SCIENTIFIC RESEARCH PUBLICATIONS
Ultra-high-performance liquid chromatography-tandem mass spectrometry assay for quantifying THC, CBD and their metabolites in hair. Application to patients treated with medical cannabis
Recently, several countries approved the use of cannabis flowering tops with standardized amount of ∆9-tetrahydrocannabinol (THC), cannabidiol (CBD) to treat several diseases. Therapeutic monitoring of medical cannabis products administered to patients for the established pathologies is rarely carried out. Previous few investigations have been developed in conventional matrices like blood and urine. This is the first study involving hair analysis of THC, CBD and their metabolites in patients treated with medical cannabis. An ultra-high-performance liquid chromatography-tandem mass spectrometry method to quantify THC, CBD, and metabolites, i.e., 11-nor-9-carboxy-THC (THC-COOH), 11-hydroxy-THC (11-OH-THC) cannabidiol-7-oic acid (7-COOH-CBD), 7-hydroxycannabidiol (7-OH-CBD), 6-α-hydroxycannabidiol (6-α-OH-CBD) and 6-β-hydroxycannabidiol (6-β-OH-CBD) in hair samples was developed and fully validated. The validation results indicated that the method was accurate (average inter/intra-day error, <10%), precise (inter/intra-day imprecision, <10%), and fast (10 min run time). Average hair concentrations in four patients treated with different formulations of medical cannabis were 2.75 ng/mg THC, 2.87 ng/mg 11-OH-THC, and 0.32 ng/mg THC-COOH (n = 3); 1.65 ng/mg CBD, 2.73 ng/mg 7-OH-CBD, 1.29 ng/mg 7-COOH-CBD, 0.35 ng/mg 6-α-OH-CBD, and 0.03 ng/mg 6-β-OH-CBD. The proposed method proved suitable for a fast and sensitive determination of all target compounds allowing high throughput testing in individuals monitored for medical cannabis treatments.
Pharmacological effects of cannabidiol by transient receptor potential channels
Cannabidiol (CBD), as a major phytocannabinoid of Cannabis sativa, has emerged as a promising natural compound in the treatment of diseases. Its diverse pharmacological effects with limited side effects have promoted researchers to pursue new therapeutic applications. It has little affinity for classical cannabinoid receptors (CB1 and CB2). Considering this and its diverse pharmacological effects, it is logical to set up studies for finding its putative potential targets other than CB1 and CB2. A class of ion channels, namely transient potential channels (TRP), has been identified during two recent decades. More than 30 members of this family have been studied, so far. They mediate diverse physiological functions and are associated with various pathological conditions. Some have been recognized as key targets for natural compounds such as capsaicin, menthol, and CBD. Studies show that CBD has agonistic effects for TRPV1-4 and TRPA1 channels with antagonistic effects on the TRPM8 channel. In this article, we reviewed the recent findings considering the interaction of CBD with these channels. The review indicated that TRP channels mediate, at least in part, the effects of CBD on seizure, inflammation, cancer, pain, acne, and vasorelaxation. This highlights the role of TRP channels in CBD-mediated effects, and binding to these channels may justify part of its paradoxical effects in comparison to classical phytocannabinoids.
Cannabidiol (CBD) in Rheumatic Diseases (Musculoskeletal Pain)
This review will address the many uncertainties surrounding the medical use of cannabidiol (CBD). We will begin with an overview of the legal and commercial environment, examine recent preclinical and clinical evidence on CBD, explore questions concerning CBD raised by healthcare professionals and patients, investigate dosing regimens and methods of administration, and address current challenges in the accumulation of sound evidence.
In the weeds: a retrospective study of patient interest in and experience with cannabis at a cancer center
Cannabis products, including the cannabinoids CBD and THC, are rising in popularity and increasingly used for medical purposes. While there is some evidence that cannabinoids improve cancer-associated symptoms, understanding regarding appropriate use remains incomplete.
Prophylactic administration of cannabidiol reduces microglial inflammatory response to kainate-induced seizures and neurogenesis
Microglia, the dynamic innate immune cells of the central nervous system, become activated in epilepsy. The process of microglial activation in epilepsy results in the creation of an inflammatory environment around the site of seizure onset, which contributes to the epileptogenic process and epilepsy progression. Cannabidiol (CBD) has been effective for use as an adjunctive treatment for two severe pediatric seizure disorders. Newly recognized as an Food and Drug Administration (FDA)-approved drug treatment in epilepsy, it has gained in popularity primarily for pain management. Although CBD is readily available in stores and online retailers, its mechanism of action and specifically its effects on microglia and their functions are yet fully understood. In this study, we examine the effects of commercially available CBD on microglia inflammatory activation and neurogenic response, in the presence and absence of seizures. We use systemic administration of kainate to elicit seizures in mice, which are assessed behaviorally. Artisanal CBD is given in different modes of administration and timing to dissect its effect on seizure intensity, microglial activation and aberrant seizure-related neurogenesis. CBD significantly dampens microglial migration and accumulation to the hippocampus. While long term artisanal CBD use does not prevent or lessen seizure severity, CBD is a promising adjunctive partner for its ability to depress epileptogenic processes. These studies indicate that artisanal CBD is beneficial as it both decreases inflammation in the CNS and reduces the number of ectopic neurons deposited in the hippocampal area post seizure.
Use of cannabis in the treatment of animals: a systematic review of randomized clinical trials
Cannabis is used in the treatment of several human conditions; however, its use is still less explored in veterinary medicine. This systematic review aims to summarize the evidence of efficacy and safety of the use of cannabis for the treatment of animal disease. A literature search was performed for studies published until 16 March 2021 in five databases. Randomized clinical trials (RCTs) that reported the efficacy or safety of cannabis in the treatment of animal disease were included. The RoB 2 Tool was used to assess the risk of bias. A total of 2427 records were identified, of which six studies fully met the eligibility criteria. RCTs were conducted in dogs with osteoarthritis ( = 4), with epilepsy ( = 1), and with behavioral disorders ( = 1). All studies used cannabidiol (CBD) oil in monotherapy or in combination with other drugs. Studies used CBD at 2 or 2.5 mg kg twice daily ( = 4), orally ( = 5), during 4 or 6 weeks ( = 3), and compared CBD with placebo ( = 5). CBD significantly reduced pain and increased activity in dogs with osteoarthritis ( = 3). Moreover, CBD significantly reduced the frequency of seizures in dogs with epilepsy ( = 1) and the aggressive behavior of dogs ( = 1). Although promising results were identified, studies were heterogeneous and presented risks of bias that required caution in the interpretation of findings. Therefore, there was some evidence to support the use of CBD in dogs with osteoarthritis to reduce pain and increased activity, but limited evidence against epilepsy and behavioral problems. In addition, CBD was well tolerated with mild adverse effects. More RCTs with high quality of evidence are needed, including greater numbers of animal subjects, additional species, and clear readout measures to confirm these findings.
Sex differences exist in the perceived relief of cancer symptoms with medical cannabis: results from the Quebec Cannabis Registry
This study explored whether symptom relief differs by sex in patients with cancer receiving medical cannabis (MC) therapy.
A critical review of cannabis in medicine and dentistry: A look back and the path forward
In the last two decades, our understanding of the therapeutic utility and medicinal properties of cannabis has greatly changed. This change has been accompanied by widespread cannabis use in various communities and different age groups, especially within the United States. With this increase, we should consider the potential effects of cannabis-hemp on general public health and how they could alter therapeutic outcomes.
Cannabinoids for Symptom Management in Patients with Kidney Failure: A Narrative Review
People with kidney failure can experience a range of symptoms that lead to suffering and poor quality of life. Available therapies are limited, and evidence for new treatment options is sparse, often resulting in incomplete relief of symptoms. There is growing interest in the potential for cannabinoids, including cannabidiol and tetrahydrocannabinol, to treat symptoms across a wide range of chronic diseases. As legal prohibitions are withdrawn or minimized in many jurisdictions, patients are increasingly able to access these agents. Cannabinoid receptors, CB1 and CB2, are widely expressed in the body, including within the nervous and immune systems, and exogenous cannabinoids can have anxiolytic, antiemetic, analgesic, and anti-inflammatory effects. Considering their known physiologic actions and successful studies in other patient populations, cannabinoids may be viewed as potential therapies for a variety of common symptoms affecting those with kidney failure, including pruritus, nausea, insomnia, chronic neuropathic pain, anorexia, and restless legs syndrome. In this review, we summarize the pharmacology and pharmacokinetics of cannabinoids, along with what is known about the use of cannabinoids for symptom relief in those with kidney disease, and the evidence available concerning their role in management of common symptoms. Presently, although these agents show varying efficacy with a reasonable safety profile in other patient populations, evidence-based prescribing of cannabinoids for people with symptomatic kidney failure is not possible. Given the symptom burden experienced by individuals with kidney failure, there is an urgent need to understand the tolerability and safety of these agents in this population, which must ultimately be followed by robust, randomized controlled trials to determine if they are effective for symptom relief.
Role of Cannabidiol and Tetrahydrocannabivarin on Paclitaxel-induced neuropathic pain in rodents
The purpose of this study was to evaluate if phytocannabinoids, synthetic cannabidiol (CBD), and tetrahydrocannabivarin (THCV), and their combination, could protect mice from Paclitaxel-induced peripheral neuropathy (PIPN). Six groups of C57BL/6J mice (n = 6) were used in this study. The mice were given paclitaxel (PTX) (8 mg/kg/day, i.p.) on days 1, 3, 5, and 7 to induce neuropathy. Mice were evaluated for behavioral parameters, and dorsal root ganglions (DRG) were collected from the animals and subjected to RNA sequencing and westernblot analysis at the end of the study. On cultured DRGs derived from adult male rats, immunocytochemistry and mitochondrial functional assays were also performed. When compared to individual treatments, the combination of CBD and THCV improved thermal and mechanical neurobehavioral symptoms in mice by twofold. Targets for CBD and THCV therapy were identified by KEGG (RNA sequencing). PTX reduced the expression of p-AMPK, SIRT1, NRF2, HO1, SOD2, and catalase while increasing the expression of PI3K, p-AKT, p-P38 MAP kinase, BAX, TGF-β, NLRP3 inflammasome, and caspase 3 in DRG homogenates of mice. Combination therapy outperformed monotherapy in reversing these protein expressions. The addition of CBD and THCV to DRG primary cultures reduced mitochondrial superoxides while increasing mitochondrial membrane potentials. WAY100135 and rimonabant altered the neuroprotective effects of CBD and THCV respectively by blocking 5-HT1A and CB1 receptors in mice and DRG primary cultures. The entourage effect of CBD and THCV against PIPN appears to protect neurons in mice via 5HT1A and CB1 receptors respectively.
Assessing Efficacy and Use Patterns of Medical Cannabis for Symptom Management in Elderly Cancer Patients
Our study sought to further characterize patterns of medical cannabis use in elderly cancer patients. Furthermore, we sought to assess efficacy of medical cannabis for the treatment of pain, nausea, anorexia, insomnia and anxiety in elderly cancer patients.
Cannabinoids and Pain for the Plastic Surgeon: What Is the Evidence?
Since the passage of the 2018 Farm Bill, practitioners have encountered more patients self-treating pain with over-the-counter topical cannabidiol (CBD) derived from hemp-Cannabis sativa with less than 0.3% delta-9-tetrahydrocannabinol-with reported improvements in pain control and activities of daily living. Cannabidiol has been touted for its capacity to improve inflammatory, arthritic, and neuropathic pain conditions, and increasing numbers of patients are exploring its use as potential replacement for opioids. However, limited rigorous clinical trials have been performed evaluating the safety and efficacy of cannabinoids for the treatment of pain.
