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International Journal of Molecular... Mar 2022Medical case reports suggest that cannabinoids extracted from have therapeutic effects; however, the therapeutic employment is limited due to the psychotropic effect of... (Review)
Review
Medical case reports suggest that cannabinoids extracted from have therapeutic effects; however, the therapeutic employment is limited due to the psychotropic effect of its major component, Δ9-tetrahydrocannabinol (THC). The new scientific discoveries related to the endocannabinoid system, including new receptors, ligands, and mediators, allowed the development of new therapeutic targets for the treatment of several pathological disorders minimizing the undesirable psychotropic effects of some constituents of this plant. Today, FDA-approved drugs, such as nabiximols (a mixture of THC and non-psychoactive cannabidiol (CBD)), are employed in alleviating pain and spasticity in multiple sclerosis. Dronabinol and nabilone are used for the treatment of chemotherapy-induced nausea and vomiting in cancer patients. Dronabinol was approved for the treatment of anorexia in patients with AIDS (acquired immune deficiency syndrome). In this review, we highlighted the potential therapeutic efficacy of natural and synthetic cannabinoids and their clinical relevance in cancer, neurodegenerative and dermatological diseases, and viral infections.
Topics: Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Endocannabinoids; Humans; Neoplasms
PubMed: 35328765
DOI: 10.3390/ijms23063344 -
British Journal of Clinical Pharmacology Nov 2018There is increasing interest in the use of cannabinoids for disease and symptom management, but limited information available regarding their pharmacokinetics and... (Review)
Review
There is increasing interest in the use of cannabinoids for disease and symptom management, but limited information available regarding their pharmacokinetics and pharmacodynamics to guide prescribers. Cannabis medicines contain a wide variety of chemical compounds, including the cannabinoids delta-9-tetrahydrocannabinol (THC), which is psychoactive, and the nonpsychoactive cannabidiol (CBD). Cannabis use is associated with both pathological and behavioural toxicity and, accordingly, is contraindicated in the context of significant psychiatric, cardiovascular, renal or hepatic illness. The pharmacokinetics of cannabinoids and the effects observed depend on the formulation and route of administration, which should be tailored to individual patient requirements. As both THC and CBD are hepatically metabolized, the potential exists for pharmacokinetic drug interactions via inhibition or induction of enzymes or transporters. An important example is the CBD-mediated inhibition of clobazam metabolism. Pharmacodynamic interactions may occur if cannabis is administered with other central nervous system depressant drugs, and cardiac toxicity may occur via additive hypertension and tachycardia with sympathomimetic agents. More vulnerable populations, such as older patients, may benefit from the potential symptomatic and palliative benefits of cannabinoids but are at increased risk of adverse effects. The limited availability of applicable pharmacokinetic and pharmacodynamic information highlights the need to initiate prescribing cannabis medicines using a 'start low and go slow' approach, carefully observing the patient for desired and adverse effects. Further clinical studies in the actual patient populations for whom prescribing may be considered are needed, to derive a better understanding of these drugs and enhance safe and optimal prescribing.
Topics: Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Drug Interactions; Humans
PubMed: 30001569
DOI: 10.1111/bcp.13710 -
Neuron Feb 2023Δ-tetrahydrocannabinol (THC) and its sibling, cannabidiol (CBD), are produced by the same Cannabis plant and have similar chemical structures but differ dramatically in... (Review)
Review
Δ-tetrahydrocannabinol (THC) and its sibling, cannabidiol (CBD), are produced by the same Cannabis plant and have similar chemical structures but differ dramatically in their mechanisms of action and effects on brain functions. Both THC and CBD exhibit promising therapeutic properties; however, impairments and increased incidence of mental health diseases are associated with acute and chronic THC use, respectively, and significant side effects are associated with chronic use of high-dose CBD. This review covers recent molecular and preclinical discoveries concerning the distinct mechanisms of action and bioactivities of THC and CBD and their impact on human behavior and diseases. These discoveries provide a foundation for the development of cannabinoid-based therapeutics for multiple devastating diseases and to assure their safe use in the growing legal market of Cannabis-based products.
