SCIENTIFIC RESEARCH PUBLICATIONS
Specific phytocannabinoid compositions are associated with analgesic response and adverse effects in chronic pain patients treated with medical cannabis
Medical cannabis (MC) treatment for chronic pain is increasing, but evidence regarding short- and long-term efficacy and associated adverse effects (AEs) of the different cannabis plant components is limited. Most reports focus on two phytocannabinoids, (-)-Δ-trans-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). This study, aimed to identify patterns of phytocannabinoid compositions associated with MC treatment response and with related AEs. Participants in this multicenter prospective cohort were patients with chronic non-cancer pain that were prescribed MC by physicians. Data was collected before MC treatment, at one month (short-term) and at 12 months (long-term). Simultaneously, liquid chromatography mass spectrometry identification and quantification of phytocannabinoids from the cultivars were performed. The monthly dose of each phytocannabinoid for each patient was z-scaled and clustered into ten groups to assess the difference in analgesic treatment response (≥30%/50% pain intensity reduction) and AEs rates. We identified ten clusters that had similar analgesic treatment response rates. However, there were significant differences in AEs rates both at short- and long-term. We identified specific phytocannabinoid compositions that were associated with overall AEs rates (5% compared to 53% at short-term and 44% at long-term) and with specific AEs rates such as MC related central nervous system, gastrointestinal and psychological AEs. To conclude, Evaluating only Δ9-THC or CBD is insufficient to find associations with MC related AEs. Therefore, comprehensive profiling of phytocannabinoids is needed to discover associations to related AEs and help physicians prescribe safer cannabis with less AEs while still relieving pain.
Systematic review and meta-analysis of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators tested for antinociceptive effects in animal models of injury-related or pathological persistent pain
We report a systematic review and meta-analysis of studies that assessed the antinociceptive efficacy of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators on pain-associated behavioural outcomes in animal models of pathological or injury-related persistent pain. In April 2019, we systematically searched 3 online databases and used crowd science and machine learning to identify studies for inclusion. We calculated a standardised mean difference effect size for each comparison and performed a random-effects meta-analysis. We assessed the impact of study design characteristics and reporting of mitigations to reduce the risk of bias. We meta-analysed 374 studies in which 171 interventions were assessed for antinociceptive efficacy in rodent models of pathological or injury-related pain. Most experiments were conducted in male animals (86%). Antinociceptive efficacy was most frequently measured by attenuation of hypersensitivity to evoked limb withdrawal. Selective cannabinoid type 1, cannabinoid type 2, nonselective cannabinoid receptor agonists (including delta-9-tetrahydrocannabinol) and peroxisome proliferator-activated receptor-alpha agonists (predominantly palmitoylethanolamide) significantly attenuated pain-associated behaviours in a broad range of inflammatory and neuropathic pain models. Fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors, and cannabidiol significantly attenuated pain-associated behaviours in neuropathic pain models but yielded mixed results in inflammatory pain models. The reporting of criteria to reduce the risk of bias was low; therefore, the studies have an unclear risk of bias. The value of future studies could be enhanced by improving the reporting of methodological criteria, the clinical relevance of the models, and behavioural assessments. Notwithstanding, the evidence supports the hypothesis of cannabinoid-induced analgesia.
Use of Cannabis and Cannabinoids in Patients With Cancer
To review pharmacology, available dosage forms, efficacy, and safety of cannabis and cannabinoids in cancer patients.
Biomechanical Effects of Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD), the Major Constituents of Cannabis, in a Sprague Dawley Rat Achilles Tendon Surgical Repair Model: A Pilot Study
The use of cannabis is common among athletes and the US population at large. Cannabinoids are currently being evaluated as alternatives to opioid medications for chronic pain management. However, the effects of recreational and/or medical use of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on musculoskeletal injury and healing remain largely unknown.
Rates of self-directed perioperative cannabidiol use in patients undergoing total hip or knee arthroplasty
To evaluate the prevalence of self-directed cannabidiol (CBD) use in patients with end-stage degenerative hip and knee arthritis who underwent total hip arthroplasty and total knee arthroplasty. Anonymous surveys for 109 patients were completed at 6 weeks follow-up after either total hip arthroplasty or total knee arthroplasty at a single tertiary care US orthopedic hospital. Within the perioperative window encompassing both preoperative and postoperative periods, 22% (95% CI: 14-30%) of patients used CBD. There was no difference in pain satisfaction between patients who used CBD and patients who did not. Given high rates of self-directed perioperative CBD use and the mixed body of evidence, further research is needed to better understand whether CBD is safe and effective.
Modulatory Potential of Cannabidiol on the Opioid-Induced Inflammatory Response
Opioids are effective analgesics; however, there are many negative consequences of chronic use. One important side effect of chronic opioid use is the continuous engagement of the immune response that can exacerbate chronic pain. The opioid, morphine, initiates a Toll-like receptor 4 (TLR4) signaling cascade that drives the activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome proteins, resulting in cytokine production and effectively creating a positive feedback loop for continuous TLR4 activation. In addition to driving cytokine production, morphine drives changes in proinflammatory lipid signaling. The alteration of both cytokine and lipid signaling systems by morphine suggests that its chronic use leads to a pathological immune response that would benefit from targeted therapy. Engaging the endogenous cannabinoid system has shown therapeutic benefit, particularly regarding its anti-inflammatory and immunosuppressive effects. Promising preclinical and clinical investigations suggest that cannabidiol (CBD) is an effective adjuvant for treatment of symptoms of opioid use disorders; however, the mechanism through which CBD drives this outcome is unclear. One potential source of insight into this mechanism is in how CBD regulates immune regulators such as cytokines and lipid signaling systems, including endocannabinoids and related immune-responsive lipids. In this review, we outline the immune response to chronic opioid use as well as CBD in the context of a lipopolysaccharide-induced immune response and speculate on the mechanism of CBD as a modulator of chronic opioid-induced immune system dysregulation.
Integrative Medicine: Cannabis and Cannabis-Related Drugs
is a genus of flowering herbs in the Cannabaceae family. Federal law defines dried plant material preparations of the subspecies as . The term refers to all products derived from plants. The active compounds in cannabis are cannabinoids, which include delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the psychoactive component, whereas CBD has no psychoactive effects. There are three Food and Drug Administration (FDA)-approved cannabis-related drugs. Dronabinol and nabilone (Cesamet) are approved for chemotherapy-induced nausea and vomiting; cannabidiol (Epidiolex) is approved for two pediatric epilepsy syndromes. FDA-approved cannabis-related drugs, marijuana, and cannabis formulations have been studied for the management of other conditions and symptoms (eg, cachexia, chemotherapy-induced nausea and vomiting, chronic pain, muscle spasticity) and have shown varying effectiveness. CBD formulations have been shown to be effective for certain forms of epilepsy. However, marijuana, cannabis-containing products, and cannabis-derived products in general are not approved by the FDA for any indication. Adverse effects include impaired executive function, cognition, and driving. Physicians can recommend use of marijuana under medical marijuana laws but cannot prescribe it, as it is classified as a Schedule I controlled substance. Laws regulating use of marijuana and cannabis products vary among states.