Cannabis use in Parkinson's disease-A nationwide online survey study
The aim of this study was to investigate the frequency of use, attitudes toward, and experiences with cannabis and cannabis-related products among people with Parkinson's disease (PwP) living in Norway.
Evidence-based management of multiple sclerosis spasticity with nabiximols oromucosal spray in clinical practice: a 10-year recap
Effective symptomatic management of multiple sclerosis (MS) spasticity remains an unmet need for many patients. The second-line option nabiximols is the most widely investigated of the noninvasive antispasticity medications in this patient population. Clinical evidence accumulated with nabiximols since it was first approved in Europe in 2010 suggests that about 40% of initial responders (i.e., those with ≥20% improvement in their baseline 0-10 Numerical Rating Scale score) may expect to achieve clinically meaningful (≥30% Numerical Rating Scale response) and durable symptomatic improvement in MS spasticity. During 10 years' routine use of nabiximols, no new safety signals have emerged. Nabiximols-associated improvement in MS spasticity-related symptoms such as pain and sleep disruption suggests a need to track possible therapeutic effects beyond muscle tone control.
Cannabis and orofacial pain: a systematic review
The naturally occurring cannabis plant has played an established role in pain management throughout recorded history. However, in recent years, both natural and synthetic cannabis-based products for medicinal use (CBPM) have gained increasing worldwide attention due to growing evidence supporting their use in alleviating chronic inflammatory and neuropathic pain associated with an array of conditions. In view of these products' growing popularity in both the medical and commercial fields, we carried out a systematic review to ascertain the effects of cannabis and its synthetically derived products on orofacial pain and inflammation. The application of topical dermal cannabidiol formulation has shown positive findings such as reducing pain and improving muscle function in patients suffering from myofascial pain. Conversely, two orally-administered synthetic cannabinoid receptor agonists (AZD1940 and GW842166) failed to demonstrate significant analgesic effects following surgical third molar removal. There is a paucity of literature pertaining to the effects of cannabis-based products in the orofacial region; however, there is a wealth of high-quality evidence supporting their use for treating chronic nociceptive and neuropathic pain conditions in other areas. Further research is warranted to explore and substantiate the therapeutic role of CBPMs in the context of orofacial pain and inflammation. As evidence supporting their use expands, healthcare professionals should pay close attention to outcomes and changes to legislation that may impact and potentially benefit their patients.
Molecular and Biochemical Mechanism of Cannabidiol in the Management of the Inflammatory and Oxidative Processes Associated with Endometriosis
Endometriosis is usually associated with inflammation and chronic pelvic pain. This paper focuses the attention on the anti-inflammatory, anti-oxidant and analgesic effects of cannabidiol (CBD) and on its potential role in endometriosis. We employed an in vivo model of endometriosis and administered CBD daily by gavage. CBD administration strongly reduced lesions diameter, volume and area. In particular, it was able to modify lesion morphology, reducing epithelial glands and stroma. CBD showed anti-oxidant effects reducing lipid peroxidation, the expression of Nox-1 and Nox-4 enzymes. CBD restored the oxidative equilibrium of the endogenous cellular defense as showed by the SOD activity and the GSH levels in the lesions. CBD also showed important antifibrotic effects as showed by the Masson trichrome staining and by downregulated expression of MMP-9, iNOS and TGF-β. CBD was able to reduce inflammation both in the harvested lesions, as showed by the increased Ikb-α and reduced COX2 cytosolic expressions and reduced NFkB nuclear localization, and in the peritoneal fluids as showed by the decreased TNF-α, PGE2 and IL-1α levels. CBD has important analgesic effects as showed by the reduced mast cells recruitment in the spinal cord and the reduced release of neuro-sensitizing and pro-inflammatory mediators. In conclusion, the collected data showed that CBD has an effective and coordinated effects in endometriosis suppression.
Alternative Options for Complex, Recurrent Pain States Using Cannabinoids, Psilocybin, and Ketamine: A Narrative Review of Clinical Evidence
With emerging information about the potential for morbidity and reduced life expectancy with long-term use of opioids, it is logical to evaluate nonopioid analgesic treatments to manage pain states. Combinations of drugs can provide additive and/or synergistic effects that can benefit the management of pain states. In this regard, tetrahydrocannabinol (THC) and cannabidiol (CBD) modulate nociceptive signals and have been studied for chronic pain treatment. Psilocybin, commonly known as "magic mushrooms", works at the serotonin receptor, 5-HT. Psilocybin has been found in current studies to help with migraines since it has a tryptamine structure and works similarly to triptans. Psilocybin also has the potential for use in chronic pain treatment. However, the studies that have looked at alternative plant-based medications such as THC, CBD, and psilocybin have been small in terms of their sample size and may not consider the demographic or genetic differences in the population because of their small sample sizes. At present, it is unclear whether the effects reported in these studies translate to the general population or even are significant. In summary, additional studies are warranted to evaluate chronic pain management with alternative and combinations of medications in the treatment of chronic pain.
Cannabis and cannabinoids for symptomatic treatment for people with multiple sclerosis
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.
Mood, sleep and pain comorbidity outcomes in cannabis dependent patients: Findings from a nabiximols versus placebo randomised controlled trial
Mood, sleep and pain problems are common comorbidities among treatment-seeking cannabis-dependent patients. There is limited evidence suggesting treatment for cannabis dependence is associated with their improvement. This study explored the impact of cannabis dependence treatment on these comorbidities.
CANNABIDIOL FOR FUNCTIONAL DYSPEPSIA WITH NORMAL GASTRIC EMPTYING: A RANDOMIZED, CONTROLLED TRIAL
Cannabidiol (CBD), a CBR2 agonist with limited psychic effects, antagonizes CB1/CB2 receptors. Allelic variation CNR1 (gene for CBR1) rs806378 and FAAH rs324420 were associated with altered gut motility and sensation. This study aimed to compare pharmacodynamics and clinical effects of 4-week treatment with pharmaceutical grade CBD vs. placebo and also to assess interactions of FAAH and CNR1 gene variants on effects of CBD in patients with functional dyspepsia (FD).
Purified oral cannabidiol for pain management in severe recessive dystrophic epidermolysis bullosa
Systematic Review on Transdermal/Topical Cannabidiol Trials: A Reconsidered Way Forward
This systematic review aimed to assess efficacy and safety for skin-applied formulations containing CBD. Bibliographic and clinical trial registries were searched for interventional human trials using cutaneously administered CBD or reported plasma CBD concentrations (any species). Eight of 544 articles fitted the selection criteria: 3 placebo-controlled randomized and 5 single-arm trials. Eleven more studies were found in clinical trial databases but not accessible. Symptoms targeted were dermatopathologies or safety (two studies), pain (two), and behavior (one). Doses were 50-250 mg or 0.075-1.0% CBD, but coformulated with other ingredients. Risk of bias was high and reporting deficiencies further compromised data reliability. Diverse methodologies and formulations hampered syntheses for CBD dose, efficacy, and safety. Plasma CBD levels in dogs and rodents were 0.01-5 μM translating to <100 nM free, unbound CBD in humans. Adverse events were uncommon and mild, but meaningless without CBD's contribution to efficacy data. Achievable CBD plasma concentrations ∼100 nM can interact predominantly with high-affinity CBD targets, for example, TRPA1 and TRPM8 membrane channels that are abundantly expressed in pathological conditions. Even if reached, higher CBD concentrations on less susceptible targets risk complex and unsafe CBD therapy. A conceptual framework is proposed where dermal capillary loops create sinking for topical CBD demonstrating parallels between topical and transdermal CBD administration. Users risk generalizing inadequately designed trials to all CBD preparations. New clinical trials are urgently needed: they must demonstrate that outcomes are solely from CBD pharmacology, are reliable, unbiased, safe, and comparable. Measurements of sustained plasma CBD levels are mandatory, irrespective of administration route for successful translation from systems that express human molecular targets. Placebos must be appropriate. Transcutaneous and topical formulations need preliminary studies to optimize CBD skin penetration. Then, users can rationally balance efficacy against potential harms and cost-effectiveness of CBD formulations.
Description and Disposition of Patients With Cancer Accessing a Novel, Pharmacist-Led Cannabis Consultation Service
The Cannabis Consultation Service (CCS) is an innovative pharmacist-led resource at the Sunnybrook Odette Cancer Centre. Its mandate is to provide education and guide patients through access and appropriate use of high-quality plant-derived cannabinoids (PDCs). Our objective was to describe the CCS, explain its processes, and characterize patient disposition with respect to use of PDCs.
Mechanisms of Cannabidiol (CBD) in Cancer Treatment: A Review
L. () and its bioactive compounds, including cannabinoids and non-cannabinoids, have been extensively studied for their biological effects in recent decades. Cannabidiol (CBD), a major non-intoxicating cannabinoid in , has emerged as a promising intervention for cancer research. The purpose of this review is to provide insights into the relationship between CBD and cancer based on recent research findings. The anticancer effects of CBD are mainly mediated via its interaction with the endocannabinoid system, resulting in the alleviation of pain and the promotion of immune regulation. Published reviews have focused on the applications of CBD in cancer pain management and the possible toxicological effects of its excessive consumption. In this review, we aim to summarize the mechanisms of action underlying the anticancer activities of CBD against several common cancers. Studies on the efficacy and mechanisms of CBD on cancer prevention and intervention in experimental models (i.e., cell culture- and animal-based assays) and human clinical studies are included in this review.
A Randomized Controlled Trial of Topical Cannabidiol for the Treatment of Thumb Basal Joint Arthritis
Since the passage of the Agricultural Improvement Act of 2018, hand surgeons have increasingly encountered patients seeking counseling on over-the-counter, topical cannabidiol (CBD) for the treatment of pain. To this end, we designed a human clinical trial to investigate the therapeutic potential of CBD for the treatment of pain associated with thumb basal joint arthritis.
Structural snapshots of the mechanism of TRPV2 channel activation by small-molecule agonists
Transient receptor potential (TRP) channels are polymodal sensors that play critical roles in various physiological processes in living organisms. These cation-permeable channels respond to a variety of physical and chemical stimuli, including cold and hot temperatures, acidic pH, and mechanical stress, often determining a sensory frontier of defense against hostile environments. Vanilloid (V) subfamily is the most studied category of TRP channels that includes six closely related members: highly calcium-selective TRPV5-6 and non-selective TRPV1-4. A remarkable feature of TRPV1-4 is their ability to sense heat, which makes them temperature-sensitive TRP channels or thermo-TRPs. TRPV channels are associated with a multitude of human diseases, including cancers, chronic pain, cardiovascular, neurological and nociceptive disorders. Despite the great clinical interest, pharmacology of TRPV channels remains largely undeveloped because of insufficient knowledge about the mechanisms of their regulation. For instance, activation of TRPV channels by small molecules or heat remains poorly understood. Numerous identified TRPV channel agonists, while effective in physiological experiments, appear limited in their ability to act in the conditions of structural biology experiments. In this regard, the recent study by Pumroy et al.  makes a significant contribution towards our understanding of TRPV2 structural dynamics that leads to opening of this channel in physiological conditions.
Synthesis of the Cannabimovone and Cannabifuran Class of Minor Phytocannabinoids and Their Anti-inflammatory Activity
Despite centuries-long use of in human culture and the now ubiquitous claims of its medicinal value, only a small handful of phytocannabinoids have been rigorously evaluated for pharmacological properties. While more than 100 distinct minor cannabinoids have been documented to date, a paucity of studies on their biological activities have been conducted due to a lack of routine access to sufficient quantities for testing. Herein, we report a strategy to prepare several structurally diverse minor cannabinoids deriving synthetically from readily available cannabidiol. Furthermore, we examined their ability to polarize activated microglia toward an anti-inflammatory phenotype using LPS-stimulated BV2 microglial cells. The minor cannabinoids studied, especially cannabielsoin, dehydrocannabielsoin, cannabimovone, and 3'-epicannabimovone, inhibited the production of prototypical pro-inflammatory biomarkers. This study represents the beginning of a systematic mapping of the roles minor cannabinoids may play in the medicinal properties of cannabis used for the treatment of pain and inflammation.