Topics: Humans; Cannabidiol; Dronabinol; Siblings; Cannabinoids; Cannabinoid Receptor Agonists
PubMed: 36638804
DOI: 10.1016/j.neuron.2022.12.022 -
BMC Medicine Aug 2022Medical cannabinoids differ in their pharmacology and may have different treatment effects. We aimed to conduct a pharmacology-based systematic review (SR) and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Medical cannabinoids differ in their pharmacology and may have different treatment effects. We aimed to conduct a pharmacology-based systematic review (SR) and meta-analyses of medical cannabinoids for efficacy, retention and adverse events.
METHODS
We systematically reviewed (registered at PROSPERO: CRD42021229932) eight databases for randomized controlled trials (RCTs) of dronabinol, nabilone, cannabidiol and nabiximols for chronic pain, spasticity, nausea /vomiting, appetite, ALS, irritable bowel syndrome, MS, Chorea Huntington, epilepsy, dystonia, Parkinsonism, glaucoma, ADHD, anorexia nervosa, anxiety, dementia, depression, schizophrenia, PTSD, sleeping disorders, SUD and Tourette. Main outcomes and measures included patient-relevant/disease-specific outcomes, retention and adverse events. Data were calculated as standardized mean difference (SMD) and ORs with confidence intervals (CI) via random effects. Evidence quality was assessed by the Cochrane Risk of Bias and GRADE tools.
RESULTS
In total, 152 RCTs (12,123 participants) were analysed according to the type of the cannabinoid, outcome and comparator used, resulting in 84 comparisons. Significant therapeutic effects of medical cannabinoids show a large variability in the grade of evidence that depends on the type of cannabinoid. CBD has a significant therapeutic effect for epilepsy (SMD - 0.5[CI - 0.62, - 0.38] high grade) and Parkinsonism (- 0.41[CI - 0.75, - 0.08] moderate grade). There is moderate evidence for dronabinol for chronic pain (- 0.31[CI - 0.46, - 0.15]), appetite (- 0.51[CI - 0.87, - 0.15]) and Tourette (- 1.01[CI - 1.58, - 0.44]) and moderate evidence for nabiximols on chronic pain (- 0.25[- 0.37, - 0.14]), spasticity (- 0.36[CI - 0.54, - 0.19]), sleep (- 0.24[CI - 0.35, - 0.14]) and SUDs (- 0.48[CI - 0.92, - 0.04]). All other significant therapeutic effects have either low, very low, or even no grade of evidence. Cannabinoids produce different adverse events, and there is low to moderate grade of evidence for this conclusion depending on the type of cannabinoid.
CONCLUSIONS
Cannabinoids are effective therapeutics for several medical indications if their specific pharmacological properties are considered. We suggest that future systematic studies in the cannabinoid field should be based upon their specific pharmacology.
Topics: Cannabinoids; Chronic Pain; Dronabinol; Humans; Nausea; Vomiting
PubMed: 35982439
DOI: 10.1186/s12916-022-02459-1 -
Nature Reviews. Neuroscience Jul 2021Recent years have been transformational in regard to the perception of the health risks and benefits of cannabis with increased acceptance of use. This has unintended... (Review)
Review
Recent years have been transformational in regard to the perception of the health risks and benefits of cannabis with increased acceptance of use. This has unintended neurodevelopmental implications given the increased use of cannabis and the potent levels of Δ-tetrahydrocannabinol today being consumed by pregnant women, young mothers and teens. In this Review, we provide an overview of the neurobiological effects of cannabinoid exposure during prenatal/perinatal and adolescent periods, in which the endogenous cannabinoid system plays a fundamental role in neurodevelopmental processes. We highlight impaired synaptic plasticity as characteristic of developmental exposure and the important contribution of epigenetic reprogramming that maintains the long-term impact into adulthood and across generations. Such epigenetic influence by its very nature being highly responsive to the environment also provides the potential to diminish neural perturbations associated with developmental cannabis exposure.
