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.
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.
Despite current therapeutic strategies for immunomodulation and relief of symptoms in multiple sclerosis (MS), remyelination falls short due to dynamic neuropathologic deterioration and relapses, leading to accrual of disability and associated patient dissatisfaction. The potential of cannabinoids includes add-on immunosuppressive, analgesic, neuroprotective, and remyelinative effects. This study evaluates the efficacy of medical marijuana in MS and its experimental animal models. A systematic review was conducted by a literature search through PubMed, ProQuest, and EBSCO electronic databases for studies reported since 2007 on the use of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) in MS and in experimental autoimmune encephalomyelitis (EAE), Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), and toxin-induced demyelination models. Study selection and data extraction were performed by 3 reviewers, and 28 studies were selected for inclusion. The certainty of evidence was appraised using the Cochrane GRADE approach. In clinical studies, there was low- and moderate-quality evidence that treatment with ~1:1 CBD/THC mixtures as a nabiximols (Sativex®) oromucosal spray reduced numerical rating scale (NRS) scores for spasticity, pain, and sleep disturbance, diminished bladder overactivity, and decreased proinflammatory cytokine and transcription factor expression levels. Preclinical studies demonstrated decreases in disease severity, hindlimb stiffness, motor function, neuroinflammation, and demyelination. Other experimental systems showed the capacity of cannabinoids to promote remyelination in vitro and by electron microscopy. Modest short-term benefits were realized in MS responders to adjunctive therapy with CBD/THC mixtures. Future studies are recommended to investigate the cellular and molecular mechanisms of cannabinoid effects on MS lesions and to evaluate whether medical marijuana can accelerate remyelination and retard the accrual of disability over the long term.
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.
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.