Efficacy of cannabis and its constituents in disease management: Insights from clinical studies
There is a long history of informal use of Cannabis sativa (commonly called cannabis) for many purposes, including treating various ailments worldwide. However, the legalization of cannabis in multiple countries, specifically for medical purposes, has grabbed the researchers' attention to discover the scientific evidence of cannabis's beneficial effects. Among over 500 identified compounds (cannabinoids), Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two major active cannabinoids derived from cannabis. Cannabinoids exert their effects through cannabinoid receptors (CB1R and CB2R). In the recent past, clinical trials have shown the efficacy of cannabis and cannabinoids for various human ailments such as cancer, neurological disorders, inflammatory bowel disease, chronic pain, and metabolic disorders. The commonly used constituents and derivatives of cannabis include CBD, THC, THCV, dronabinol, nabilone, and nabiximol. The cannabis constituents have also been used in combination with other agents such as megestrol acetate in some clinical trials. The common routes for the administration of cannabis are oral, sublingual, or topical. Cannabis has also been consumed through smoking, inhalation, or with food and tea. As high as 572 patients and as low as nine patients have participated in a single clinical trial. Cannabis is legalized in some countries with restrictions, such as Belize, Canada, Colombia, Costa Rica, The Czech Republic, Jamaica, Netherlands, South Africa, Spain, and Uruguay. This article provides a compilation of published studies focusing on clinal trials on the therapeutic effects of cannabis. The adverse effects of cannabis and its constituents are also discussed.
Safety and Efficacy of the Therapeutic Use of Cannabis-Based Products in the Treatment of Dogs: An Integrative Review
The use of cannabis-based products for therapeutic purposes is a reality in the field of animal health. However, although cannabis is considered safe when appropriately used by human patients, cannabis-based products can pose a risk to companion animals such as dogs, depending on their composition or route of administration. Thus, this article discusses aspects of the safety and efficacy of different cannabis-based products in dogs' treatment through an integrative review. The review was systematically performed in Medline (via Pubmed) and Latin American and Caribbean Health Sciences Literature (LILACS) databases, with period restriction (between 1990 and 2021). The qualified articles (=19), which met the previously established inclusion criteria, were critically evaluated. Based on the literature review, it is possible to infer safety in the administration of cannabis-based products for the treatment of dogs, especially products rich in cannabidiol (CBD), free or with low concentrations of tetrahydrocannabinol, under the conditions evaluated. In addition, CBD products potentially promote improved quality of life and reduce pain perception in animals affected by canine osteoarthritis. Finally, owing to the lack of large-scale and robust clinical research studies, the performance of clinical trials, considering the individual characteristics of each cannabis-based product (composition, concentration, nature of adjuvants, dosage form, route of administration), is strongly encouraged.
Cannabinoid tetrad effects of oral Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in male and female rats: sex, dose-effects and time course evaluations
The legalization of medicinal use of Cannabis sativa in most US states and the removal of hemp from the Drug Enforcement Agency (DEA) controlled substances act has resulted in a proliferation of products containing Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) for oral consumption (e.g., edibles, oils, and tinctures) that are being used for recreational and medicinal purposes.
Cannabidiol and substance use disorder: Dream or reality
Cannabidiol (CBD) is one of the major constituents of Cannabis sativa L. that lacks psychotomimetic and rewarding properties and inhibits the rewarding and reinforcing effects of addictive drugs such as cocaine, methamphetamine (METH), and morphine. Additionally, CBD's safety profile and therapeutic potential are currently evaluated in several medical conditions, including pain, depression, movement disorders, epilepsy, multiple sclerosis, Alzheimer's disease, ischemia, and substance use disorder. There is no effective treatment for substance use disorders such as addiction, and this review aims to describe preclinical and clinical investigations into the effects of CBD in various models of opioid, psychostimulant, cannabis, alcohol, and nicotine abuse. Furthermore, the possible mechanisms underlying the therapeutic potential of CBD on drug abuse disorders are reviewed.
Effects of Cannabidiol on Locomotor Activity
Cannabidiol (CBD) is the second cannabinoid, in order of importance after Δ9-tetrahydrocannabinol (THC), from . Unlike THC, CBD does not cause psychotomimetic effects, and although these compounds have the same chemical formula, their pharmacological characteristics are not equivalent. Preclinical studies suggest that CBD has anti-inflammatory, analgesic, anxiolytic, antiemetic, anticonvulsant, and antipsychotic properties and influences the sleep-wake cycle. The evaluation of effects on spontaneous motor activity is crucial in experimental pharmacology, and the careful measurement of laboratory animal movement is an established method to recognize the effects of stimulant and depressant drugs. The potential influence of CBD on locomotor activity has been investigated through numerous in vivo experiments. However, there is no clear picture of the impact of CBD on these issues, even though it is administered alone for medical uses and sold with THC as a drug for pain caused by muscle spasms in multiple sclerosis, and it was recently licensed as a drug for severe forms of infantile epilepsy. On this basis, with the aim of developing deeper knowledge of this issue, scientific data on CBD's influence on locomotor activity are discussed here. We conducted research using PubMed, Scopus, Google Scholar, and a search engine for literature between January 2009 and December 2021 on life sciences and biomedical topics using the keywords "motor activity", "locomotor activity", and "locomotion" in combination with "cannabidiol". In this article, we discuss findings describing the effects on locomotor activity of the CBD precursor cannabidiolic acid and of CBD alone or in combination with THC, together with the effects of CBD on locomotor modifications induced by diseases and on locomotor changes induced by other substances.
Analyzing the Impact of Cannabinoids on the Treatment of Spinal Disorders
Cannabis is among the most used illicit substances globally, with medical applications, increased legalization, and shifting social attitudes leading to increased use in recent years. Cannabinoids are a group of psychoactive substances found within the cannabis plant, with the most common being Δ-tetrahydrocannabinol and cannabidiol. Due to the high prevalence of use, it is increasingly important to evaluate the effects of cannabis and cannabinoids on spine patients, in both operative and nonoperative settings.
Exploring the self-reported motivations of kratom ( Korth.) use: a cross-sectional investigation
Kratom ( Korth.) use outside of Southeast Asia has increased over the past decade.
Topical Cannabidiol (CBD) After Total Knee Arthroplasty Does Not Decrease Pain or Opioid Use: A Prospective Randomized Double-Blinded Placebo-Controlled Trial
Multimodal analgesia has become the standard of care for pain management following total knee arthroplasty (TKA). Cannabidiol (CBD) is increasingly utilized in the postoperative period. The purpose of this study was to analyze the analgesic benefits of topical CBD following primary TKA.
Higher Risk, Higher Reward? Self-Reported Effects of Real-World Cannabis Use in Parkinson's Disease
Despite limited evidence, people with Parkinson's disease (PD) use cannabis for therapeutic purposes. Given barriers to performing randomized trials, exploring real-world experiences with cannabis in PD is valuable.
Adult Medical Cannabinoid Use and Changes in Prescription Controlled Substance Use
Nonopioid-based strategies for managing chronic noncancer pain are needed to help reduce overdose deaths. Although lab studies and population-level data suggest that cannabinoids could provide opioid-sparing effects, among medical cannabis participants they may also impact overdose risk by modifying other controlled substance use such as sedative hypnotics. However, no study has combined observational data at the individual level to empirically address interactions between the use of cannabinoids and prescribed controlled substances. Electronic health records, including prescription drug monitoring program data, from a large multisite medical cannabis program in New York State were abstracted for all participants with noncancer pain and recently prescribed noncannabinoid controlled substances who completed a new intake visit from April 15, 2018-April 14, 2019 and who remained actively in treatment for >180 days. Participants were partitioned into two samples: those with recent opioid use and those with active opioid use and co-use of sedative hypnotics. A patient-month level analysis assessed total average equivalent milligrams by class of drug (i.e., cannabinoid distinguishing tetrahydrocannabinol [THC] vs. cannabidiol [CBD], opioids, and sedative-hypnotics) received as a time-varying outcome measure across each 30-day "month" period postintake for at least 6 months for all participants. Sample 1 of 285 opioid users were 61.1 years of age (±13.5), 57.5% female, and using an average of 49.7 (±98.5) morphine equivalents daily at intake. Unadjusted analyses found a modest decline in morphine equivalents to 43.9 mg (±94.1 mg) from 49.7 (±98.5) in month 1 (=0.047) while receiving relatively low doses of THC (2.93 mg/day) and CBD (2.15 mg/day). Sample 2 of 95 opioid and sedative-hypnotic users were 60.9 years of age (±13.1), 63.2% female, and using an average of 86.6 (±136.2) morphine equivalents daily, and an average of 4.3 (±5.6) lorazepam equivalents. Unadjusted analyses did not find significant changes in either morphine equivalents (=0.81) or lorazepam equivalents (=0.980), and patients similarly received relatively low doses of THC (2.32 mg/day) and CBD (2.24 mg/day). Findings demonstrated minimal to no change in either opioids or sedative hypnotics over the 6 months of medical cannabis use but may be limited by low retention rates, external generalizability, and an inability to account for nonprescribed substance use.
Guideline No. 425b: Cannabis Use Throughout Women's Lifespans - Part 2: Pregnancy, the Postnatal Period, and Breastfeeding
To provide health care providers with the best evidence on cannabis use and women's health. Areas of focus include screening, dependence, and withdrawal; communication and documentation; pregnancy (including maternal and fetal outcomes); maternal pain control; postpartum care (including second-hand smoking and parenting); and breastfeeding.
Effects of Cannabidiol Interactions with and Vitamin D Receptors on Spatial Memory, Pain, Inflammation, and Aging in Vitamin D Deficiency Diet-Induced Rats
The study was planned to investigate memory-enhancing, anti-inflammatory, and antiaging potential of cannabidiol (CBD) on vitamin D deficient diet (VDD)-induced rats. Cytochrome P-450 enzymes were analyzed by RT-PCR method and others biomarkers by enzyme-linked immunosorbent assay. and -mRNA were significantly increased by 39.29 and 38.37%, respectively, while; mRNA was significantly reduced by 21.39% compared to VDD. Vitamin D receptor protein expression was significantly increased by 148.3%, 60.48%, and 142.03% in liver, kidney, and brain, respectively, compared to VDD group. Vitamin D metabolites and serotonin were significantly increased more than 60% and 100%, respectively, compared to VDD. Spatial memory (in terms of total distance, escape latency) and pain score were improved compared to VDD. Cytokines were significantly reduced than VDD. Besides, levels of superoxide dismutase (49.61%), glutathione peroxidase (178.87%), acetylcholine (25.40%), and klotho (145.57%) were significantly increased than VDD. Study findings supported that CBD interacts with , , , and vitamin D receptors, resulting in increased vitamin D metabolites, which improved memory, pain tolerance, reduced inflammation, and aging through modulating antioxidative enzymes, cytokines, and neurotransmitters in VDD-induced rats.
Cannabinoids: Therapeutic Use in Clinical Practice
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.
Routes of administration, reasons for use, and approved indications of medical cannabis in oncology: a scoping review
Some patients diagnosed with cancer use medical cannabis to self-manage undesirable symptoms, including nausea and pain. To improve patient safety and oncological care quality, the routes of administration for use of medical cannabis, patients' reasons, and prescribed indications must be better understood.