Utilization and Impact of Complementary and Alternative Medicines in Symptomatic Autoimmune Hepatitis Patients
Complementary and alternative medicine (CAM) use has become increasingly common. It is also prevalent in patients with chronic liver disease, but the scope, depth, and safety of use is not well known.
The Effects of Cannabinoids on Pro- and Anti-Inflammatory Cytokines: A Systematic Review of Studies
Some cannabinoids have been identified as anti-inflammatory agents; however, their potential therapeutic or prophylactic applications remain controversial. The aim of this systematic review was to provide a timely and comprehensive insight into cannabinoid-mediated pro- and anti-inflammatory cytokine responses in preclinical studies. A systematic search was conducted using PubMed, Web of Science, EMBASE, and Scopus. Eligible studies where cannabinoids had been evaluated for their effect on inflammation in animal models were included in the analysis. Data were extracted from 26 of 4247 eligible full text articles, and risk of bias was assessed using the SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) tool. Studies examined cannabidiol (CBD; =20); cannabigerol (CBG; =1); delta 9-tetrahydrocannabinol (THC; =2); THC and CBD separately (=1); and THC and CBD in combination (=2). Tumor necrosis factor alpha, interleukin (IL)-1β, IL-6, and interferon gamma were the most commonly studied pro-inflammatory cytokines and their levels were consistently reduced after treatment with CBD, CBG, or CBD+THC, but not with THC alone. The association between cannabinoid-induced anti-inflammatory response and disease severity was examined. In 22 studies where CBD, CBG, or CBD in combination with THC were administered, a reduction in the levels of at least one inflammatory cytokine was observed, and in 24 studies, some improvements in disease or disability were apparent. THC alone did not reduce pro-inflammatory cytokine levels (=3), but resulted in improvements in neuropathic pain in one study. This review shows that CBD, CBG, and CBD+THC combination exert a predominantly anti-inflammatory effect , whereas THC alone does not reduce pro-inflammatory or increase anti-inflammatory cytokines. It is anticipated that this information could be used to inform human clinical trials of cannabinoids, focusing on CBD and CBG to reduce inflammation across a range of pathophysiological processes.
Immunomodulatory Potential of Cannabidiol in Multiple Sclerosis: a Systematic Review
Multiple sclerosis (MS) is the most common chronic autoimmune disease of the central nervous system. Efficacy of treatments for MS is associated with risk of adverse effects, and effective and well-tolerated drugs remain a major unmet need. Cannabis (Cannabis sativa L., fam. Cannabaceae) and cannabinoids are popular among MS patients to treat spasticity and pain. Cannabinoids are endowed with remarkable immunomodulating properties, and in particular the non-psychotropic cannabinoid cannabidiol (CBD) is increasingly recognized as anti-inflammatory and immunosuppressive, nevertheless with excellent tolerability even at high doses. In this systematic review, we retrieved and critically evaluated available evidence regarding the immune and disease-modifying effects of CBD in experimental autoimmune encephalomyelitis (EAE) and in MS. Evidence in rodent models of EAE strongly supports CBD as effective, while clinical evidence is still limited and usually negative, due to paucity of studies and possibly to the use of suboptimal dosing regimens. Better characterization of targets acted upon by CBD in MS should be obtained in ex vivo/in vitro studies in human immune cells, and higher doses should be tested in well-designed clinical trials with clinically relevant efficacy endpoints. Graphical Abstract.
Health Claims About Cannabidiol Products: A Retrospective Analysis of U.S. Food and Drug Administration Warning Letters from 2015 to 2019
Cannabidiol (CBD) products are increasingly available to consumers in the United States and are subject to regulation by the U.S. Food and Drug Administration (FDA). CBD products cannot be marketed as unapproved new drugs with claims of therapeutic benefit. In addition, because CBD is the active ingredient in a FDA-approved CBD product, Epidiolex, CBD cannot be marketed as, or in, food products or dietary supplements. The FDA has issued Warning Letters to promote voluntary regulatory compliance. These letters provide insights as to the types of violations for CBD products detected in the U.S. market. The goal of this retrospective study was to content analyze Warning Letters issued by the FDA to identify illicit marketing of CBD products. Warning Letters issued by the FDA between 2015 and 2019 were content analyzed using a deductive approach. We extracted year of issuance, issuing office, and claim types that are currently prohibited by the FDA, including (i) unapproved new drug, (ii) misbranded drug, (iii) false and/or misleading, (iv) FDA-approved/endorsed, (v) dietary supplement, and (vi) adulterated food product. In addition, we documented the disease or conditions the product claimed to affect, pharmacological effects, and location of violation. Of the 39 Warning Letters issued, 97% were for violations made on company websites and 56% were for social media accounts. Almost all letters (97%) cited violations of marketing CBD as an unapproved new drug. These illicit therapeutic claims were made for >125 unique health problems, including cancer (87.2%), diabetes (71.8%), inflammation (66.7%), pain (66.7%), and arthritis (66.7%). The majority of letters (79.5%) also cited illicit marketing of CBD as a dietary supplement or food product. CBD was promoted as having 16 unique pharmacological effects, including anti-inflammatory (53.8%), anticancer (43.6%), and antipsychotic (30.8%). CBD products have been unlawfully advertised online as unauthorized drugs with health claims that promote therapeutic benefits and as dietary supplements. Efforts are needed to regulate and monitor illicit advertising so consumers are not misled about the risks and benefits of CBD use.
Cannabidiol in low back pain: scientific rationale for clinical trials in low back pain
The pooled worldwide prevalence of low-back pain-related presentations in primary care varies between 6.8% and 28.4% in the high-income countries rendering it a major healthcare/economy problem. To best manage this complex bio-psycho-social condition a 360-degree approach is needed, as the psycho-social components are often more important than the scant pathophysiology. Pattern analysis of cannabis users suggested that attempts to alleviate musculo-skeletal pain is often seen as a major drive to use cannabinoids.
Authorization Patterns, Safety, and Effectiveness of Medical Cannabis in Quebec
Despite increasing demand for data, little is known about the authorization patterns, safety, and effectiveness of medical cannabis products. We conducted a 2 year observational study of adult patients who were legally authorized a medical cannabis product from a single licensed producer; we captured and analyzed authorized cannabis use patterns by cannabinoid profile (tetrahydrocannabinol [THC]-dominant; cannabidiol [CBD]-dominant; and balanced (THC:CBD) and clinical outcomes using standardized outcome measures every 3 months for 12 months at a network of medical cannabis clinics in Quebec, Canada. We recruited 585 patients (average age 56.5 years), of whom 61% identified as female and 85% reported pain as their primary complaint. Over 12 months, there was a significant increase in the number of products authorized (=2.59, =0.01). The proportion of authorizations for a THC-dominant or CBD-dominant product increased relative to the proportion of authorizations for a balanced (THC:CBD) product (all <0.01). Symptom improvement over time was observed for pain, tiredness, drowsiness, anxiety, and well-being. Patients authorized THC-dominant products exhibited less symptom improvement for anxiety and well-being relative to those authorized CBD-dominant or balanced (THC:CBD) products. Medical cannabis was well tolerated across all product profiles. These real-world data reveal changes in medical cannabis authorization patterns and suggest that symptom improvement may vary by cannabinoid profile over 12 months of follow-up.