Topics: Adolescent; Adult; Age Factors; Animals; Brain; Cannabis; Child; Child, Preschool; Dronabinol; Endocannabinoids; Epigenesis, Genetic; Female; Humans; Infant; Lactation; Lipase; Male; Marijuana Smoking; Maternal Exposure; Mice; Milk, Human; Neurodevelopmental Disorders; Neuronal Plasticity; Neurotransmitter Agents; Paternal Exposure; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Receptor, Cannabinoid, CB1; Species Specificity; Young Adult
PubMed: 34021274
DOI: 10.1038/s41583-021-00465-5 -
Sports Medicine (Auckland, N.Z.) Sep 2021Cannabis is widely used for both recreational and medicinal purposes on a global scale. There is accumulating interest in the use of cannabis and its constituents for... (Review)
Review
Cannabis is widely used for both recreational and medicinal purposes on a global scale. There is accumulating interest in the use of cannabis and its constituents for athletic recovery, and in some instances, performance. Amidst speculation of potential beneficial applications, the effects of cannabis and its two most abundant constituents, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), remain largely un-investigated. The purpose of this review is to critically evaluate the literature describing the effects of whole cannabis, THC, and CBD, on athletic performance and recovery. While investigations of whole cannabis and THC have generally shown either null or detrimental effects on exercise performance in strength and aerobic-type activities, studies of sufficient rigor and validity to conclusively declare ergogenic or ergolytic potential in athletes are lacking. The ability of cannabis and THC to perturb cardiovascular homeostasis warrants further investigation regarding mechanisms by which performance may be affected across different exercise modalities and energetic demands. In contrast to cannabis and THC, CBD has largely been scrutinized for its potential to aid in recovery. The beneficial effects of CBD on sleep quality, pain, and mild traumatic brain injury may be of particular interest to certain athletes. However, research in each of these respective areas has yet to be thoroughly investigated in athletic populations. Elucidating the effects of whole cannabis, THC, and CBD is pertinent for both researchers and practitioners given the widespread use of these products, and their potential to interact with athletes' performance and recovery.
Topics: Athletic Performance; Cannabidiol; Cannabis; Dronabinol; Humans; Pain
PubMed: 34515970
DOI: 10.1007/s40279-021-01505-x -
Handbook of Experimental Pharmacology 2020Since antiquity, Cannabis has provoked enormous intrigue for its potential medicinal properties as well as for its unique pharmacological effects. The elucidation of its...
Since antiquity, Cannabis has provoked enormous intrigue for its potential medicinal properties as well as for its unique pharmacological effects. The elucidation of its major cannabinoid constituents, Δ-tetrahydrocannabinol (THC) and cannabidiol (CBD), led to the synthesis of new cannabinoids (termed synthetic cannabinoids) to understand the mechanisms underlying the pharmacology of Cannabis. These pharmacological tools were instrumental in the ultimate discovery of the endogenous cannabinoid system, which consists of CB and CB cannabinoid receptors and endogenously produced ligands (endocannabinoids), which bind and activate both cannabinoid receptors. CB receptors mediate the cannabimimetic effects of THC and are highly expressed on presynaptic neurons in the nervous system, where they modulate neurotransmitter release. In contrast, CB receptors are primarily expressed on immune cells. The endocannabinoids are tightly regulated by biosynthetic and hydrolytic enzymes. Accordingly, the endocannabinoid system plays a modulatory role in many physiological processes, thereby generating many promising therapeutic targets. An unintended consequence of this research was the emergence of synthetic cannabinoids sold for human consumption to circumvent federal laws banning Cannabis use. Here, we describe research that led to the discovery of the endogenous cannabinoid system and show how knowledge of this system benefitted as well as unintentionally harmed human health.
Topics: Cannabidiol; Cannabinoids; Dronabinol; Endocannabinoids; Humans; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2
PubMed: 32236882
DOI: 10.1007/164_2019_298 -
The Cochrane Database of Systematic... Mar 2018This review is one of a series on drugs used to treat chronic neuropathic pain. Estimates of the population prevalence of chronic pain with neuropathic components range... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This review is one of a series on drugs used to treat chronic neuropathic pain. Estimates of the population prevalence of chronic pain with neuropathic components range between 6% and 10%. Current pharmacological treatment options for neuropathic pain afford substantial benefit for only a few people, often with adverse effects that outweigh the benefits. There is a need to explore other treatment options, with different mechanisms of action for treatment of conditions with chronic neuropathic pain. Cannabis has been used for millennia to reduce pain. Herbal cannabis is currently strongly promoted by some patients and their advocates to treat any type of chronic pain.
OBJECTIVES
To assess the efficacy, tolerability, and safety of cannabis-based medicines (herbal, plant-derived, synthetic) compared to placebo or conventional drugs for conditions with chronic neuropathic pain in adults.
SEARCH METHODS
In November 2017 we searched CENTRAL, MEDLINE, Embase, and two trials registries for published and ongoing trials, and examined the reference lists of reviewed articles.