Inhibition of human recombinant T-type calcium channels by phytocannabinoids in vitro
T-type Ca channels (I ) regulate neuronal excitability and contribute to neurotransmitter release. The phytocannabinoids Δ -tetrahydrocannabinol and cannabidiol effectively modulate T-type I , but effects of other biologically active phytocannabinoids on these channels are unknown. We thus investigated the modulation of T-type I by low abundance phytocannabinoids.
Nonopioid drugs for pain
Cannabinoids for the Treatment of Dermatologic Conditions
In recent years, cannabinoid (CB) products have gained popularity among the public. The anti-inflammatory properties of CBs have piqued the interest of researchers and clinicians because they represent promising avenues for the treatment of autoimmune and inflammatory skin disorders that may be refractory to conventional therapy. The objective of this study was to review the existing literature regarding CBs for dermatologic conditions. A primary literature search was conducted in October 2020, using the PubMed and Embase databases, for all articles published from 1965 to October 2020. Review articles, studies using animal models, and nondermatologic and pharmacologic studies were excluded. From 248 nonduplicated studies, 26 articles were included. There were 13 articles on systemic CBs and 14 reports on topical CBs. Selective CB receptor type 2 agonists were found to be effective in treating diffuse cutaneous systemic sclerosis and dermatomyositis. Dronabinol showed efficacy for trichotillomania. Sublingual cannabidiol and Δ-9-tetrahydrocannabinol were successful in treating the pain associated with epidermolysis bullosa. Available evidence suggests that CBs may be effective for the treatment of various inflammatory skin disorders. Although promising, additional research is necessary to evaluate efficacy and to determine dosing, safety, and long-term treatment guidelines.
Pharmacokinetics, Safety, and Tolerability of a Medicinal Cannabis Formulation in Patients with Chronic Non-cancer Pain on Long-Term High Dose Opioid Analgesia: A Pilot Study
This phase I open-label study examined pharmacokinetics, safety, and tolerability of escalating doses of a novel combination cannabinoid medication (1:1 tetrahydrocannabinol [THC]/cannabidiol [CBD]) in patients with chronic non-cancer pain (CNCP) on high dose opioid analgesia.
Inhibition of sodium conductance by cannabigerol contributes to a reduction of dorsal root ganglion neuron excitability
Cannabigerol (CBG), a non-psychotropic phytocannabinoid and a precursor of ∆ -tetrahydrocannabinol and cannabidiol, has been suggested to act as an analgesic. A previous study reported that CBG (10 μM) blocks voltage-gated sodium (Na ) currents in CNS neurons, although the underlying mechanism is not well understood. Genetic and functional studies have validated Na 1.7 channels as an opportune target for analgesic drug development. The effects of CBG on Na 1.7 channels, which may contribute to its analgesic properties, have not been previously investigated.
Tackling the taboo: a sensible prescription for appropriate cannabis use in fibromyalgia
Cannabidiol for the Management of Endometriosis and Chronic Pelvic Pain
To review the available literature on the effect of cannabis-based products on the female reproductive system and establish whether there is any evidence that they benefit or harm patients with endometriosis and, therefore, whether there is sufficient evidence to recommend them.
Marijuana in Orthopaedics: Effects on Bone Health, Wound-Healing, Surgical Complications, and Pain Management
Marijuana use is on the rise in the United States, and there is a paucity of information on the effects of cannabis and its chemical constituents on bone health, wound-healing, surgical complications, and pain management.
Neurological Benefits, Clinical Challenges, and Neuropathologic Promise of Medical Marijuana: A Systematic Review of Cannabinoid Effects in Multiple Sclerosis and Experimental Models of Demyelination
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.
Medical Cannabis for Gynecologic Pain Conditions: A Systematic Review
The endocannabinoid system is involved in pain perception and inflammation. Cannabis contains delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which are cannabinoids that bind to endocannabinoid system receptors. A fatty acid amide called palmitoylethanolamide (PEA) enhances endogenous cannabinoids. Given that use of medical cannabis is increasing, we sought to characterize patterns of cannabis use for gynecologic pain and its effectiveness as an analgesic.
Is there a rational basis for cannabinoids research and development in ocular pain therapy? A systematic review of preclinical evidence
Purpose of the present systematic review is to investigate preclinical evidence in favor of the working hypothesis of efficacy of cannabinoids in ocular pain treatment.
Medical Cannabis Use Among Older Adults in Canada: Self-Reported Data on Types and Amount Used, and Perceived Effects
Medical cannabis use is growing among older adults. In this retrospective study, we aimed to assess the characteristics of older medical cannabis users including the indications, type and amount of cannabis used, perceived changes in symptoms after cannabis use, change in dose of concurrent medications, and adverse effects.
Cannabis Use in a Cohort of Healthcare-Seeking United States Military Veterans With Persisting Symptoms After Mild Traumatic Brain Injury: Preliminary Observations
Cannabis products, including cannabidiol (CBD) and tetrahydrocannabinol (THC), are increasingly easy to procure and use across the United States. The 2018 National Survey on Drug Use and Health (NSDUH) reported a past-month cannabis use rate of 8.6% among adults 26 years of age or older in the U.S. general population. Cannabis use is commonly reported by U.S. Military Veterans with histories of mild traumatic brain injury (mTBI) receiving services at the Marcus Institute for Brain Health (MIBH), a specialty interdisciplinary clinic serving this population. The aims of this study are to describe the frequency and characteristics of cannabis product use among Veterans evaluated at MIBH and to compare the rate of cannabis use in this group to that in the general and Veteran populations reported in the 2018 NSDUH.
An Updated Analysis of Clinical Outcome Measures Across Patients From the UK Medical Cannabis Registry
There is a growing body of literature supporting the efficacy of cannabis-based medicinal products (CBMPs). Despite an increase in prescribing globally, there is a paucity of high-quality clinical data on the efficacy of CBMPs for many conditions. This study aims to detail the changes in health-related quality of life (HRQoL) and associated clinical safety in patients prescribed CBMPs for any clinical indication from the UK Medical Cannabis Registry (UKMCR). An uncontrolled prospective case series of the UKMCR was analyzed. Primary outcomes included change from baseline in patient-reported outcome measures collected across all patients (the Generalized Anxiety Disorder Scale [GAD-7], EQ-5D-5L, and Sleep Quality Scale [SQS]) at 1, 3, and 6 months. Secondary outcomes included the self-reported incidence and severity of adverse events. Statistical significance was defined as <0.050. Three hundred twelve patients were included in the final analysis, with a mean age of 44.8. The most common primary diagnoses were chronic pain of undefined etiology (=102, 32.7%), neuropathic pain (=43, 13.8%), and fibromyalgia (=31, 9.9%). Before enrolment, 112 (35.9%) patients consumed cannabis daily. The median cannabidiol and (-)-trans-Δ-tetrahydrocannabinol doses prescribed at baseline were 20.0 mg (0.0-510.0 mg) and 3.0 mg (0.0-660.0 mg), respectively. Statistically significant improvements were observed in GAD-7, EQ-5D-5L Index, EQ-5D Visual Analog Scale and SQS scores at 1, 3, and 6 months (<0.050). There were 94 (30.1%) reported adverse events, of which nausea (=12, 3.8%), dry mouth (=10, 3.2%), dizziness (=7, 2.2%), and somnolence (=7, 2.2%) were the most common. This study demonstrated CBMP treatment to be associated with a relatively low incidence of severe adverse events in the medium-term. Positive changes following treatment were observed in general, as well as anxiety and sleep-specific, HRQoL outcomes. Randomized controlled trials are still awaited to assess causation; however, real-world evidence can help inform current clinical practice, future trials, and is an important component of pharmacovigilance.
Pain response to cannabidiol in opioid-induced hyperalgesia, acute nociceptive pain, and allodynia using a model mimicking acute pain in healthy adults in a randomized trial (CANAB II)
Opioids in general and remifentanil in particular can induce hyperalgesia. Preclinical data suggest that cannabidiol might have the capacity to reduce opioid-induced hyperalgesia (OIH). Thus, we investigated the effect of oral cannabidiol on OIH in healthy volunteers using an established pain model. Twenty-four healthy participants were included in this randomized, double-blinded, crossover study and received either a 1600-mg single-dose oral cannabidiol or placebo. Hyperalgesia, allodynia, and pain were induced by intracutaneous electrical stimulation. To provoke OIH, participants recieved an infusion of 0.1 µg/kg/min remifentanil over a time frame of 30 minutes, starting 100 minutes after oral cannabidiol ingestion. The primary outcome was the area of hyperalgesia (in square centimetres) up to 60 minutes after remifentanil administration. The area of allodynia (in square centimetres) and pain (numeric rating scale) were also assessed.Cannabidiol had no significant effect on hyperalgesia, allodynia, or pain at any time point of measurement compared with placebo. The area of hyperalgesia after remifentanil administration significantly increased compared with baseline (17.0 cm2 [8.1-28.7] vs 25.3 cm2 [15.1-39.6]; P = 0.013). Mean cannabidiol blood levels were 4.1 ± 3.0 µg/L (mean ± SD) at 130 minutes after ingestion and were 8.2 μg/L ± 6.9 µg/L (mean ± SD) at 200 minutes. Cannabidiol was well tolerated. We conclude that a high single-oral dose of 1600-mg cannabidiol is not effective in reducing OIH. Before excluding an effect of cannabidiol on OIH, research should focus on drug formulations enabling higher cannabidiol concentrations.
The Cannabidiol Analog PECS-101 Prevents Chemotherapy-Induced Neuropathic Pain via PPARγ Receptors
Chemotherapy-induced peripheral neuropathy (CIPN) is the main dose-limiting adverse effect of chemotherapy drugs such as paclitaxel (PTX). PTX causes marked molecular and cellular damage, mainly in the peripheral nervous system, including sensory neurons in the dorsal root ganglia (DRG). Several studies have shown the therapeutic potential of cannabinoids, including cannabidiol (CBD), the major non-psychotomimetic compound found in the Cannabis plant, to treat peripheral neuropathies. Here, we investigated the efficacy of PECS-101 (former HUF-101), a CBD fluorinated analog, on PTX-induced neuropathic pain in mice. PECS-101, administered after the end of treatment with PTX, did not reverse mechanical allodynia. However, PECS-101 (1 mg/kg) administered along with PTX treatment caused a long-lasting relief of the mechanical and cold allodynia. These effects were blocked by a PPARγ, but not CB1 and CB2 receptor antagonists. Notably, the effects of PECS-101 on the relief of PTX-induced mechanical and cold allodynia were not found in macrophage-specific PPARγ-deficient mice. PECS-101 also decreased PTX-induced increase in Tnf, Il6, and Aif1 (Iba-1) gene expression in the DRGs and the loss of intra-epidermal nerve fibers. PECS-101 did not alter motor coordination, produce tolerance, or show abuse potential. In addition, PECS-101 did not interfere with the chemotherapeutic effects of PTX. Thus, PECS-101, a new fluorinated CBD analog, could represent a novel therapeutic alternative to prevent mechanical and cold allodynia induced by PTX potentially through the activation of PPARγ in macrophages.
Efficacy and safety of therapeutic use of cannabis derivatives and their synthetic analogs: Overview of systematic reviews
The debate on the use of cannabinoids for therapeutic purposes is constantly on the rise. This overview aimed to map the evidence on the therapeutic effects of cannabis derivatives and their synthetic analogs. Systematic reviews (SRs) of randomized trials were identified through a comprehensive search in several databases, and their methodological quality were evaluated with AMSTAR-2. The results for main outcomes are presented, prioritizing those from updated and better quality SRs. Finally, 68 SRs, addressing 37 different health conditions, were included. The methodological quality was high for eight SRs. The evidence certainty (GRADE) for the effects of cannabinoids is not high for any of the outcomes identified. Evidence certainty was moderate for the following: (a) cannabidiol appears to be beneficial for quality of life but increases the risk of adverse events in ulcerative colitis; (b) cannabinoids in general appear to have no clinically important benefit for chronic non-oncologic pain, spasticity-related pain in multiple sclerosis, or for acute post-operative pain; (c) cannabinoids in general appear to have a benefit in reducing chemotherapy-related nausea and vomiting. For all other outcomes from remaining comparisons, the evidence certainty was low, very low, or not evaluated, which prevents recommendations for or against their routine use.