Cannabinoid use among liver transplant recipients
The effect of cannabinoids on liver transplant outcomes is an area of active research. We aimed to investigate marijuana (MJ) and cannabidiol (CBD) use among liver transplant recipients at the University of Colorado Hospital (UCH), specifically prevalence, habits and predictors of use.
Novel cannabidiol aspartame combination treatment (JW-100) significantly reduces ISGA score in atopic dermatitis: Results from a randomized double-blinded placebo-controlled interventional study
Atopic dermatitis (AD) is a common and chronic inflammatory skin disease that erupts periodically. Although the negative impact of the disorder on overall quality of life has been well established, new treatments for AD are still needed. Various studies have reported on cannabidiol's effectiveness in relieving pain and easing inflammation while not presenting major health risks.
Can Cannabidiol Affect the Efficacy of Chemotherapy and Epigenetic Treatments in Cancer?
The success of cannabinoids with chronic neuropathic pain and anxiety has been demonstrated in a multitude of studies. With the high availability of a non-intoxicating compound, cannabidiol (CBD), an over-the-counter medication, has generated heightened interest in its use in the field of oncology. This review focuses on the widespread therapeutic potential of CBD with regard to enhanced wound healing, lowered toxicity profiles of chemotherapeutics, and augmented antitumorigenic effects. The current literature is sparse with regard to determining the clinically relevant concentrations of CBD given the biphasic nature of the compound's response. Therefore, there is an imminent need for further dose-finding studies in order to determine the optimal dose of CBD for both intermittent and regular users. We address the potential influence of regular or occasional CBD usage on therapeutic outcomes in ovarian cancer patients. Additionally, as the development of chemoresistance in ovarian cancer results in treatment failure, the potential for CBD to augment the efficacy of conventional chemotherapeutic and epigenetic drugs is a topic of significant importance. Our review is focused on the widespread therapeutic potential of CBD and whether or not a synergistic role exists in combination with epigenetic and classic chemotherapy medications.
Cannabidiol Use for Fibromyalgia: Prevalence of Use and Perceptions of Effectiveness in a Large Online Survey
Cannabidiol (CBD) is widely advertised as helpful for chronic pain management but research is limited. Using a cross-sectional, anonymous survey, we examined patterns of naturalistic CBD use among individuals with fibromyalgia (FM) and other chronic pain conditions. Our objective was to better understand rates of CBD use, reasons for use and discontinuation, communication with healthcare professionals about CBD, and perceptions of CBD effectiveness and safety among people with FM. After excluding incomplete surveys, our study population consisted of N = 2,701 participants with fibromyalgia, primarily in the United States. Overall, 38.1% reported never using CBD, 29.4% reported past CBD use, and 32.4% reported current CBD use. Past-year cannabis use was strongly associated with past or current CBD use. Those using CBD typically did so due to inadequate symptom relief, while those not using CBD typically cited safety concerns as their reason for not using CBD. Two-thirds of participants disclosed CBD use to their physician, although only 33% asked for physician advice on using CBD. Participants used CBD for numerous FM-related symptoms (most commonly pain), and generally reported slight to much improvement across symptom domains. Around half of participants reported side effects, which were typically minor. Our findings are limited by selection bias and our cross-sectional design, which prevents causal associations. In conclusion, CBD use is common among individuals with FM and many individuals using CBD report improvements across numerous FM-related symptoms. Our findings highlight the need for additional rigorous studies to better understand CBD's potential for FM management. PERSPECTIVE: This article indicates that CBD use is common among people with fibromyalgia, and the results suggest that many derive benefit from using CBD across multiple symptoms domains. Clinicians should discuss CBD use with fibromyalgia patients, and future studies are needed to rigorously assess CBD's therapeutic value for fibromyalgia symptoms.
An initial analysis of the UK Medical Cannabis Registry: Outcomes analysis of first 129 patients
Cannabis-based medicinal products (CBMPs) are prescribed with increased frequency, despite a paucity of high-quality randomized controlled trials. The aim of this study is to analyze the early outcomes of the first series of patients prescribed CBMPs in the UK with respect to effects on health-related quality of life and clinical safety.
Developing a real-world evidence base for prescribed cannabis in the United Kingdom: preliminary findings from Project Twenty21
The therapeutic potential of medical cannabis to treat a variety of conditions is becoming increasingly recognised. Globally, a large number of countries have now legalised cannabis for medical uses and a substantial number of patients are able to access their medications. Yet in the UK, where medical cannabis was legalised in November 2018, only a handful of NHS prescriptions have been written, meaning that most patients are unable to access the medicine. Reasons for this are manyfold and include the perceived lack of clinical evidence due to the challenges of studying medical cannabis through randomised controlled trials. In order to develop the current evidence base, the importance of incorporating real-world data (RWD) to assess the effectiveness and efficacy of medical cannabis has gradually become recognised. The current paper provides a detailed outline of Project Twenty21 (T21), the UK's first medical cannabis registry, launched in August 2020. We provide the rationale for T21 and describe the methodology before reporting the characteristics of the 'first patients' enrolled in the registry. We describe the health status of all patients enrolled into the project during its first 7 months of operation and the sociodemographic characteristics and primary presenting conditions for these patients, as well as details of the medical cannabis prescribed to these individuals. By 12th March 2021, 678 people had been enrolled into T21; the majority (64%) were male and their average age was 38.7 years (range = 18-80). The most commonly reported primary conditions were chronic pain (55.6%) and anxiety disorders (32.0%) and they reported high levels of multi-morbidity, including high rates of insomnia and depression. We also present preliminary evidence from 75 patients followed up after 3 months indicating that receipt of legal, prescribed cannabis was associated with a significant increase in self-reported health, assessed using the visual analogue scale of the EQ-5D-5L (Cohen's d = .77, 95% CI = .51-1.03). Our initial findings complement reports from other large-scale databases globally, indicating that the current RWD is building up a pattern of evidence. With many clinicians demanding better and faster evidence to inform their decisions around prescribing medical cannabis, the current and future results of T21 will expand the existing evidence base on the effectiveness of cannabis-based medical products (CBMPs).
Substituting Cannabidiol for Opioids and Pain Medications Among Individuals With Fibromyalgia: A Large Online Survey
People report substituting cannabis for pain medications, but whether cannabidiol (CBD) is used similarly remains unknown. CBD products can be CBD alone (isolate), hemp extract (containing <0.3% Δ-9-tetrahydrocannabinol [THC], other cannabinoids, and terpenes), or CBD-cannabis (containing >0.3% THC). In a secondary analysis from a cross-sectional survey, we examined substitution patterns among n = 878 individuals with fibromyalgia who currently used CBD. We sub-grouped participants by most commonly used CBD product (CBD isolate, hemp, CBD-cannabis, no preference) and whether they substituted CBD for medications. We investigated rationale for substituting, substitution-driven medication changes, CBD use patterns, and changes in pain-related symptoms (eg, sleep, anxiety). The study population was 93.6% female and 91.5% Caucasian, with an average age of 55.5 years. The majority (n = 632, 72.0%) reported substituting CBD products for medications, most commonly NSAIDs (59.0%), opioids (53.3%), gabapentanoids (35.0%), and benzodiazepines (23.1%). Most substituting participants reported decreasing or stopping use of these pain medications. The most common reasons for substitution were fewer side effects and better symptom management. Age, hemp products, past-year use of marijuana, and higher somatic burden were all associated with substituting (P's ≤ .05). Those who substituted reported larger improvements in health and pain than those who did not. Participants using CBD-cannabis reported significantly more substitutions than any other group (P's ≤ .001) and larger improvements in health, pain, memory, and sleep than other subgroups. This widespread naturalistic substitution for pain medications suggests the need for more rigorous study designs to examine this effect. PERSPECTIVE: This article shows that people with fibromyalgia are deliberately substituting CBD products for conventional pain medications despite the dearth of evidence suggesting CBD products may be helpful for fibromyalgia. CBD's medication-sparing and therapeutic potential should be examined in more rigorous study designs.
