated using the relevant Cochrane tools. Results were described in terms of whether THC had a significant effect on performance relative to the primary comparator (i.e., placebo or baseline, as appropriate). RESULTS: Twenty studies (n=458) involving 345 performance tests were reviewed. Most studies administered a single dose of THC (median [interquartile range]: 16 [11-26] mg) and assessed performance between >12 and 24 h post-treatment. N=209/345 tests conducted across 16 published studies showed no "next day" effects of THC. Nine of these 16 studies used randomized, double-blind, placebo-controlled designs. Half (N=8) had "some" RoB, and half (N=8) had a "high" RoB. Notably, N=88 of these 209 tests failed to demonstrate "acute" (i.e., <8 h post-treatment) THC-induced impairment. N=12/345 tests conducted across five published studies indicated negative (i.e., impairing) "next day" effects of THC. None of these five studies used randomized, double-blind, placebo-controlled designs and all were published >18 years ago (four, >30 years ago). Three had "some" RoB, and two had a "high" RoB. A further N=121/345 tests indicated "unclear" "next day" effects of THC with insufficient information provided to assess outcomes. The remaining N=3/345 tests indicated positive (i.e., enhancing) "next day" effects of THC. CONCLUSIONS: Some lower quality studies have reported "next day" effects of THC on cognitive function and safety-sensitive tasks. However, most studies, including some of higher quality, have found no such effect. Overall, it appears that there is limited scientific evidence to support the assertion that cannabis use impairs "next day" performance. Further studies involving improved methodologies are required to better address this issue.
BACKGROUND: Spasticity and chronic neuropathic pain are common and serious symptoms in people with multiple sclerosis (MS). These symptoms increase with disease progression and lead to worsening disability, impaired activities of daily living and quality of life. Anti-spasticity medications and analgesics are of limited benefit or poorly tolerated. Cannabinoids may reduce spasticity and pain in people with MS. Demand for symptomatic treatment with cannabinoids is high. A thorough understanding of the current body of evidence regarding benefits and harms of these drugs is required.
OBJECTIVES: To assess benefit and harms of cannabinoids, including synthetic, or herbal and plant-derived cannabinoids, for reducing symptoms for adults with MS.
SEARCH METHODS: We searched the following databases from inception to December 2021: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), CINAHL (EBSCO host), LILACS, the Physiotherapy Evidence Database (PEDro), the World Health Organisation International Clinical Trials Registry Platform, the US National Institutes of Health clinical trial register, the European Union Clinical Trials Register, the International Association for Cannabinoid Medicines databank. We hand searched citation lists of included studies and relevant reviews.
SELECTION CRITERIA: We included randomised parallel or cross-over trials (RCTs) evaluating any cannabinoid (including herbal Cannabis, Cannabis flowers, plant-based cannabinoids, or synthetic cannabinoids) irrespective of dose, route, frequency, or duration of use for adults with MS.
DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane Risk of bias 2 tool for parallel RCTs and crossover trials. We rated the certainty of evidence using the GRADE approach for the following outcomes: reduction of 30% in the spasticity Numeric Rating Scale, pain relief of 50% or greater in the Numeric Rating Scale-Pain Intensity, much or very much improvement in the Patient Global Impression of Change (PGIC), Health-Related Quality of Life (HRQoL), withdrawals due to adverse events (AEs) (tolerability), serious adverse events (SAEs), nervous system disorders, psychiatric disorders, physical dependence.