SELECTION CRITERIA
We selected randomised, double-blind controlled trials of medical cannabis, plant-derived and synthetic cannabis-based medicines against placebo or any other active treatment of conditions with chronic neuropathic pain in adults, with a treatment duration of at least two weeks and at least 10 participants per treatment arm.
DATA COLLECTION AND ANALYSIS
Three review authors independently extracted data of study characteristics and outcomes of efficacy, tolerability and safety, examined issues of study quality, and assessed risk of bias. We resolved discrepancies by discussion. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 30% and 50% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardised mean differences for pain intensity, sleep problems, health-related quality of life (HRQoL), and psychological distress. For tolerability, we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawal due to adverse events and specific adverse events, nervous system disorders and psychiatric disorders. For safety, we calculated NNTH for serious adverse events. Meta-analysis was undertaken using a random-effects model. We assessed the quality of evidence using GRADE and created a 'Summary of findings' table.
MAIN RESULTS
We included 16 studies with 1750 participants. The studies were 2 to 26 weeks long and compared an oromucosal spray with a plant-derived combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (10 studies), a synthetic cannabinoid mimicking THC (nabilone) (two studies), inhaled herbal cannabis (two studies) and plant-derived THC (dronabinol) (two studies) against placebo (15 studies) and an analgesic (dihydrocodeine) (one study). We used the Cochrane 'Risk of bias' tool to assess study quality. We defined studies with zero to two unclear or high risks of bias judgements to be high-quality studies, with three to five unclear or high risks of bias to be moderate-quality studies, and with six to eight unclear or high risks of bias to be low-quality studies. Study quality was low in two studies, moderate in 12 studies and high in two studies. Nine studies were at high risk of bias for study size. We rated the quality of the evidence according to GRADE as very low to moderate.Primary outcomesCannabis-based medicines may increase the number of people achieving 50% or greater pain relief compared with placebo (21% versus 17%; risk difference (RD) 0.05 (95% confidence interval (CI) 0.00 to 0.09); NNTB 20 (95% CI 11 to 100); 1001 participants, eight studies, low-quality evidence). We rated the evidence for improvement in Patient Global Impression of Change (PGIC) with cannabis to be of very low quality (26% versus 21%;RD 0.09 (95% CI 0.01 to 0.17); NNTB 11 (95% CI 6 to 100); 1092 participants, six studies). More participants withdrew from the studies due to adverse events with cannabis-based medicines (10% of participants) than with placebo (5% of participants) (RD 0.04 (95% CI 0.02 to 0.07); NNTH 25 (95% CI 16 to 50); 1848 participants, 13 studies, moderate-quality evidence). We did not have enough evidence to determine if cannabis-based medicines increase the frequency of serious adverse events compared with placebo (RD 0.01 (95% CI -0.01 to 0.03); 1876 participants, 13 studies, low-quality evidence).Secondary outcomesCannabis-based medicines probably increase the number of people achieving pain relief of 30% or greater compared with placebo (39% versus 33%; RD 0.09 (95% CI 0.03 to 0.15); NNTB 11 (95% CI 7 to 33); 1586 participants, 10 studies, moderate quality evidence). Cannabis-based medicines may increase nervous system adverse events compared with placebo (61% versus 29%; RD 0.38 (95% CI 0.18 to 0.58); NNTH 3 (95% CI 2 to 6); 1304 participants, nine studies, low-quality evidence). Psychiatric disorders occurred in 17% of participants using cannabis-based medicines and in 5% using placebo (RD 0.10 (95% CI 0.06 to 0.15); NNTH 10 (95% CI 7 to 16); 1314 participants, nine studies, low-quality evidence).We found no information about long-term risks in the studies analysed.Subgroup analysesWe are uncertain whether herbal cannabis reduces mean pain intensity (very low-quality evidence). Herbal cannabis and placebo did not differ in tolerability (very low-quality evidence).
AUTHORS' CONCLUSIONS
The potential benefits of cannabis-based medicine (herbal cannabis, plant-derived or synthetic THC, THC/CBD oromucosal spray) in chronic neuropathic pain might be outweighed by their potential harms. The quality of evidence for pain relief outcomes reflects the exclusion of participants with a history of substance abuse and other significant comorbidities from the studies, together with their small sample sizes.