Oral efficacy of Δ(9)-tetrahydrocannabinol and cannabidiol in a mouse neuropathic pain model
The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have synergistic analgesic efficacy in animal models of neuropathic pain when injected systemically. However, the relevance of this preclinical synergy to clinical neuropathic pain studies is unclear because many of the latter use oral administration. We therefore examined the oral effectiveness of these phytocannabinoids and their interactions in a mouse chronic constriction injury (CCI) model of neuropathic pain. THC produced a dose-dependent reduction in mechanical and cold allodynia, but also induced side-effects with similar potency. CBD also reduced allodynia, albeit with lower potency than THC, but did not produce cannabinoid-like side-effects at any dose tested. Combination THC:CBD produced a dose-dependent reduction in allodynia, however, it displayed little to no synergy. Combination THC:CBD produced substantial, synergistic side-effects which increased with the proportion of CBD. These findings demonstrate that oral THC and CBD, alone and in combination, have analgesic efficacy in an animal neuropathic pain model. Unlike prior systemic injection studies, combination THC:CBD lacks analgesic synergy when delivered orally. Furthermore, both THC and combination THC:CBD display a relatively poor therapeutic window when delivered orally. This suggests that CBD provides a safer, albeit lower efficacy, oral treatment for nerve injury induced neuropathic pain than THC-containing preparations. This article is part of the special issue on 'Cannabinoids'.
Safety and tolerability of nabiximols oromucosal spray: a review of real-world experience in observational studies, registries, and case reports
: Nabiximols oromucosal spray,a cannabis-based medicine containing a balanced ratio of Δ-9-tetrahydrocannabinol and cannabidiol, is approved widely as an add-on therapy for symptomatic relief of spasticity in people with multiple sclerosis (MS). Most safety data for nabiximols derive from use in MS spasticity, with some data available from the analgesia area.
Lack of efficacy of cannabidiol for relieving back pain: time to re-set expectations?
The CANBACK trial: a randomised, controlled clinical trial of oral cannabidiol for people presenting to the emergency department with acute low back pain
To assess the analgesic efficacy and safety of single-dose oral cannabidiol (CBD) as an adjunct to standard care for patients presenting to an emergency department with acute low back pain.
Calling for Openness to the Study of Cannabis Use in Chronic Pelvic Pain
Chronic pelvic pain affects women across all demographics. Its management is complex and requires a multimodal approach. Cannabis has been legal for medical purposes for many years; however, its pharmacokinetics are just beginning to be understood, as are its analgesic effects and other benefits, such as improved sleep quality and reduced nausea and vomiting. Given the recent Canada-wide legalization of cannabis for non-medical use, patients may be more willing to disclose cannabis use and use it for pain management. Given the complexity of chronic pain management, physicians must be open to cannabis as an analgesic option. Cannabis use may decrease the need for opioids, a phenomenon that could reduce opioid dependency. Now is the ideal time to study patients' use of and perspectives on cannabis for pain relief in order to establish its effectiveness and safety. Cannabis shows potential to be a key player in a multimodal approach to chronic pelvic pain.
Knowledge and Opinion on Cannabinoids Among Orthopaedic Traumatologists
Cannabinoids are an increasingly popular therapy among orthopaedic patients for musculoskeletal conditions. A paucity of evidence to support their use in orthopaedics exists, likely because of the incongruence of federal and state legalization and the stigma surrounding cannabis. The purpose of this study is to elucidate sentiments and knowledge base of the orthopaedic trauma community with regard to cannabinoid-containing compounds.
Pain response to cannabidiol in induced acute nociceptive pain, allodynia, and hyperalgesia by using a model mimicking acute pain in healthy adults in a randomized trial (CANAB I)
Preclinical studies have demonstrated the analgesic potential of cannabidiol (CBD). Those suggesting an effect on pain-processing receptors have brought CBD back into focus. This study assessed the effect of CBD on acute pain, hyperalgesia, and allodynia compared with placebo. Twenty healthy volunteers were included in this randomized, placebo-controlled, double-blinded, crossover study assessing pain intensities (using numeric rating scale), secondary hyperalgesia (von Frey filament), and allodynia (dry cotton swab) in a well-established acute pain model with intradermal electrical stimulation. The authors compared the effect of 800-mg orally administered CBD on pain compared with placebo. They further examined the effect on hyperalgesia and allodynia. Cannabidiol whole blood levels were also measured. Pain ratings (mean ± SD) did not differ significantly after CBD application compared with placebo (5.2 ± 0.7 vs 5.3 ± 0.7, P-value 0.928), neither did the areas of hyperalgesia and allodynia differ significantly after CBD application compared with placebo (hyperalgesia 23.9 ± 19.2 cm2 vs 27.4 ± 17.0 cm2, P-value 0.597; allodynia 16.6 ± 13.1 cm2 vs 17.3 ± 14.1 cm2, P-value 0.884). The CBD whole blood level (median, first to third quartile) was 2.0 µg/L (1.5-5.1) 60 minutes and 5.0 µg/L (4.0-10.4) 130 minutes after CBD application. Although the oral application of 800-mg CBD failed to show a significant effect, it is important to focus future research on different dosing, routes of administration, and CBD as a part of multimodal treatment strategies before negating its effects on acute pain.
Inhaled Cannabis Suppresses Chemotherapy-Induced Neuropathic Nociception by Decoupling the Raphe Nucleus: A Functional Imaging Study in Rats
Efficacy of inhaled cannabis for treating pain is controversial. Effective treatment for chemotherapy-induced neuropathy represents an unmet medical need. We hypothesized that cannabis reduces neuropathic pain by reducing functional coupling in the raphe nuclei.
Cannabidiol (CBD) and other drug use among young adults who use cannabis in Los Angeles
Cannabidiol (CBD) is purportedly a promising therapeutic agent to provide relief for a variety of medical conditions with mild or no psychoactive effects. However, little is known about young adults who use cannabis and CBD-dominant products, and associations between CBD use and other drug use.