MAIN RESULTS: We included 25 RCTs with 3763 participants of whom 2290 received cannabinoids. Age ranged from 18 to 60 years, and between 50% and 88% participants across the studies were female. The included studies were 3 to 48 weeks long and compared nabiximols, an oromucosal spray with a plant derived equal (1:1) combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (13 studies), synthetic cannabinoids mimicking THC (7 studies), an oral THC extract of Cannabis sativa (2 studies), inhaled herbal Cannabis (1 study) against placebo. One study compared dronabinol, THC extract of Cannabis sativa and placebo, one compared inhaled herbal Cannabis, dronabinol and placebo. We identified eight ongoing studies. Critical outcomes • Spasticity: nabiximols probably increases the number of people who report an important reduction of perceived severity of spasticity compared with placebo (odds ratio (OR) 2.51, 95% confidence interval (CI) 1.56 to 4.04; 5 RCTs, 1143 participants; I2 = 67%; moderate-certainty evidence). The absolute effect was 216 more people (95% CI 99 more to 332 more) per 1000 reporting benefit with cannabinoids than with placebo. • Chronic neuropathic pain: we found only one small trial that measured the number of participants reporting substantial pain relief with a synthetic cannabinoid compared with placebo (OR 4.23, 95% CI 1.11 to 16.17; 1 study, 48 participants; very low-certainty evidence). We are uncertain whether cannabinoids reduce chronic neuropathic pain intensity. • Treatment discontinuation due to AEs: cannabinoids may increase slightly the number of participants who discontinue treatment compared with placebo (OR 2.41, 95% CI 1.51 to 3.84; 21 studies, 3110 participants; I² = 17%; low-certainty evidence); the absolute effect is 39 more people (95% CI 15 more to 76 more) per 1000 people. Important outcomes • PGIC: cannabinoids probably increase the number of people who report 'very much' or 'much' improvement in health status compared with placebo (OR 1.80, 95% CI 1.37 to 2.36; 8 studies, 1215 participants; I² = 0%; moderate-certainty evidence). The absolute effect is 113 more people (95% CI 57 more to 175 more) per 1000 people reporting improvement. • HRQoL: cannabinoids may have little to no effect on HRQoL (SMD -0.08, 95% CI -0.17 to 0.02; 8 studies, 1942 participants; I2 = 0%; low-certainty evidence); • SAEs: cannabinoids may result in little to no difference in the number of participants who have SAEs compared with placebo (OR 1.38, 95% CI 0.96 to 1.99; 20 studies, 3124 participants; I² = 0%; low-certainty evidence); • AEs of the nervous system: cannabinoids may increase nervous system disorders compared with placebo (OR 2.61, 95% CI 1.53 to 4.44; 7 studies, 1154 participants; I² = 63%; low-certainty evidence); • Psychiatric disorders: cannabinoids may increase psychiatric disorders compared with placebo (OR 1.94, 95% CI 1.31 to 2.88; 6 studies, 1122 participants; I² = 0%; low-certainty evidence); • Drug tolerance: the evidence is very uncertain about the effect of cannabinoids on drug tolerance (OR 3.07, 95% CI 0.12 to 75.95; 2 studies, 458 participants; very low-certainty evidence).
AUTHORS' CONCLUSIONS: Compared with placebo, nabiximols probably reduces the severity of spasticity in the short-term in people with MS. We are uncertain about the effect on chronic neurological pain and health-related quality of life. Cannabinoids may increase slightly treatment discontinuation due to AEs, nervous system and psychiatric disorders compared with placebo. We are uncertain about the effect on drug tolerance. The overall certainty of evidence is limited by short-term duration of the included studies.
BACKGROUND: Tremor is a relatively common symptom in Multiple Sclerosis (MS). It can negatively affect several aspects of the patients' life and is one of the most disabling symptoms in MS. Pharmacological treatment of MS-related tremor was studied for several years, though treatment is still challenging. This study will review all studies on the pharmacological treatment of tremor in MS and update the treatment recommendations.
METHODS: Any relevant English-language clinical trial that investigated the pharmacological treatment of MS-related tremor in adults was eligible in this study. We searched Medline (PubMed), Scopus, EMBASE, and Web of Science. Bias assessment was performed by the CASP (Critical Appraisal Skills Programme) checklist. All methods followed PRISMA guidelines.
RESULTS: The initial search resulted in 3024 articles; 26 articles were included as eligible studies, 13 articles had a low risk of bias, and remained for full manuscript review. The results of studies on 5-HT3 receptor antagonists as a single dose treatment were inconsistent. Botulinum toxin A had significant effects on MS-related tremor, but adverse effects and injection procedures limited its application. The application of cannabis-based medicine to treat MS-related tremor could not be recommended due to inconclusive therapeutic effects and several side effects. Levetiracetam had inconsistent results, and other anti-epileptic drugs were not studied precisely. Isoniazid has minor therapeutic effects and possible adverse effects in the treatment of MS-related tremor.
CONCLUSION: Further well-designed comparative clinical trials with a large sample size can improve clinical management of tremor in patients with MS.
BACKGROUND: Overactive bladder (OAB) symptoms of frequency, urgency and urge incontinence are frequently associated with known neurological diseases like multiple sclerosis (MS), spinal cord injury (SCI), Parkinson's disease (PD), stroke.
OBJECTIVE: The aim of our study was to review the efficacy of pharmacological and non-pharmacological treatments for neurogenic overactive bladder.
MATERIALS AND METHODS: We searched two electronic databases (PubMed and EMBASE) for randomized controlled trials focusing on pharmacological and non-pharmacological medical treatments for overactive bladder symptoms associated with neurological diseases published up to 30 April 2022.