Topics: Adult; Analgesics, Non-Narcotic; Analgesics, Opioid; Cannabidiol; Chronic Pain; Codeine; Dronabinol; Humans; Medical Marijuana; Neuralgia; Numbers Needed To Treat; Randomized Controlled Trials as Topic
PubMed: 29513392
DOI: 10.1002/14651858.CD012182.pub2 -
Cannabis and Cannabinoid Research Oct 2021In recent years, marketers of cannabis (i.e., marijuana) products have claimed that cannabinol (CBN) has unique sleep-promoting effects. Despite a plausible mechanism,... (Review)
Review
In recent years, marketers of cannabis (i.e., marijuana) products have claimed that cannabinol (CBN) has unique sleep-promoting effects. Despite a plausible mechanism, it is possible that such claims are merely rooted in cannabis lore. The aim of this narrative review was to answer the question: "Is there sufficient clinical evidence to support claims that CBN has sleep-promoting effects?" A systematic search of PubMed/MEDLINE was performed to evaluate the published evidence. The abstracts of 99 human studies were screened for relevance by the author and reviewed for compliance with the inclusion criteria. The characteristics and principal findings were extracted from eight full-text articles that met inclusion criteria for detailed review. Pre-clinical and clinical research investigating the effects of CBN is dated and limited, with the preponderance of human studies occurring in the 1970-1980s with small sample sizes lacking diversity in sociodemographic characteristics. Studies specifically assessing subjective effects associated with sleep, such as sedation or fatigue, are rare. Most importantly, published clinical trials investigating associations between CBN and validated sleep questionnaires and/or formal polysomnography were not identified in this review. In addition, evidence demonstrating that CBN itself elicits cannabis-like effects in humans is mixed, with the majority of available evidence demonstrating a lack of such an effect. Consequently, there is insufficient published evidence to support sleep-related claims. Randomized controlled trials are needed to substantiate claims made by manufacturers of cannabis products containing CBN. These studies should specifically evaluate its effects on sleep through polysomnography, or at minimum, through validated sleep questionnaires, and use dosages significantly higher than those found in currently available cannabis products marketed for sleep (typically ≤5 mg). Individuals seeking cannabis-derived sleep aids should be skeptical of manufacturers' claims of sleep-promoting effects.
Topics: Cannabinoids; Cannabinol; Cannabis; Dronabinol; Humans; Sleep
PubMed: 34468204
DOI: 10.1089/can.2021.0006 -
Drug and Alcohol Dependence Nov 2014Synthetic cannabinoids (SC) are a heterogeneous group of compounds developed to probe the endogenous cannabinoid system or as potential therapeutics. Clandestine... (Review)
Review
BACKGROUND
Synthetic cannabinoids (SC) are a heterogeneous group of compounds developed to probe the endogenous cannabinoid system or as potential therapeutics. Clandestine laboratories subsequently utilized published data to develop SC variations marketed as abusable designer drugs. In the early 2000s, SC became popular as "legal highs" under brand names such as Spice and K2, in part due to their ability to escape detection by standard cannabinoid screening tests. The majority of SC detected in herbal products have greater binding affinity to the cannabinoid CB1 receptor than does Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive compound in the cannabis plant, and greater affinity at the CB1 than the CB2 receptor. In vitro and animal in vivo studies show SC pharmacological effects 2-100 times more potent than THC, including analgesic, anti-seizure, weight-loss, anti-inflammatory, and anti-cancer growth effects. SC produce physiological and psychoactive effects similar to THC, but with greater intensity, resulting in medical and psychiatric emergencies. Human adverse effects include nausea and vomiting, shortness of breath or depressed breathing, hypertension, tachycardia, chest pain, muscle twitches, acute renal failure, anxiety, agitation, psychosis, suicidal ideation, and cognitive impairment. Long-term or residual effects are unknown. Due to these public health consequences, many SC are classified as controlled substances. However, frequent structural modification by clandestine laboratories results in a stream of novel SC that may not be legally controlled or detectable by routine laboratory tests.
METHODS
We present here a comprehensive review, based on a systematic electronic literature search, of SC epidemiology and pharmacology and their clinical implications.
Topics: Animals; Cannabinoids; Designer Drugs; Dronabinol; Humans; Protein Binding; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2
PubMed: 25220897
DOI: 10.1016/j.drugalcdep.2014.08.005