Cannabis-Based Medicines and Medical Cannabis for Chronic Neuropathic Pain
Neuropathic pain represents a broad category of pain syndromes that include a wide variety of peripheral and central disorders. The overall prevalence of neuropathic pain in the general population is reported to be between 7 and 10%. Management of neuropathic pain presents an unmet clinical need, with less than 50% of patients achieving substantial pain relief with medications currently recommended such as pregabalin, gabapentin, duloxetine and various tricyclic antidepressants. It has been suggested that cannabis-based medicines (CbMs) and medical cannabis (MC) may be a treatment option for those with chronic neuropathic pain. CbMs/MC are available in different forms: licensed medications or medical products (plant-derived and/or synthetic products such as tetrahydrocannabinol or cannabidiol); magistral preparations of cannabis plant derivatives with defined molecular content such as dronabinol (tetrahydrocannabinol); and herbal cannabis with a defined content of tetrahydrocannabinol and/or cannabidiol, together with other active ingredients (phytocannabinoids other than cannabidiol/tetrahydrocannabinol, terpenes and flavonoids). The availability of different types of CbMs/MC varies between countries worldwide. Systematic reviews of available randomised controlled trials have stated low-quality evidence for CbMs and MC for chronic neuropathic pain. Depending on the studies included in the various quantitative syntheses, authors have reached divergent conclusions on the efficacy of CbMs/MC for chronic neuropathic pain (from not effective to a clinically meaningful benefit). Clinically relevant side effects of CbMs/MC, especially for central nervous system and psychiatric disorders, have been reported by some systematic reviews. Recommendations for the use of CbMs/MC for chronic neuropathic pain by various medical associations also differ, from negative recommendations, no recommendation possible, recommended as third-line therapy, or recommended as an alternative in selected cases failing standard therapies within a multimodal concept. After reading this paper, readers are invited to formulate their own conclusions regarding the potential benefits and harms of CbMs/MC for the treatment of chronic neuropathic pain.
Therapeutic Claims in Cannabidiol (CBD) Marketing Messages on Twitter
Although the U.S. FDA has only approved exactly one cannabidiol (CBD) drug product (specifically to treat seizures), CBD products are proliferating rapidly through different modes of usage including food products, cosmetics, vaping pods, and supplements (typically, oils). Despite the FDA clearly warning consumers about unproven health claims made by manufacturers selling CBD products over the counter, the CBD market share was nearly 3 billion USD in 2020 and is expected to top 55 billion USD in 2028. In this context, it is important to assess the presence of health claims being made on social media, especially claims that are part of marketing messages. To this end, we collected over two million English tweets discussing CBD themes. We created a hand-labeled dataset and built machine learned classifiers to identify marketing tweets from regular tweets that may be generated by consumers. The best classifier achieved 85% precision, 83% recall, and 84% F-score. Our analyses showed that , , , and are the four main therapeutic claims made constituting 31.67%, 27.11%, 13.77%, and 10.37% of all medical claims made on Twitter, respectively. Also, more than 93% of advertised CBD products are or . Our effort is the first to demonstrate the feasibility of surveillance of marketing claims for CBD products. We believe this could pave way for more explorations into this indispensable task in the current landscape of social media driven health (mis)information and communication.
Efficacy of cannabis-based medications compared to placebo for the treatment of chronic neuropathic pain: a systematic review with meta-analysis
Chronic neuropathic pain (NP) presents therapeutic challenges. Interest in the use of cannabis-based medications has outpaced the knowledge of its efficacy and safety in treating NP. The objective of this review was to evaluate the effectiveness of cannabis-based medications in individuals with chronic NP.
Assessment of Medical Cannabis in Patients With Osteoarthritis of the Thumb Basal Joint
With the increasingly widespread availability of cannabidiol-derived products, more patients with hand and wrist pain are seeking evidence for use of these products. We explored current utilization practices of medical cannabis for treatment of pain in patients with a diagnosis of thumb basal joint arthritis. Secondary aims were to determine patient and thumb arthritis disease characteristics of cannabis users and nonusers and to investigate patient perceptions of the efficacy of medical cannabis in various formulations for the treatment of thumb arthritis pain.
Cannabinoids in Breast Cancer: Differential Susceptibility According to Subtype
Although cannabinoids have been used for centuries for diverse pathological conditions, recently, their clinical interest and application have emerged due to their diverse pharmacological properties. Indeed, it is well established that cannabinoids exert important actions on multiple sclerosis, epilepsy and pain relief. Regarding cancer, cannabinoids were first introduced to manage chemotherapy-related side effects, though several studies demonstrated that they could modulate the proliferation and death of different cancer cells, as well as angiogenesis, making them attractive agents for cancer treatment. In relation to breast cancer, it has been suggested that estrogen receptor-negative (ER) cells are more sensitive to cannabinoids than estrogen receptor-positive (ER) cells. In fact, most of the studies regarding their effects on breast tumors have been conducted on triple-negative breast cancer (TNBC). Nonetheless, the number of studies on human epidermal growth factor receptor 2-positive (HER2) and ER breast tumors has been rising in recent years. However, besides the optimistic results obtained thus far, there is still a long way to go to fully understand the role of these molecules. This review intends to help clarify the clinical potential of cannabinoids for each breast cancer subtype.
Cannabis-Based Medicines and Medical Cannabis in the Treatment of Nociplastic Pain
Nociplastic pain is defined as pain due to sensitization of the nervous system, without a sufficient underlying anatomical abnormality to explain the severity of pain. Nociplastic pain may be manifest in various organ systems, is often perceived as being more widespread rather than localized and is commonly associated with central nervous system symptoms of fatigue, difficulties with cognition and sleep, and other somatic symptoms; all features that contribute to considerable suffering. Exemplified by fibromyalgia, nociplastic conditions also include chronic visceral pain, chronic headaches and facial pain, and chronic musculoskeletal pain. It has been theorized that dysfunction of the endocannabinoid system may contribute to persistent pain in these conditions. As traditional treatments for chronic pain in general and nociplastic pain in particular are imperfect, there is a need to identify other treatment options. Cannabis-based medicines and medical cannabis (MC) may hold promise and have been actively promoted by the media and advocacy. The medical community must be knowledgeable of the current evidence in this regard to be able to competently advise patients. This review will briefly explain the understanding of nociplastic pain, examine the evidence for the effect of cannabinoids in these conditions, and provide simplified guidance for healthcare providers who may consider prescribing cannabinoids for these conditions.
UK Medical Cannabis registry: an analysis of clinical outcomes of medicinal cannabis therapy for chronic pain conditions
To explore pain-specific, general health-related quality of life (HRQoL), and safety outcomes of chronic pain patients prescribed cannabis-based medicinal products (CBMPs).
Endocannabinoid System Attenuates Oxaliplatin-Induced Peripheral Sensory Neuropathy Through the Activation of CB1 Receptors
Oxaliplatin-induced neurotoxicity is expressed as a dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid substances have been investigated for the analgesic effect. This study aimed to investigate the role of cannabinoid receptors in oxaliplatin-associated PSN. Swiss male mice received nine oxaliplatin injections (2 mg/kg, i.v.). Mechanical and thermal nociceptive tests were performed for 56 days. CB1, CB2, and c-Fos expression were assessed in dorsal root ganglia (DRG), spinal cord (SC), trigeminal ganglia (TG), spinal trigeminal nucleus caudalis (Sp5C), and periaqueductal gray (PAG). Iba-1 expression was assessed in DRG and ATF3 in TG. Cannabidiol (10 mg/kg, p.o.) or a CB1/CB2 non-selective agonist (WIN 55,212-2; 0.5 mg/kg, s.c.) or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) (3 mg/kg, i.p.) were injected before oxaliplatin. Oxaliplatin increased CB1 in DRG, SC, TG, Sp5C, and ventrolateral PAG, with no interference in CB2 expression. Cannabidiol increased CB1 in DRG, reduced mechanical hyperalgesia and c-Fos expression in DRG and SC. Additionally, WIN 55,212-2 increased CB1 in DRG, reduced mechanical hyperalgesia, cold allodynia and c-Fos expression in DRG and SC. CB1 blockage hastened the cold allodynia response, but the CB2 antagonist failed to modulate the oxaliplatin-induced nociceptive behavior. Oxaliplatin also increased Iba-1 in DRG, suggesting immune response modulation which was reduced by cannabidiol and enhanced by AM630. The modulation of the endocannabinoid system, through the CB1 receptor, attenuates the oxaliplatin-associated PNS. The activation of the endocannabinoid system could be considered as a therapeutic target for controlling oxaliplatin-associated neuropathy.
Differential Effects of Cannabidiol and a Novel Cannabidiol Analog on Oxycodone Place Preference and Analgesia in Mice: an Opioid Abuse Deterrent with Analgesic Properties
This study sought to determine whether cannabidiol (CBD) or a CBD derivative, CBD monovalinate monohemisuccinate (CBD-val-HS), could attenuate the development of oxycodone reward while retaining its analgesic effects. To determine the effect on oxycodone reward, animals were enrolled in the conditioned place preference paradigm and received either saline or oxycodone (3.0 mg/kg) in combination with either CBD or CBD-val-HS utilizing three sets of drug-/no drug-conditioning trials. To determine if the doses of CBD or CBD-val-HS that blocked opioid reward would affect nociceptive processes, animals were enrolled in the hot plate and abdominal writhing assays when administered alone or in combination with a subanalgesic (1.0 mg/kg) or analgesic (3.0 mg/kg) dose of oxycodone. Results from condition place preference demonstrated CBD was not able attenuate oxycodone place preference while CBD-val-HS attenuated these rewarding effects at 8.0 mg/kg and was void of rewarding or aversive properties. In contrast to CBD, CBD-val-HS alone produced analgesic effects in both nociceptive assays but was most effective compared with oxycodone against thermal nociception. Of interest, there was a differential interaction of CBD and CBD-val-HS×oxycodone across the two nociceptive assays producing subadditive responses on the hot plate assay, whereas additive responses were observed in the abdominal writhing assay. These findings suggest CBD-val-HS alone, a nonrewarding analgesic compound, could be useful in pain management and addiction treatment settings.
Analgesia in Athletes: A Review of Commonly Used Oral and Injectable Modalities
Pain is common among athletes at all levels and the treatment of pain can be a challenging and frustrating task. The team physician needs a fundamental knowledge of analgesic strategies as it relates to athletes. It is important to understand the mechanism of action, side effect profile/associated complications, incidence of and indications for use, as well as the controversies associated with the most common analgesic medications used in sports medicine. Several "in vogue" treatment modalities, including cannabidiol, are also becoming more commonly used and are worth discussion.
Major Phytocannabinoids and Their Related Compounds: Should We Only Search for Drugs That Act on Cannabinoid Receptors?