RESULTS: A total of 157 articles were retrieved; 94 were selected by title and abstract screening; after removal of 17 duplicates, 77 records were evaluated by full-text examination. Sixty-two studies were finally selected. The articles selected for review focused on the following interventions: anticholinergics (n = 9), mirabegron (n = 5), comparison of different drugs (n = 3), cannabinoids (n = 2), intravesical instillations (n = 3), botulinum toxin (n = 16), transcutaneous tibial nerve stimulation (TTNS) (n = 6), acupuncture (n = 2), transcutaneous electrical nerve stimulation TENS (n = 4), pelvic floor muscle training (PFMT) (n = 10), others (n = 2). Anticholinergics were more effective than placebo in decreasing the number of daily voids in patients with PD (mean difference [MD]- 1.16, 95 % CI - 1.80 to - 0.52, 2 trials, 86 patients, p < 0.004), but no significant difference from baseline was found for incontinence episodes and nocturia. Mirabegron was more effective than placebo in increasing the cystometric capacity in patients with MS (mean difference [MD] 89.89 mL, 95 % CI 29.76 to 150.01, 2 trials, 98 patients, p < 0.003) but no significant difference was observed for symptom scores and bladder diary parameters. TTNS was more effective than its sham-control in decreasing the number of nocturia episodes (MD -1.40, 95 % CI -2.39 to -0.42, 2 trials, 53 patients, p < 0.005) but no significant changes of OAB symptom scores were reported. PFMT was more effective than conservative advice in decreasing the ICIQ symptom score (MD, -1.12, 95 % CI -2.13 to -0.11, 2 trials, 91 patients, p = 0.03), although the number of incontinence episodes was not significantly different between groups.
CONCLUSIONS: The results of the meta-analysis demonstrate a moderate efficacy of all considered treatments without proving the superiority of one therapy over the others. Combination treatment using different pharmacological and non-pharmacological therapies could achieve the best clinical efficacy due to the favorable combination of the different mechanisms of action. This could be associated with fewer side effects due to drug dosage reduction. These data are only provisional and should be considered with caution, due to the few studies included in metaanalysis and to the small number of patients.
BACKGROUND: Cannabis-based medicines are widely used in the treatment of a number of medical conditions. Unfortunately, cognitive disturbances are often reported as adverse events, although conversely, cognitive improvements have been reported. Hence, the objective of the present study was to identify, critically appraise and synthesise research findings on the potential impact of cannabis-based medicines on cognitive functioning.
METHODS: Four databases (EMBASE, PsycINFO, PubMed and Scopus) were systematically searched. Studies were included if they provided findings on the impact of cannabis-based medicines in controlled settings on cognitive functioning measured by recognised cognitive tests in human adults. Study participants were required to be their own case-control, and neither studies on abuse, abstinences, patients with severe neurodegenerative diseases nor cancer-related pain conditions were included. Screening, risk of bias assessment and data extraction were conducted independently by two researchers. Findings were tabulated and synthesised by outcome.
FINDINGS: Twenty-three studies were included, comprising a total of N = 917. Eight studies used Sativex as the cannabis-based medicine two used Epidiolex, two other studies used sprays, three studies used gelatine capsules, five smoked cannabis, two other and finally one studied cannabis withdrawal. Fifteen studies reported non-significant findings; six reported cognitive impairments; one study found cognitive improvement and a single study found improvement following withdrawal. Thirteen studies had cognitive or neuropsychological functioning as the primary outcome.
CONCLUSIONS: Due to a large heterogeneity and methodological limitations across studies, it is not possible to make any definite conclusions about the impact of cannabis-based medicines on cognitive functioning. However, the majority of high-quality evidence points in the direction that the negative impact of cannabis-based medicines on cognitive functioning is minor, provided that the doses of THC are low to moderate. On the other hand, long-term use of cannabis based medicines may still adversely affect cognitive functioning. In the studies that found impaired cognitive functioning to be significant, all of the test scores were either within the normal range or below what would be characterised as a neuropsychologically cognitive impairment.
BACKGROUND: Impairment in cognition is frequently associated with acute cannabis consumption. However, some questions remain unanswered as to which deficits are most prominent and which demographic groups are most vulnerable.
METHODS: A literature search yielded 40 experimental studies of acute administration of partial CB1 receptor agonists (i.e. cannabis, THC, and nabilone) that assessed cognitive dysfunction in 1403 healthy volunteers. Effect size estimates were calculated using the Comprehensive Meta-Analysis for the following six cognitive domains: attention, executive functions, impulsivity, speed of processing, verbal learning/memory, and working memory.