Cannabis sativa and Skin Health: Dissecting the Role of Phytocannabinoids
The use of is currently recognized to ease certain types of chronic pain, reduce chemotherapy-induced nausea, and improve anxiety. Nevertheless, few studies highlighted the therapeutic potential of extracts and related phytocannabinoids for a variety of widespread skin disorders including acne, atopic dermatitis, psoriasis, pruritus, and pain. This review summarized the current evidence on the effects of phytocannabinoids at the cutaneous level through the collection of and clinical studies published on PubMed, Scopus, Embase, and Web of Science until October 2020. Phytocannabinoids have demonstrated potential anti-inflammatory, antioxidant, anti-aging, and anti-acne properties by various mechanisms involving either CB/-dependent and independent pathways. Not only classical immune cells, but also several skin-specific actors, such as keratinocytes, fibroblasts, melanocytes, and sebocytes, may represent a target for phytocannabinoids. Cannabidiol, the most investigated compound, revealed photoprotective, antioxidant, and anti-inflammatory mechanisms at the cutaneous level, while the possible impact on cell differentiation, especially in the case of psoriasis, would require further investigation. Animal models and pilot clinical studies supported the application of cannabidiol in inflammatory-based skin diseases. Also, one of the most promising applications of non-psychotropic phytocannabinoids is the treatment of seborrheic disorders, especially acne. In conclusion, the incomplete knowledge of the role of the endocannabinoid system in skin disorders emerged as an important limit for pharmacological investigations. Moreover, the limited studies conducted on extracts suggested a higher potency than single phytocannabinoids, thus stimulating new research on phytocannabinoid interaction.
Homegrown perceptions about the medical use and potential abuse of CBD and THC
Despite heightened consumer interest in cannabinoids such as cannabidiol (CBD) and tetrahydrocannabinol (THC), little is known about public perceptions regarding their medical use and potential for abuse, particularly relative to commonly used medications. Using data from 1,050 U.S. adult respondents from a national survey conducted in 2019, this study found that more than half of respondents perceived CBD, THC, hemp, and marijuana as having medical use. They also perceived the potential for abuse of CBD, THC, hemp, and marijuana as significantly less than potential for abuse of commonly prescribed anti-anxiety and pain medications. At the nexus of medical use and potential abuse, public perceptions classified CBD and hemp as similar to over-the-counter pain relief medications such as Advil and Tylenol and did not classify marijuana as a Schedule I substance. Slightly more than 20% of respondents reported having consumed CBD and/or THC. CBD was consumed more than THC to reduce pain while THC was consumed more than CBD for recreation. There were no differences in the types of medications they were replacing with CBD and THC.
State of the science: cannabis and cannabinoids in palliative medicine-the potential
Cannabinoids are chemicals derived naturally from the cannabis plant or are synthetically manufactured. They interact directly with cannabinoid receptors or share chemical similarity with endocannabinoids (or both). Within palliative medicine, cannabinoid receptors (CB1 and CB2) may modulate some cancer symptoms: appetite, chemotherapy-induced nausea and vomiting, and mood, pain and sleep disorders. Opioid and cannabinoid receptors have overlapping neuroanatomical receptor distribution, particularly at the dorsal horn, dorsal striatum and locus coeruleus. They have a favourable safety profile compared with opioids, and cannabis-based medicines help chronic pain. While cannabidiol (CBD) has anti-inflammatory properties, tetrahydrocannabinol (THC) is the psychoactive substance for issues such as mood and sleep. Nabiximols (Sativex), a CBD:THC combination, is Food and Drug Administration approved for some multiple sclerosis symptoms and epilepsy. There has been a swift societal evolution in attitudes about use of cannabis and cannabinoid medicines for chronic pain. In the USA, 33 states have now legalised prescription-based medical cannabis for several medical conditions; Canada has had legislation since 2001 authorising medical use. The European Union (EU) recently declared all EU citizens must have access to medical cannabis over the next 4 years. The integration into medicine and routine clinical use of cannabis is fraught with information gaps, regulatory issues and scarcity of research. Each patient should have a comprehensive assessment and risk-benefit discussion before any cannabis-based intervention to avoid possible complications such as hallucinations, psychosis and potential cardiac harm.
A response to Kong et al.'s January 2021 article "Cannabinoids in dermatologic surgery"
Nabiximols in Chronic Neuropathic Pain: A Meta-Analysis of Randomized Placebo-Controlled Trials
Pooled analysis of nabiximols and placebo in randomized controlled studies (RCTs) of chronic neuropathic pain.
Anti-seizure medications for Lennox-Gastaut syndrome
Lennox-Gastaut syndrome (LGS) is an age-specific epilepsy syndrome characterised by multiple seizure types, including drop seizures. LGS has a characteristic electroencephalogram, an onset before age eight years and an association with drug resistance. This is an updated version of the Cochrane Review published in 2013.
Cannabis-based medicines and pain: a review of potential synergistic and entourage effects
The recent legalization of medicinal cannabis in several jurisdictions has spurred the development of therapeutic formulations for chronic pain. Unlike pure delta-9-tetrahydrocannabinol (THC), full-spectrum products contain naturally occurring cannabinoids and have been reported to show improved efficacy or tolerability, attributed to synergy between cannabinoids and other components in the cannabis plant. Although 'synergy' indicates that two or more active compounds may produce an additive or combined effect greater than their individual analgesic effect, potentiation of the biological effect of a compound by related but inactive compounds, in combination, was termed the 'entourage effect'. Here, we review current evidence for potential synergistic and entourage effects of cannabinoids in pain relief. However, definitive clinical trials and functional studies are still required.
Mucoadhesive nanostructured lipid carriers as a cannabidiol nasal delivery system for the treatment of neuropathic pain
The therapeutic potential of cannabidiol (CBD) has been explored to treat several pathologies, including those in which pain is prevalent. However, the oral bioavailability of CBD is low owing to its high lipophilicity and extensive first-pass metabolism. Considering the ability of the nasal route to prevent liver metabolism and increase brain bioavailability, we developed nanostructured lipid carriers (NLCs) for the nasal administration of CBD. We prepared particles with a positively charged surface, employing stearic acid, oleic acid, Span 20, and cetylpyridinium chloride to obtain mucoadhesive formulations. Characterisation of the CBD-NLC dispersions showed uniform nano-sized particles with diameters smaller than 200 nm, and high drug encapsulation. The mucoadhesion of cationic particles has been related to interactions with negatively charged mucin. Next, we added in-situ gelling polymers to the CBD-NLC dispersion to obtain a CBD-NLC-gel. A thermo-reversible in-situ forming gel was prepared by the addition of Pluronics. CBD-NLC-gel was characterised by its gelation temperature, rheological behaviour, and mucoadhesion. Both formulations, CBD-NLC and CBD-NLC-gel, showed high mucoadhesion, as assessed by the flow-through method and similar in vitro drug release profiles. The in vivo evaluation showed that CBD-NLC dispersion (without gel), administered intranasally, produced a more significant and lasting antinociceptive effect in animals with neuropathic pain than the oral or nasal administration of CBD solution. However, the nasal administration of CBD-NLC-gel did not lessen mechanical allodynia. These findings demonstrate that in-situ gelling hydrogels are not suitable vehicles for highly lipophilic drugs such as CBD, while cationic CBD-NLC dispersions are promising formulations for the nasal administration of CBD.
Behavioural and pharmacological effects of cannabidiol (CBD) and the cannabidiol analogue KLS-13019 in mouse models of pain and reinforcement
Cannabidiol (CBD) is a non-euphorigenic component of Cannabis sativa that prevents the development of paclitaxel-induced mechanical sensitivity in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). We recently reported that the CBD structural analogue KLS-13019 shows efficacy in an in vitro model of CIPN. The present study was to characterize the behavioural effects of KLS-13019 compared to CBD and morphine in mouse models of CIPN, nociceptive pain and reinforcement.