The most important discoveries in pharmacology, such as certain classes of analgesics or chemotherapeutics, started from natural extracts which have been found to have effects in traditional medicine. Cannabis, traditionally used in Asia for the treatment of pain, nausea, spasms, sleep, depression, and low appetite, is still a good candidate for the development of new compounds. If initially all attention was directed to the endocannabinoid system, recent studies suggest that many of the clinically proven effects are based on an intrinsic chain of mechanisms that do not necessarily involve only cannabinoid receptors. Recent research has shown that major phytocannabinoids and their derivatives also interact with non-cannabinoid receptors such as vanilloid receptor 1, transient receptor ankyrin 1 potential, peroxisome proliferator-activated receptor-gamma or glitazone receptor, G55 protein-coupled receptor, and nuclear receptor, producing pharmacological effects in diseases such as Alzheimer's, epilepsy, depression, neuropathic pain, cancer, and diabetes. Nonetheless, further studies are needed to elucidate the precise mechanisms of these compounds. Structure modulation of phytocannabinoids, in order to improve pharmacological effects, should not be limited to the exploration of cannabinoid receptors, and it should target other courses of action discovered through recent research.
The use of medical cannabis in pediatric palliative care: a case series
Medical cannabis may be a useful tool for managing treatment-resistant epilepsy and chronic pain, which affect many patients in pediatric palliative care (PPC); however, little evidence is available in this setting.
Social, psychological, and substance use characteristics of U.S. adults who use kratom: Initial findings from an online, crowdsourced study
Kratom, a plant that produces opioid-like effects, has gained popularity in the U.S. for self-treating symptoms of chronic pain, mood disorders, and substance-use disorders (SUDs). Most data on kratom are from surveys into which current kratom-using adults could self-select; such surveys may underrepresent people who have used kratom and chosen to stop. Available data also do not adequately assess important psychosocial factors surrounding kratom use. In this study, U.S. adults who reported past 6-month alcohol, opioid, and/or stimulant use ( = 1,670) were recruited via Amazon Mechanical Turk between September and December 2020. Of the 1,510 evaluable respondents, 202 (13.4%) reported lifetime kratom use. Kratom-using adults, relative to others, were typically younger, male, unpartnered, without children, and had lower income. They had higher rates of chronic pain (31.7% vs. 21.9%, = .003), childhood adversity, anxiety, and depression ( < .001), and lower perceived social rank ( = .19, .02-.22) and socioeconomic status ( = .37 .16-.26). They also reported higher use rates for most substances (except alcohol); this included medically supervised and unsupervised use of prescription opioids and diverted opioid agonist therapy (OAT) medications. Most (83.2%) met diagnostic criteria for any past-year SUD. Those reporting kratom use were less likely to reside in an urban/suburban area. The strongest predictors of kratom use were use of other drugs: cannabidiol ( = 3.73), psychedelics ( = 3.39), and nonmedical prescription opioids ( = 1.72). Another strong predictor was lifetime OAT utilization ( = 2.31). Despite seemingly poorer psychosocial functioning and health among respondents reporting lifetime kratom use, use of other substances may be the strongest indicators of kratom use. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Evaluating the Antinociceptive Efficacy of Cannabidiol Alone or in Combination with Morphine Using the Formalin Test in Male and Female Mice
Phytocannabinoids have emerged as a potential alternative treatment option for individuals experiencing persistent pain. However, evidence-based research regarding their clinical utility in both males and females remains incomplete. In addition, it is unknown whether combining readily available cannabinoids with opioids has a synergistic or subadditive effect on pain modulation. To begin to fill this knowledge gap, we investigated the antinociceptive effects of the phytocannabinoid, CBD, either alone or in combination with opioids in male and female C57BL/6J mice. Using the formalin test, our results show that CBD (10 mg/kg, i.p.) treatment evoked antinociception in phase I, but not in phase II, of the formalin test in male mice. However, in female mice, CBD showed no significant antinociceptive effect. In addition, a direct sex comparison showed that CBD evoked a significant increase in nociceptive behaviors in female versus male mice during phase I of the formalin test. Furthermore, we show that CBD (10 mg/kg, i.p.) in combination with low-dose morphine (1 mg/kg, i.p.) was ineffective at eliciting a synergistic antinociceptive response in both male and female mice. Lastly, consistent with previous literature, we showed that females treated with a relatively higher dose of morphine (10 mg/kg, i.p.) displayed a significant increase in the variability of nociceptive behaviors compared to morphine-treated male mice. Overall, our results suggest that CBD treatment may have beneficial antinociceptive effects during the acute phase of persistent pain, but these effects are more beneficial to males than females. We provide further pre-clinical support that treatments geared toward reducing nociceptive behaviors differentially affect males and females.
Analgesic Potential of Terpenes Derived from
Pain prevalence among adults in the United States has increased 25% over the past two decades, resulting in high health-care costs and impacts to patient quality of life. In the last 30 years, our understanding of pain circuits and (intra)cellular mechanisms has grown exponentially, but this understanding has not yet resulted in improved therapies. Options for pain management are limited. Many analgesics have poor efficacy and are accompanied by severe side effects such as addiction, resulting in a devastating opioid abuse and overdose epidemic. These problems have encouraged scientists to identify novel molecular targets and develop alternative pain therapeutics. Increasing preclinical and clinical evidence suggests that cannabis has several beneficial pharmacological activities, including pain relief. contains more than 500 chemical compounds, with two principle phytocannabinoids, Δ-tetrahydrocannabinol (Δ-THC) and cannabidiol (CBD). Beyond phytocannabinoids, more than 150 terpenes have been identified in different cannabis chemovars. Although the predominant cannabinoids, Δ-THC and CBD, are thought to be the primary medicinal compounds, terpenes including the monoterpenes -myrcene, -pinene, limonene, and linalool, as well as the sesquiterpenes -caryophyllene and -humulene may contribute to many pharmacological properties of cannabis, including anti-inflammatory and antinociceptive effects. The aim of this review is to summarize our current knowledge about terpene compounds in cannabis and to analyze the available scientific evidence for a role of cannabis-derived terpenes in modern pain management. SIGNIFICANCE STATEMENT: Decades of research have improved our knowledge of cannabis polypharmacy and contributing phytochemicals, including terpenes. Reform of the legal status for cannabis possession and increased availability (medicinal and recreational) have resulted in cannabis use to combat the increasing prevalence of pain and may help to address the opioid crisis. Better understanding of the pharmacological effects of cannabis and its active components, including terpenes, may assist in identifying new therapeutic approaches and optimizing the use of cannabis and/or terpenes as analgesic agents.
Healing of a Chronic Pressure Injury in a Patient Treated With Medical Cannabis for Pain and Sleep Improvement: A Case Report
A small body of evidence suggests medical cannabis may facilitate wound healing, but the exact mechanism of this effect is unclear.
Safety of Medical Cannabis in Neuropathic Chronic Pain Management
Products derived from the plant are widely appreciated for their analgesic properties and are employed for the treatment of chronic neuropathic pain. Only nabiximols, a product composed of two extracts containing similar percentages of the two cannabinoids cannabidiol and delta-9-tetrahydrocannabinol, is approved by regulatory authorities for neuropathic pain and spasticity due to multiple sclerosis in many European countries and Canada. It is also included in pharmacovigilance systems monitoring the occurrence of adverse drug reactions. However, it is not the same for the great variety of other cannabis preparations widely used for medical purposes. This creates a situation characterized by insufficient knowledge of the safety of cannabis preparations and the impossibility of establishing a correct risk-benefit profile for their medical use in the treatment of chronic neuropathic pain. With the aim to explore this issue more deeply, we collected data on adverse reactions from published clinical studies reporting the use of cannabis for neuropathic relief.
Adjunctive Management of Opioid Withdrawal with the Nonopioid Medication Cannabidiol
Opioid use disorder (OUD) is a major public health crisis worldwide. Patients with OUD inevitably experience withdrawal symptoms when they attempt to taper down on their current opioid use, abstain completely from opioids, or attempt to transition to certain medications for opioid use disorder. Acute opioid withdrawal can be debilitating and include a range of symptoms such as anxiety, pain, insomnia, and gastrointestinal symptoms. Whereas acute opioid withdrawal only lasts for 1-2 weeks, protracted withdrawal symptoms can persist for months after the cessation of opioids. Insufficient management of opioid withdrawal often leads to devastating results including treatment failure, relapse, and overdose. Thus, there is a critical need for cost-effective, nonopioid medications, with minimal side effects to help in the medical management of opioid withdrawal syndrome. We discuss the potential consideration of cannabidiol (CBD), a nonintoxicating component of the cannabis plant, as an treatment in managing the opioid withdrawal syndrome. A review of the literature was performed using keywords related to CBD and opioid withdrawal syndrome in PubMed and Google Scholar. A total of 144 abstracts were identified, and 41 articles were selected where CBD had been evaluated in clinical studies relevant to opioid withdrawal. CBD has been reported to have several therapeutic properties including anxiolytic, antidepressant, anti-inflammatory, anti-emetic, analgesic, as well as reduction of cue-induced craving for opioids, all of which are highly relevant to opioid withdrawal syndrome. In addition, CBD has been shown in several clinical trials to be a well-tolerated with no significant adverse effects, even when co-administered with a potent opioid agonist. Growing evidence suggests that CBD could potentially be added to the standard opioid detoxification regimen to mitigate acute or protracted opioid withdrawal-related symptoms. However, most existing findings are either based on preclinical studies and/or small clinical trials. Well-designed, prospective, randomized-controlled studies evaluating the effect of CBD on managing opioid withdrawal symptoms are warranted.
Perspectives of pediatric oncologists and palliative care physicians on the therapeutic use of cannabis in children with cancer
Children with cancer are increasingly using cannabis therapeutically.
Computational Approach Reveals Pronociceptive Potential of Cannabidiol in Osteoarthritis: Role of Transient Receptor Potential Channels
Systems pharmacology employs computational and mathematical methods to study the network of interactions a drug may have within complex biological pathways. These tools are well suited for research on multitarget drugs, such as natural compounds, in diseases with complex etiologies, such as osteoarthritis (OA). The present study focuses on cannabidiol (CBD), a non-psychoactive constituent of cannabis, targeting over 60 distinct molecular targets as a potential treatment for OA, a degenerative joint disease leading to chronic pain with a neuropathic component. We successfully identified molecular targets of CBD that were relevant in the context of OA treatment with both beneficial and detrimental effects. Our findings were confirmed by in vivo and molecular studies. A key role of PPARγ in mediating the therapeutic potential of CBD was revealed, whereas upregulation of multiple transient receptor potential channels demasked CBD-induced heat hyperalgesia. Our findings pave the way for novel CBD-based therapy with improved therapeutic potential but also encourage the use of bioinformatic tools to predict the mechanism of action of CBD in different conditions. We have also created an accessible web tool for analogous analysis of CBD pharmacology in the context of any disease of interest and made it publicly available.
Cannabis, a Miracle Drug with Polyvalent Therapeutic Utility: Preclinical and Clinical-Based Evidence
L. is an annual herbaceous dioecious plant which was first cultivated by agricultural human societies in Asia. Over the period of time, various parts of the plant like leaf, flower, and seed were used for recreational as well as therapeutic purposes. The main chemical components of are termed as cannabinoids, among them the key psychoactive constituent is Δ-9-tetrahydrocannabinol and cannabidiol (CBD) as active nonpsychotic constituent. Upon doing extensive literature review, it was found that cannabis has been widely studied for a number of disorders. Very recently, a pure CBD formulation, named Epidiolex, got a green flag from both United States Food and Drug Administration and Drug Enforcement Administration for 2 rare types of epilepsies. This laid a milestone in medical cannabis research. This review intends to give a basic and extensive assessment, from past till present, of the ethnological, plant, chemical, pharmacological, and legal aspects of . Further, this review contemplates the evidence the studies obtained of cannabis components on Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, multiple sclerosis, emesis, epilepsy, chronic pain, and cancer as a cytotoxic agent as well as a palliative therapy. The assessment in this study was done by reviewing in extensive details from studies on historical importance, ethnopharmacological aspects, and legal grounds of from extensive literature available on the scientific databases, with a vision for elevating further pharmaceutical research to investigate its total potential as a therapeutic agent.