RESULTS: There were small-to-moderate impairments across all cognitive domains. Deficits in verbal learning/memory and working memory were more prominent, whereas attention and impulsivity were the least affected. Meta-regression analysis revealed that the greater the male ratio is in a sample, the greater the negative effect of cannabinoids on speed of processing and impulsivity. Analysis of route of administration showed that the deficits in speed of processing were smaller in the oral, relative to smoking, vaping, and intravenous administration studies. A publication bias was observed.
DISCUSSION: Verbal learning/memory and working memory are most prominently affected by acute administration of partial CB1 receptor agonists. The results are consistent with the residual cognitive effects that have been documented among chronic cannabis users.
ABSTRACT: BACKGROUND: Cannabis is known to have a broad range of effects on behavior, including experiencing a "high" and tranquility/relaxation. However, there are several adverse behavioral sequalae that can arise from cannabis use, depending on frequency of use, potency (e.g., THC content), age of onset, and cumulative exposure. This systematic review examined evidence for cannabis-related adverse behavioral sequalae in otherwise healthy human subjects. METHODS: Following PRISMA guidelines, we conducted a systematic review of cross-sectional and longitudinal studies from 1990 to 2020 that identified cannabis-related adverse behavioral outcomes in subjects without psychiatric and medical co-morbidities from PubMed and PsychInfo searches. Key search terms included "cannabis" OR "tetrahydrocannabinol" OR "cannabidiol" OR "marijuana" AND "anxiety" OR "depression" OR "psychosis" OR "schizophrenia" "OR "IQ" OR "memory" OR "attention" OR "impulsivity" OR "cognition" OR "education" OR "occupation". Results: Our search detected a total of 2,870 studies, from which we extracted 124 relevant studies from the literature on cannabis effects in the non-clinical population. Effects of cannabis on several behavioral sequelae including cognition, motivation, impulsivity, mood, anxiety, psychosis intelligence, and psychosocial functioning were identified. The preponderance of the evidence suggests that frequency of cannabis use, THC (but not CBD) content, age of onset, and cumulative cannabis exposure can all contribute to these adverse outcomes in individuals without a pre-existing medical condition or psychiatric disorder. The strongest evidence for the negative effects of cannabis are for psychosis and psychosocial functioning. CONCLUSIONS: Although more research is needed to determine risk factors for development of adverse behavioral sequelae of cannabis use, these findings underline the importance of understanding vulnerability to the adverse effects of cannabis, which has implications for prevention and treatment of problematic cannabis use.
The increasing legal availability of cannabis has important implications for road safety. This systematic review characterised the acute effects of Δ9-THC on driving performance and driving-related cognitive skills, with a particular focus on the duration of Δ9-THC-induced impairment. Eighty publications and 1534 outcomes were reviewed. Several measures of driving performance and driving-related cognitive skills (e.g. lateral control, tracking, divided attention) demonstrated impairment in meta-analyses of "peak" Δ9-THC effects (p's<0.05). Multiple meta-regression analyses further found that regular cannabis use was associated with less impairment than 'other' (mostly occasional) cannabis use (p = 0.003) and that the magnitude of oral (n = 243 effect estimates [EE]) and inhaled (n = 481 EEs) Δ9-THC-induced impairment depended on various factors (dose, post-treatment time interval, the performance domain (skill) assessed) in other cannabis users (p's<0.05). The latter model predicted impairment would take ∼7 -hs to subside (Hedges' g=-0.25) after inhaling 20 mg of Δ9-THC; oral Δ9-THC-induced impairment may take longer to subside. These results suggest individuals should wait at least 7 -hs following inhaled cannabis use before performing safety-sensitive tasks.
Previous studies have shown that tetrahydrocannabinol (THC), the main psychoactive component of cannabis, can impair cognitive abilities. There is also some evidence that cannabidiol (CBD), the most abundant non-intoxicating constituent of cannabis, can attenuate these effects. The purpose of this study was to investigate the effects of THC, CBD oromucosal spray (with equal parts THC and CBD) on cognition compared with control conditions in human studies.
METHODS:
A systematic literature search was performed on four major bibliographic databases. Studies were included in the present review if they evaluated the cognitive effects of THC, CBD oromucosal spray compared with a control condition.
RESULTS:
Ten studies were identified (7 on patients with multiple sclerosis, 1 on those with Huntington, and 2 on healthy volunteers) with 510 participants in total. There was considerable heterogeneity among the studies in terms of dose and duration of administration. All studies have used an equal or nearly equal dose of THC and CBD.
CONCLUSIONS:
Although the results across studies were somewhat inconsistent, most evidence revealed that there is no significant difference between THC, CBD oromucosal spray and control treatments in terms of cognitive outcomes. However, more trials are needed with longer follow-up periods, and dose considerations, particularly comparing lower and higher doses of the spray.