Antinociceptive effects of minor cannabinoids, terpenes and flavonoids in Cannabis
Cannabis has been used for centuries for its medicinal properties. Given the dangerous and unpleasant side effects of existing analgesics, the chemical constituents of Cannabis have garnered significant interest for their antinociceptive, anti-inflammatory and neuroprotective effects. To date, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) remain the two most widely studied constituents of Cannabis in animals. These studies have led to formulations of THC and CBD for human use; however, chronic pain patients also use different strains of Cannabis (sativa, indica and ruderalis) to alleviate their pain. These strains contain major cannabinoids, such as THC and CBD, but they also contain a wide variety of cannabinoid and noncannabinoid constituents. Although the analgesic effects of Cannabis are attributed to major cannabinoids, evidence indicates other constituents such as minor cannabinoids, terpenes and flavonoids also produce antinociception against animal models of acute, inflammatory, neuropathic, muscle and orofacial pain. In some cases, these constituents produce antinociception that is equivalent or greater compared to that produced by traditional analgesics. Thus, a better understanding of the extent to which these constituents produce antinociception alone in animals is necessary. The purposes of this review are to (1) introduce the different minor cannabinoids, terpenes, and flavonoids found in Cannabis and (2) discuss evidence of their antinociceptive properties in animals.
Application of medical cannabis in unstable angina and coronary artery disease: A case report
First discovered in 1990, the endocannabinoid system (ECS) was initially shown to have an intimate relationship with central areas of the nervous system associated with pain, reward, and motivation. Recently, however, the ECS has been extensively implicated in the cardiovascular system with contractility, heart rate, blood pressure, and vasodilation. Emerging data demonstrate modulation of the ECS plays an essential role in cardio metabolic risk, atherosclerosis, and can even limit damage to cardiomyocytes during ischemic events.
Disposition of cannabinoids and their metabolites in serum, oral fluid, sweat patch and urine from healthy individuals treated with pharmaceutical preparations of medical cannabis
Recently, several countries authorized the use of cannabis flowering tops (dried inflorescences) with a standardized amount of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) and their acidic precursors [Δ-9-tetrahydrocannabinolic acid A (THCA-A) and cannabidiolic acid (CBDA)] to treat neurogenic pain. We studied the acute pharmacological effects and disposition of cannabinoids and their metabolites in serum, oral fluid, sweat patch and urine of 13 healthy individuals treated with medical cannabis decoction and oil. Cannabinoids and their metabolites were quantified by ultrahigh performance tandem mass spectrometry. Even if the oil contained a significantly higher amount of THC, the absorption of THC and its metabolites were similar in both herbal preparations. Conversely, whereas oil contained a significantly higher amount of CBD and a lower amount of CBDA, absorption was significantly higher after decoction intake. Only cannabinoids present in both herbal preparations (THC, CBD, THCA-A and CBDA) were found in oral fluid, due to the higher acidity compared with that of serum. THC metabolites urinary excretion was always higher after decoction administration. Decoction induced greater feeling of hunger and drowsiness than oil preparation. Pharmacokinetics of cannabinoids, their precursors and their metabolites in biological fluids of individuals treated with cannabis decoction and oil showed a high interindividual variability. The aqueous preparation was generally better absorbed than the oil, even if it contained a minor amount of THC, THCA-A and CBD.
Endocannabinoid System as Therapeutic Target of PTSD: A Systematic Review
Post-Traumatic Stress Disorder (PTSD) is a complex disorder involving dysregulation of stress-related hormones and neurotransmitter systems. Research focused on the endocannabinoid system (eCBS) for anxiety and stress regulation, cognitive and emotional responses modulation and aversive memories extinction, leading to the hypothesis that it could represent a possible alternative treatment target for PTSD. In this systematic review, we summarize evidence about the efficacy and safety of medicinal cannabidiol (CBD), Δ-tetrahydrocannabinol (Δ-THC), and nabilone in PTSD treatment. The PRISMA statement guidelines were followed. A systematic literature search was conducted in MEDLINE/PubMed, Scopus and Web of Science by two independent researchers, who also performed data extraction and quality assessment. Among the initial 495 papers, 234 were screened for eligibility and 10 were included. Studies suggested that different medicinal cannabinoids at distinct doses and formulations could represent promising treatment strategies for the improvement of overall PTSD symptomatology as well as specific symptom domains (e.g., sleep disorders, arousal disturbances, suicidal thoughts), also influencing quality of life, pain and social impact. Although there is a robust rationale for treatment with drugs that target the eCBS and the results are promising, further studies are needed to investigate the safety and efficacy profile of their prolonged use.
Assessment of hemp oil-based cannabidiol use in a community-based pharmacy setting
The Agricultural Improvement Act of 2018 legalized the commercial use of hemp-based products, including cannabidiol (CBD). However, the U.S. Food and Drug Administration (FDA) does not currently regulate the commercial sale of hemp oil-based CBD, and there is no FDA-approved indication for its nonprescription formulations despite the growing demand for, and use of, hemp oil-based CBD.
Evaluation of the Effect of Cannabidiol on Naturally Occurring Osteoarthritis-Associated Pain: A Pilot Study in Dogs
The objective of this study was to provide preliminary data describing the safety and effect of cannabidiol (CBD) for symptom relief of canine osteoarthritis-associated pain in a clinical setting using objective outcome measures. Twenty-three client-owned dogs with naturally occurring osteoarthritis of appendicular joints completed this prospective, double-blinded, crossover, placebo-controlled study. Baseline data were acquired for 4 wk, followed by random allocation to either placebo or CBD treatment for 6 wk, followed by 6 wk with the opposite treatment. Outcome measures included objective gait analysis, activity counts (via accelerometry) and clinical metrology instruments. There were no differences noted between groups at any time point for any of the recorded outcome measures. Adverse events associated with CBD administration included elevation in liver enzymes (n = 14) and vomiting (n = 2).
The Effects of Cannabis: Implications for the Surgical Patient
Cannabis use is increasingly prevalent. Cannabinoid receptors regulate pro-inflammatory cytokines, and compounds in marijuana exert diverse physiologic effects. As more patients use cannabis, clinicians should recognize implications of perioperative cannabis use. Although the role of cannabis use in perioperative pain control has been explored, little is known about its effect on perioperative wound healing or on hematologic, pulmonary, and cardiovascular physiology.