A Mapping Literature Review of Medical Cannabis Clinical Outcomes and Quality of Evidence in Approved Conditions in the USA from 2016 to 2019
In 2017, a National Academies of Sciences, Engineering, and Medicine (NASEM) report comprehensively evaluated the body of evidence regarding cannabis health effects through the year 2016. The objectives of this study are to identify and map the most recently (2016-2019) published literature across approved conditions for medical cannabis and to evaluate the quality of identified recent systematic reviews, published following the NASEM report. Following the literature search from 5 databases and consultation with experts, 11 conditions were identified for evidence compilation and evaluation: amyotrophic lateral sclerosis, autism, cancer, chronic noncancer pain, Crohn's disease, epilepsy, glaucoma, human immunodeficiency virus/AIDS, multiple sclerosis (MS), Parkinson's disease, and posttraumatic stress disorder. A total of 198 studies were included after screening for condition-specific relevance and after imposing the following exclusion criteria: preclinical focus, non-English language, abstracts only, editorials/commentary, case studies/series, and non-U.S. study setting. Data extracted from studies included: study design type, outcome definition, intervention definition, sample size, study setting, and reported effect size. Few completed randomized controlled trials (RCTs) were identified. Studies classified as systematic reviews were graded using the Assessing the Methodological Quality of Systematic Reviews-2 tool to evaluate the quality of evidence. Few high-quality systematic reviews were available for most conditions, with the exceptions of MS (9 of 9 graded moderate/high quality; evidence for 2/9 indicating cannabis improved outcomes; evidence for 7/9 indicating cannabis inconclusive), epilepsy (3 of 4 graded moderate/high quality; 3 indicating cannabis improved outcomes; 1 indicating cannabis inconclusive), and chronic noncancer pain (12 of 13 graded moderate/high quality; evidence for 7/13 indicating cannabis improved outcomes; evidence from 6/7 indicating cannabis inconclusive). Among RCTs, we identified few studies of substantial rigor and quality to contribute to the evidence base. However, there are some conditions for which significant evidence suggests that select dosage forms and routes of administration likely have favorable risk-benefit ratios (i.e., epilepsy and chronic noncancer pain). The body of evidence for medical cannabis requires more rigorous evaluation before consideration as a treatment option for many conditions, and evidence necessary to inform policy and treatment guidelines is currently insufficient for many conditions.
Cannabinoid Therapeutics in Chronic Neuropathic Pain: From Animal Research to Human Treatment
Despite the importance of pain as a warning physiological system, chronic neuropathic pain is frequently caused by damage in the nervous system, followed by persistence over a long period, even in the absence of dangerous stimuli or after healing of injuries. Chronic neuropathic pain affects hundreds of millions of adults worldwide, creating a direct impact on quality of life. This pathology has been extensively characterized concerning its cellular and molecular mechanisms, and the endocannabinoid system (eCS) is widely recognized as pivotal in the development of chronic neuropathic pain. Scientific evidence has supported that phyto-, synthetic and endocannabinoids are efficient for pain management, while strong data arise from the therapeutic use of Cannabis-derived products. The use of medicinal Cannabis products is directed toward not only relieving symptoms of chronic pain, but also improving several aspects of patients' welfare. Here, we review the involvement of eCS, along with other cellular and molecular elements, in chronic neuropathic pain pathology and how this system can be targeted for pain management.
Medicinal Cannabis and Central Nervous System Disorders
Cannabinoids, including those found in cannabis, have shown promise as potential therapeutics for numerous health issues, including pathological pain and diseases that produce an impact on neurological processing and function. Thus, cannabis use for medicinal purposes has become accepted by a growing majority. However, clinical trials yielding satisfactory endpoints and unequivocal proof that medicinal cannabis should be considered a frontline therapeutic for most examined central nervous system indications remains largely elusive. Although cannabis contains over 100 + compounds, most preclinical and clinical research with well-controlled dosing and delivery methods utilize the various formulations of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the two most abundant compounds in cannabis. These controlled dosing and delivery methods are in stark contrast to most clinical studies using whole plant cannabis products, as few clinical studies using whole plant cannabis profile the exact composition, including percentages of all compounds present within the studied product. This review will examine both preclinical and clinical evidence that supports or refutes the therapeutic utility of medicinal cannabis for the treatment of pathological pain, neurodegeneration, substance use disorders, as well as anxiety-related disorders. We will predominately focus on purified THC and CBD, as well as other compounds isolated from cannabis for the aforementioned reasons but will also include discussion over those studies where whole plant cannabis has been used. In this review we also consider the current challenges associated with the advancement of medicinal cannabis and its derived potential therapeutics into clinical applications.
Direct Regulation of Hyperpolarization-Activated Cyclic-Nucleotide Gated (HCN1) Channels by Cannabinoids
Cannabinoids are a broad class of molecules that act primarily on neurons, affecting pain sensation, appetite, mood, learning, and memory. In addition to interacting with specific cannabinoid receptors (CBRs), cannabinoids can directly modulate the function of various ion channels. Here, we examine whether cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the most prevalent phytocannabinoids in , can regulate the function of hyperpolarization-activated cyclic-nucleotide-gated (HCN1) channels independently of CBRs. HCN1 channels were expressed in oocytes since they do not express CBRs, and the effects of cannabinoid treatment on HCN1 currents were examined by a two-electrode voltage clamp. We observe opposing effects of CBD and THC on HCN1 current, with CBD acting to stimulate HCN1 function, while THC inhibited current. These effects persist in HCN1 channels lacking the cyclic-nucleotide binding domain (HCN1ΔCNBD). However, changes to membrane fluidity, examined by treating cells with TX-100, inhibited HCN1 current had more pronounced effects on the voltage-dependence and kinetics of activation than THC, suggesting this is not the primary mechanism of HCN1 regulation by cannabinoids. Our findings may contribute to the overall understanding of how cannabinoids may act as promising therapeutic molecules for the treatment of several neurological disorders in which HCN function is disturbed.
A Case Report of Subcutaneously Injected Liposomal Cannabidiol Formulation Used as a Compassion Therapy for Pain Management in a Dog
A 14-year-old intact mixed breed dog (26 kg) was submitted for a novel cannabidiol (CBD) analgesic treatment. The dog was cachectic and had a testicular neoplasia, hip and elbow osteoarthritis and severe cervical pain. Analgesic treatment included canine osteoarthritic supplement, robencoxib and gabapentin. An additional liposomal CBD injectable formulation at 5 mg/kg was administered subcutaneously between the shoulder blades. The dog was monitored using an activity monitoring collar (PetPace), owner wellbeing questionnaire (Canine Brief Pain Inventory; CBPI), pain interactive visual analog scale (iVAS), blood work and CBD plasma concentrations. A week from the injection and up to 3 weeks afterwards the dog had improved CBPI and iVAS pain scores, and increased collar activity scores. CBD was quantified in plasma for 28 days. Due to disease progression, further difficulty to rise and walk, and relapse to pain after 3 weeks, the owners requested a second liposomal CBD injection, which was performed 4 weeks following the first injection using 3 mg/kg dose. Two days later, the dog was found dead in the yard under direct sun, while environmental temperature was 37°C. Major findings on necropsy revealed evidence of heat stroke and severe cervical disc protrusion with spinal hematoma, none related to liposomal CBD. In conclusion, subcutaneous liposomal CBD produced quantifiable CBD plasma concentrations for 28 days and may be an effective additional treatment as part of multimodal pain management in dogs.
Potency and Therapeutic THC and CBD Ratios: U.S. Cannabis Markets Overshoot
The effects exuded by cannabis are a result of the cannabinoids trans-Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), and is dependent upon their pharmacological interaction and linked to the two cannabinoids' concentrations and ratios. Based on current literature and trends of increasing cannabis potency, we postulate that most medical cannabis products with THC and CBD have ratios capable of producing significant acute intoxication and are similar to recreational products. We will test this by organizing products into clinically distinct categories according to TCH:CBD ratios, evaluating the data in terms of therapeutic potential, and comparing the data obtained from medical and recreational programs and from states with differing market policies. We utilized data encompassing online herbal dispensary product offerings from nine U.S. states. The products were analyzed after being divided into four clinically significant THC:CBD ratio categories identified based on the literature: CBD can enhance THC effects (THC:CBD ratios ≥1:1), CBD has no significant effect on THC effects (ratios ∼ 1:2), CBD can either have no effect or can mitigate THC effects (ratios 1:>2 < 6), or CBD is protective against THC effects (ratios ≤1:6). A significant number of products (58.5%) did not contain any information on CBD content. Across all states sampled, the majority (72-100%) of both medical and recreational products with CBD (>0%) fall into the most intoxicating ratio category (≥1:1 THC:CBD), with CBD likely enhancing THC's acute effects. The least intoxicating categories (1:>2 < 6 and ≤1:6 THC:CBD) provided the smallest number of products. Similarly, the majority of products without CBD (0%) contained highly potent amounts of THC (>15%). These results were consistent, regardless of differing market policies in place. Despite the distinct goals of medical and recreational cannabis users, medical and recreational program product offerings are nearly identical. Patients seeking therapeutic benefits from herbal cannabis products are therefore at a substantial risk of unwanted side effects, regardless of whether they obtain products from medical or recreational programs. Efforts are needed to better inform patients of the risks associated with high potency cannabis and the interaction between THC and CBD, and to help shape policies that promote more therapeutic options.
Promising Health Benefits of Adjuvant and Extracts Combined with Coenzyme Q10 Phytosomes, Supplementation in Chronic Pain Treated with Medical Cannabis: A Prospective and Open-Label Clinical Study
Chronic pain is a condition where pain persists for months or even years. Nowadays, several drugs comprising of medical cannabis are utilized for chronic pain relief. Even if there are some associated side effects, the use of supplements can widen the reliable tools available for improving an individual's quality of life.
Sex-Dependent Prescription Patterns and Clinical Outcomes Associated With the Use of Two Oral Cannabis Formulations in the Multimodal Management of Chronic Pain Patients in Colombia
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 ( < 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.
Comparison of the Effectiveness and Tolerability of Nabiximols (THC:CBD) Oromucosal Spray versus Oral Dronabinol (THC) as Add-on Treatment for Severe Neuropathic Pain in Real-World Clinical Practice: Retrospective Analysis of the German Pain e-Registry
To compare the effectiveness and tolerability of add-on treatment with nabiximols (NBX: delta-9-tetrahydrocannabinol: cannabidiol) oromucosal spray or oral dronabinol (DRO: synthetic tetrahydrocannabinol) in patients with severe neuropathic pain poorly responsive to established treatments.
Treatment with Delta-9-tetrahydrocannabinol/cannabidiol in Multiple Sclerosis: Influence on the Autonomy Profile according to the International Classification of Functioning, Disability and Health
Multiple sclerosis (MS) is the most common cause of non-traumatic neurological disability in young adults. It has effects at different levels: physical, emotional, psychological, cognitive and social, with a great variety of signs and symptoms. In particular, spasticity contributes to reducing the motor performance of patients with MS, causing pain, reduction in distance walked and limitations in social life. We present the case of a 39-year-old woman with MS. She was treated with delta-9-tetrahydrocannabinol/cannabidiol and the outcome was assessed with the International Classification of Functioning Disability and Health core set framework.
Cannabis-Based Products in a Neurological Setting: A Clinical and Pharmacokinetic Survey
Limited data are available in clinical settings on the pharmacokinetics of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We investigated the use of cannabis-based products in neurological practice, monitoring patients' steady-state cannabinoids (CBs) plasma concentrations matched with different preparations.