Topical Treatments and Their Molecular/Cellular Mechanisms in Patients with Peripheral Neuropathic Pain-Narrative Review
Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients' quality of life, as pharmacological and non-pharmacological methods often fail or induce side effects. Topical treatments are gaining popularity in the management of peripheral neuropathic pain, due to excellent safety profiles and preferences. Moreover, topical treatments applied locally may target the underlying mechanisms of peripheral sensitization and pain. Recent studies showed that peripheral sensitization results from interactions between neuronal and non-neuronal cells, with numerous signaling molecules and molecular/cellular targets involved. This narrative review discusses the molecular/cellular mechanisms of drugs available in topical formulations utilized in clinical practice and their effectiveness in clinical studies in patients with peripheral neuropathic pain. We searched PubMed for papers published from 1 January 1995 to 30 November 2020. The key search phrases for identifying potentially relevant articles were "topical AND pain", "topical AND neuropathic", "topical AND treatment", "topical AND mechanism", "peripheral neuropathic", and "mechanism". The result of our search was 23 randomized controlled trials (RCT), 9 open-label studies, 16 retrospective studies, 20 case (series) reports, 8 systematic reviews, 66 narrative reviews, and 140 experimental studies. The data from preclinical studies revealed that active compounds of topical treatments exert multiple mechanisms of action, directly or indirectly modulating ion channels, receptors, proteins, and enzymes expressed by neuronal and non-neuronal cells, and thus contributing to antinociception. However, which mechanisms and the extent to which the mechanisms contribute to pain relief observed in humans remain unclear. The evidence from RCTs and reviews supports 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A injections as effective treatments in patients with peripheral neuropathic pain. In turn, single RCTs support evidence of doxepin, funapide, diclofenac, baclofen, clonidine, loperamide, and cannabidiol in neuropathic pain states. Topical administration of phenytoin, ambroxol, and prazosin is supported by observational clinical studies. For topical amitriptyline, menthol, and gabapentin, evidence comes from case reports and case series. For topical ketamine and baclofen, data supporting their effectiveness are provided by both single RCTs and case series. The discussed data from clinical studies and observations support the usefulness of topical treatments in neuropathic pain management. This review may help clinicians in making decisions regarding whether and which topical treatment may be a beneficial option, particularly in frail patients not tolerating systemic pharmacotherapy.
A Multicriteria Decision Analysis Comparing Pharmacotherapy for Chronic Neuropathic Pain, Including Cannabinoids and Cannabis-Based Medical Products
Pharmacological management of chronic neuropathic pain (CNP) still represents a major clinical challenge. Collective harnessing of both the scientific evidence base and clinical experience (of clinicians and patients) can play a key role in informing treatment pathways and contribute to the debate on specific treatments (e.g., cannabinoids). A group of expert clinicians (pain specialists and psychiatrists), scientists, and patient representatives convened to assess the relative benefit-safety balance of 12 pharmacological treatments, including orally administered cannabinoids/cannabis-based medicinal products, for the treatment of CNP in adults. A decision conference provided the process of creating a multicriteria decision analysis (MCDA) model, in which the group collectively scored the drugs on 17 effect criteria relevant to benefits and safety and then weighted the criteria for their clinical relevance. Cannabis-based medicinal products consisting of tetrahydrocannabinol/cannabidiol (THC/CBD), in a 1:1 ratio, achieved the highest overall score, 79 (out of 100), followed by CBD dominant at 75, then THC dominant at 72. Duloxetine and the gabapentinoids scored in the 60s, amitriptyline, tramadol, and ibuprofen in the 50s, methadone and oxycodone in the 40s, and morphine and fentanyl in the 30s. Sensitivity analyses showed that even if the pain reduction and quality-of-life scores for THC/CBD and THC are halved, their benefit-safety balances remain better than those of the noncannabinoid drugs. The benefit-safety profiles for cannabinoids were higher than for other commonly used medications for CNP largely because they contribute more to quality of life and have a more favorable side effect profile. The results also reflect the shortcomings of alternative pharmacological treatments with respect to safety and mitigation of neuropathic pain symptoms. Further high-quality clinical trials and systematic comprehensive capture of clinical experience with cannabinoids is warranted. These results demonstrate once again the complexity and multimodal mechanisms underlying the clinical experience and impact of chronic pain.
A validated method for the simultaneous quantification of cannabidiol, Δ -tetrahydrocannabinol, and their metabolites in human plasma and application to plasma samples from an oral cannabidiol open-label trial
Cannabidiol (CBD) and Δ -tetrahydrocannabinol (THC) are the two best known and most extensively studied phytocannabinoids within Cannabis sativa. An increasing number of preclinical studies and clinical trials have been conducted with one or both compounds, often probing their therapeutic effects in conditions such as paediatric epilepsy, anxiety disorders or chronic pain. Accurate monitoring of THC and CBD and their metabolites is essential for tracking treatment adherence and pharmacokinetics. However, fully validated methods for the comprehensive analysis of major Phase I CBD metabolites are yet to be developed due to a historical lack of commercially available reference material. In the present study, we developed, optimised and validated a method for the simultaneous quantification of CBD, THC and their major Phase I metabolites 6-hydroxy-CBD (6-OH-CBD), 7-hydroxy-CBD (7-OH-CBD), 7-carboxy-CBD (7-COOH-CBD), 11-hydroxy-tetrahydrocannabinol (11-OH-THC) and 11-carboxy-tetrahydrocannabinol (11-COOH-THC) as per Food and Drug Administration (FDA) guidelines for bioanalytical method validation. The method is accurate, reproducible, sensitive and can be carried out in high-throughput 96-well formats, ideal for larger scale clinical trials. Deuterated internal standards for each analyte were crucial to account for variable matrix effects between plasma lots. The application of the method to plasma samples, taken from people who had been administered oral CBD as part of an open-label trial of CBD effects in anxiety disorders, demonstrated its immediate utility in ongoing and upcoming clinical trials. The method will prove useful for future studies involving CBD and/or THC and can likely accommodate the inclusion of additional metabolites as analytical reference materials become commercially available.
Should You Recommend Cannabinoids for This Patient With Painful Neuropathy? : Grand Rounds Discussion From Beth Israel Deaconess Medical Center
Cannabis includes 140 active cannabinoid compounds, the most important of which are tetrahydrocannabinol and cannabidiol (CBD). Tetrahydrocannabinol is primarily responsible for the intoxicating effects of cannabis; CBD has potential therapeutic effects, including reduction in chronic pain. Recent legislative changes have resulted in the legal availability of cannabinoids in all 50 states, as well as a marked increase in patients' interest in their use. Despite an abundance of data, albeit of varied quality, clinicians may feel poorly prepared to counsel patients seeking advice on the suitability of CBD products for various indications, particularly chronic neuropathic pain. In 2018, on the basis of a systematic review of the literature, a Canadian Evidence Review Group published a guideline with recommendations for clinicians on prescribing cannabinoids in primary care practice. The overall quality of evidence was low to very low. In a meta-analysis of 15 randomized trials of medical cannabis for treating chronic pain, 39% of patients achieved at least a 30% reduction in pain. The corresponding value for placebo-treated patients was 30%; the number needed to treat was 11. More evidence exists for neuropathic pain than for other types of noncancer pain. Here, a general internist with a focus on addiction medicine and an addiction psychiatrist discuss how they would apply the literature to make recommendations for a patient with painful diabetic neuropathy, including counseling on both potential benefits and harms.