Minor Cannabinoids: Biosynthesis, Molecular Pharmacology and Potential Therapeutic Uses
The medicinal use of can be traced back thousands of years to ancient China and Egypt. While marijuana has recently shown promise in managing chronic pain and nausea, scientific investigation of cannabis has been restricted due its classification as a schedule 1 controlled substance. A major breakthrough in understanding the pharmacology of cannabis came with the isolation and characterization of the phytocannabinoids -Δ-tetrahydrocannabinol (Δ-THC) and cannabidiol (CBD). This was followed by the cloning of the cannabinoid CB1 and CB2 receptors in the 1990s and the subsequent discovery of the endocannabinoid system. In addition to the major phytocannabinoids, Δ-THC and CBD, cannabis produces over 120 other cannabinoids that are referred to as minor and/or rare cannabinoids. These cannabinoids are produced in smaller amounts in the plant and are derived along with Δ-THC and CBD from the parent cannabinoid cannabigerolic acid (CBGA). While our current knowledge of minor cannabinoid pharmacology is incomplete, studies demonstrate that they act as agonists and antagonists at multiple targets including CB1 and CB2 receptors, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptors (PPARs), serotonin 5-HT receptors and others. The resulting activation of multiple cell signaling pathways, combined with their putative synergistic activity, provides a mechanistic basis for their therapeutic actions. Initial clinical reports suggest that these cannabinoids may have potential benefits in the treatment of neuropathic pain, neurodegenerative diseases, epilepsy, cancer and skin disorders. This review focuses on the molecular pharmacology of the minor cannabinoids and highlights some important therapeutic uses of the compounds.
Cannabinoids for SARS-CoV-2 and is there evidence of their therapeutic efficacy?
To combat the coronaviruses and their novel variants, therapeutic drugs and the development of vaccines that are to be effective throughout human life are urgently needed. The endocannabinoid system (ECS) acts as a modulator in the activation of the microcirculation, immune system, and autonomic nervous system, along with controlling pharmacological functions such as emotional responses, homeostasis, motor functions, cognition, and motivation. The ECS contains endogenous cannabinoids, cannabinoid receptor (CBRs), and enzymes that regulate their biosynthesis, transport, and degradation. Moreover, phytocannabinoids and synthetic cannabinoids that mimic the action of endocannabinoids also play an essential role in the modulation of the ECS. Cannabinoids, the main constituents of cannabis ( L.), are therapeutic compounds that have received international attention in the health field due to their therapeutic properties. Recently, they have been tested for the treatment of COVID-19 due to their antiviral properties. Indeed, cannabinoid-type compounds, and in particular cannabidiol (CBD), isolated from glandular trichomes found in the calyx of cannabis flowers with reported antiviral properties is hypothesized to be a therapeutic option in the ministration of SARS-CoV-2 consorted with COVID-19 disease. The relevant articles were determined from the database search published mainly in Web of Science, Google scholar, PubMed, Crossref, and ClinicalTrials.gov database during the pandemic period. The articles were evaluated for the therapeutic potentials, mechanisms of action of cannabinoids, the roles of the ECS in the immune system, impact of cannabinoids in SARS-CoV-2 septic, especially if they address the application of cannabinoids as drugs for the curability and management of SARS-CoV-2 and its novel variants. Although the evidence needed to be considered using cannabinoids in the control and treatment of viral diseases is currently in its infancy, they already offer an opportunity for clinicians due to their effects in relieving pain, improving appetite, and improving childhood epilepsy, especially in cancer and human immunodeficiency virus (HIV/AIDS) patients. In addition to these, the most recent scientific evidence emphasizes their use in the treatment of the coronavirus infected patients. In brief, all preclinic and clinic studies that have been reported show that, through the cannabinoid system, cannabinoids, particularly CBD, have many mechanisms that are effective in the treatment of patients infected by SARS-CoV-2. Thus, more extensive studies are necessary in this area to fully identify the effects of cannabinoids on SARS-CoV-2.
Adenosine receptors: Emerging non-opioids targets for pain medications
Physical and emotional pain deteriorates the quality of well-being. Also, numerous non-invasive and invasive treatments for diagnosed diseases such as cancer medications and surgical procedures cause various types of pain. Despite the multidisciplinary approaches available to manage pain, the unmet needs for medication with minimal side effects are substantial. Especially with the surge of opioid crisis during the last decades, non-opioid analgesics may reduce life-threatening overdosing and addictive liability. Although many clinical trials supported the potential potency of cannabis and cannabidiol (CBD) in pain management or treatment, the long-term benefits of cannabis or CBD are still not evident. At the same time, growing evidence shows the risk of overusing cannabis and CBD. Therefore, it is urgent to develop novel analgesic medications that minimize side effects. All four well-identified adenosine receptors, A, A, A, and A, are implicated in pain. Recently, a report demonstrated that an adenosine AR-specific positive allosteric modulator (PAM) is a potent analgesic without noticeable side effects. Also, several AR agonists are being considered as promising analgesic agent. However, the importance of adenosine in pain is relatively underestimated. To help readers understand, first, we will summarize the historical perspective of the adenosine system in preclinical and clinical studies. Then, we will discuss possible interactions of adenosine and opioids or the cannabis system focusing on pain. Overall, this review will provide the potential role of adenosine and adenosine receptors in pain treatment.
Therapeutic Potential of Cannabis, Cannabidiol, and Cannabinoid-Based Pharmaceuticals
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).
Quality of Life and a Surveillant Endocannabinoid System
The endocannabinoid system (ECS) is an important brain modulatory network. ECS regulates brain homeostasis throughout development, from progenitor fate decision to neuro- and gliogenesis, synaptogenesis, brain plasticity and circuit repair, up to learning, memory, fear, protection, and death. It is a major player in the hypothalamic-peripheral system-adipose tissue in the regulation of food intake, energy storage, nutritional status, and adipose tissue mass, consequently affecting obesity. Loss of ECS control might affect mood disorders (anxiety, hyperactivity, psychosis, and depression), lead to drug abuse, and impact neurodegenerative (Alzheimer's, Parkinson, Huntington, Multiple, and Amyotrophic Lateral Sclerosis) and neurodevelopmental (autism spectrum) disorders. Practice of regular physical and/or mind-body mindfulness and meditative activities have been shown to modulate endocannabinoid (eCB) levels, in addition to other players as brain-derived neurotrophic factor (BDNF). ECS is involved in pain, inflammation, metabolic and cardiovascular dysfunctions, general immune responses (asthma, allergy, and arthritis) and tumor expansion, both/either in the brain and/or in the periphery. The reason for such a vast impact is the fact that arachidonic acid, a precursor of eCBs, is present in every membrane cell of the body and on demand eCBs synthesis is regulated by electrical activity and calcium shifts. Novel lipid (lipoxins and resolvins) or peptide (hemopressin) players of the ECS also operate as regulators of physiological allostasis. Indeed, the presence of cannabinoid receptors in intracellular organelles as mitochondria or lysosomes, or in nuclear targets as PPARγ might impact energy consumption, metabolism and cell death. To live a better life implies in a vigilant ECS, through healthy diet selection (based on a balanced omega-3 and -6 polyunsaturated fatty acids), weekly exercises and meditation therapy, all of which regulating eCBs levels, surrounded by a constructive social network. Cannabidiol, a diet supplement has been a major player with anti-inflammatory, anxiolytic, antidepressant, and antioxidant activities. Cognitive challenges and emotional intelligence might strengthen the ECS, which is built on a variety of synapses that modify human behavior. As therapeutically concerned, the ECS is essential for maintaining homeostasis and cannabinoids are promising tools to control innumerous targets.
Natural Products and some Semi-synthetic Analogues as Potential TRPV1 Ligands for Attenuating Neuropathic Pain
Natural products and leads inspired by them have acted as a probe for successful drug discovery for many decades. Pain is an obnoxious sensory and emotional experience associated with potential tissue damage. It affects the quality of life of patients to a greater extent. Despite the availability of several agents targeting TRP receptors, none of them can proficiently alleviate neuropathic pain. TRPV1 is a prospective target for treating neuropathic pain as it is recognized to modulate the pain circuitry at the periphery and the central level. In this review, we have discussed several natural molecules, such as Capsaicinoids, Capsinoids, Piperine, Eugenol, Scutigeral, Ginsenosides, Cinnamaldehyde, Camphor, Shogaol, Gingerols, Zingerone, Allicin, Evodiamine, Allylisothiocyanate, Cannabidiol, Ricinoleic acid, Isovelleral, Capsazepine, Thapsigargin, Pellitorine, Yohimbine, Curcumin and some semi-synthetic analogues that activate TRPV1 channels and consequently, can be further harnessed for the treatment of neuropathic pain.
Dose-Related Inhibition of Capsaicin Responses by Cannabinoids CBG, CBD, THC and their Combination in Cultured Sensory Neurons
The analgesic effects of are mediated by ∆ tetrahydrocannabinol (THC), but the contributions of other bioactive complex components, including cannabigerol (CBG) and cannabidiol (CBD), are unclear. We describe the individual and combined effects of CBG, CBD and THC, on blocking capsaicin responses in dorsal root ganglion (DRG) neurons, in an in vitro model of nociceptor hypersensitivity.
Integrated Management of Multiple Sclerosis Spasticity and Associated Symptoms Using the Spasticity-Plus Syndrome Concept: Results of a Structured Specialists' Discussion Using the Workmat Methodology
Multiple sclerosis (MS) treatment has radically improved over the last years; however, MS symptom management is still challenging. The novel Spasticity-Plus syndrome was conceptualized to frame several spasticity-related symptoms that can be addressed together with broad-spectrum medication, such as certain cannabinoid-based drugs. The aim of this project was to gain insight into Spanish neurologists' clinical experience on MS spasticity and associated symptoms, and to assess the acknowledgment and applicability of the Spasticity-Plus syndrome concept in patients with MS. Ten online meetings were conducted using the Workmat methodology to allow structured discussions. Fifty-five Spanish neurologists, experts in MS management, completed and discussed a set of predefined exercises comprising MS symptom assessment and its management in clinical practice, MS symptoms clustering in clinical practice, and their perception of the Spasticity-Plus syndrome concept. This document presents the quantitative and qualitative results of these discussions. The specialists considered that polytherapy is a common concern in MS and that simplifying the management of MS spasticity and associated manifestations could be useful. They generally agreed that MS spasticity should be diagnosed before moderate or severe forms appear. According to the neurologists' clinical experience, symptoms commonly associated with MS spasticity included spasms/cramps (100% of the specialists), pain (85%), bladder dysfunction (62%), bowel dysfunction (42%), sleep disorders (42%), and sexual dysfunction (40%). The multiple correspondence analysis revealed two main symptom clusters: spasticity-spasms/cramps-pain, and ataxia-instability-vertigo. Twelve out of 16 symptoms (75%) were scored >7 in a 0-10 QoL impact scale by the specialists, representing a moderate-high impact. The MS specialists considered that pain, spasticity, spasms/cramps, bladder dysfunction, and depression should be a treatment priority given their frequency and chance of therapeutic success. The neurologists agreed on the usefulness of the new Spasticity-Plus syndrome concept to manage spasticity and associated symptoms together, and their experience with treatments targeting the cannabinoid system was satisfactory. The applicability of the new concept of Spasticity-Plus in MS clinical practice seems possible and may lead to an integrated management of several MS symptoms, thus reducing the treatment burden of disease symptoms.
Adherence, Safety, and Effectiveness of Medical Cannabis and Epidemiological Characteristics of the Patient Population: A Prospective Study
Despite the absence of rigorous prospective studies, there has been an increase in the use of cannabis-based medicinal products. During the study period, the use of medical cannabis in Israel was tightly regulated by national policy. Through a prospective study of approximately 10,000 patients, we aimed to characterize the medical cannabis patient population as well as to identify treatment adherence, safety, and effectiveness.