Effects of Cannabidiol Chewing Gum on Perceived Pain and Well-Being of Irritable Bowel Syndrome Patients: A Placebo-Controlled Crossover Exploratory Intervention Study with Symptom-Driven Dosing
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders. Its pathophysiology is diverse and variable, involving disturbed gut-brain interactions, altered motility and secretion, visceral hypersensitivity, increased intestinal permeability, immune activation, and changes in gut microbiota. Complaints experienced by patients suffering from IBS and its co-morbidities strongly impair quality of life (QoL), and available treatments are often unsatisfactory. Anecdotal reports and preclinical data suggest that the endocannabinoid system and functionally related mechanisms could offer treatment targets. Cannabidiol (CBD) is a candidate agent of interest with a broad molecular target profile and the absence of psychoactive properties. In 32 female IBS patients, we explored the effect of a chewing gum formulation containing 50 mg CBD on abdominal pain and perceived well-being in a randomized, double-blinded, placebo-controlled cross-over trial. Chewing gums were used on-demand guided by pain symptoms with a maximum of six per day. Pain intensity was assessed by a visual analogue scale (scale 0.0-10.0), and QoL was evaluated with the IBS-36 questionnaire. There was no statistically significant difference in pain scores between CBD and placebo at a group level. Subgroup and individual analyses showed a highly variable picture. No indications were found for symptom-driven intake, which also remained lower than expected overall. With the current design, based on the assumption that IBS patients would adjust their intake to their perceived symptom relief, no differences at the group level were found between CBD and placebo gum in pain scores and the number of gums used. The low use of the gums also indicates that the benefits experienced by these patients generally did not outweigh practical disadvantages such as prolonged chewing throughout the day. The very high intra- and inter-individual variation in IBS symptoms warrant future trials that are more personalized, for example by applying an N-of-1 (rotating) design with individualized dose titration.
Cannabis: A Toxin-Producing Plant with Potential Therapeutic Uses
For thousands of years, has been utilized as a medicine and for recreational and spiritual purposes. Phytocannabinoids are a family of compounds that are found in the cannabis plant, which is known for its psychotogenic and euphoric effects; the main psychotropic constituent of cannabis is Δ9-tetrahydrocannabinol (Δ9-THC). The pharmacological effects of cannabinoids are a result of interactions between those compounds and cannabinoid receptors, CB1 and CB2, located in many parts of the human body. Cannabis is used as a therapeutic agent for treating pain and emesis. Some cannabinoids are clinically applied for treating chronic pain, particularly cancer and multiple sclerosis-associated pain, for appetite stimulation and anti-emesis in HIV/AIDS and cancer patients, and for spasticity treatment in multiple sclerosis and epilepsy patients. Medical cannabis varies from recreational cannabis in the chemical content of THC and cannabidiol (CBD), modes of administration, and safety. Despite the therapeutic effects of cannabis, exposure to high concentrations of THC, the main compound that is responsible for most of the intoxicating effects experienced by users, could lead to psychological events and adverse effects that affect almost all body systems, such as neurological (dizziness, drowsiness, seizures, coma, and others), ophthalmological (mydriasis and conjunctival hyperemia), cardiovascular (tachycardia and arterial hypertension), and gastrointestinal (nausea, vomiting, and thirst), mainly associated with recreational use. Cannabis toxicity in children is more concerning and can cause serious adverse effects such as acute neurological symptoms (stupor), lethargy, seizures, and even coma. More countries are legalizing the commercial production and sale of cannabis for medicinal use, and some for recreational use as well. Liberalization of cannabis laws has led to increased incidence of toxicity, hyperemesis syndrome, lung disease cardiovascular disease, reduced fertility, tolerance, and dependence with chronic prolonged use. This review focuses on the potential therapeutic effects of cannabis and cannabinoids, as well as the acute and chronic toxic effects of cannabis use on various body systems.
Evaluation of THC-Related Neuropsychiatric Symptoms Among Adults Aged 50 Years and Older: A Systematic Review and Metaregression Analysis
Medical cannabis for the treatment of fibromyalgia syndrome: a retrospective, open-label case series
The use of cannabis for treating fibromyalgia syndrome (FMS) has not been comprehensively investigated. Thus, we have assessed the efficacy and adverse events (AEs) of short- and long-term medical cannabis (MC) treatment for FMS.
Reasons for cannabidiol use: a cross-sectional study of CBD users, focusing on self-perceived stress, anxiety, and sleep problems
Public and medical interest in cannabidiol (CBD) has been rising, and CBD is now available from various sources. Research into the effects of low-dose CBD on outcomes like stress, anxiety, and sleep problems have been scarce, so we conducted an online survey of CBD users to better understand patterns of use, dose, and self-perceived effects of CBD.
Cannabidiol Does Not Impair Anabolic Signaling Following Eccentric Contractions in Rats
Cannabidiol (CBD) has proven clinical benefits in the treatment of seizures, inflammation, and pain. The recent legalization of CBD in many countries has caused increased interest in the drug as an over-the-counter treatment for athletes looking to improve recovery. However, no data on the effects of CBD on the adaptive response to exercise in muscle are available. To address this gap, we eccentrically loaded the tibialis anterior muscle of 14 rats, injected them with a vehicle (n = 7) or 100 mg/kg CBD (n = 7), and measured markers of injury, inflammation, anabolic signaling, and autophagy 18 hr later. Pro-inflammatory signaling through nuclear factor kappa B (NF-kB) (Ser536) increased with loading in both groups; however, the effect was significantly greater (36%) in the vehicle group (p < .05). Simultaneously, anabolic signaling through ribosomal protein S6 kinase beta-1 (S6K1) (Thr389) increased after eccentric contractions in both groups with no difference between vehicle and CBD (p = .66). The ribosomal protein S6 phosphorylation (240/244) increased with stimulation (p < .001) and tended to be higher in the CBD group (p = .09). The ubiquitin-binding protein p62 levels were not modulated by stimulation (p = .6), but they were 46% greater in the CBD compared with the vehicle group (p = .01). Although liver weight did not differ between the groups (p = .99) and levels of proteins associated with stress were similar, we did observe serious side effects in one animal. In conclusion, an acute dose of CBD decreased pro-inflammatory signaling in the tibialis anterior without blunting the anabolic response to exercise in rats. Future research should determine whether these effects translate to improved recovery without altering adaptation in humans.
Antinociceptive and Anti-Inflammatory Properties of Cannabidiol Alone and in Combination with Standardized Bioflavonoid Composition
Symptom-alleviating therapies for osteoarthritis (OA) management are inadequate. Long-term application of first-line treatments, such as nonsteroidal anti-inflammatory drugs, is limited due to associated side effects. We believe that a combination of traditionally used botanical extracts, which have diverse active components that target multiple inflammatory pathways, may provide a safe and efficacious alternative to address the multifactorial nature of OA. Recently, cannabidiol (CBD), the major nonpsychoactive component of the hemp plant, has gained renewed global attention for its pharmacological actions. It has shown promise in reducing pain and inflammation in preclinical models of arthritis. In this study, widely employed inflammatory and noninflammatory animal pain models, such as the hot plate test, visceral pain model (writhing test), and carrageenan-induced rat paw edema model, were utilized to evaluate the antinociceptive and anti-inflammatory activity of CBD alone and in combination with standardized bioflavonoid compositions. CBD was tested at 5, 10, 20, and 40 mg/kg orally and at 5% topically. Administered alone, CBD produced dose-correlated, statistically significant pain inhibition in all the models. Enhanced performance in pain and inflammation reduction was observed when CBD was orally administered in complex with the bioflavonoid compositions. Data from this study show that for clinically meaningful efficacy against OA, CBD may have to be delivered in higher dosage or formulated with other medicinal plants with similar activities.
Perioperative Cannabis as a Potential Solution for Reducing Opioid and Benzodiazepine Dependence
Cannabis is increasingly being used for medicinal purposes but remains outside Western medical practice. Data on perioperative use and outcomes are scarce. Few surgeons receive training regarding legal endorsement, reported medicinal benefits, and potential risks, making it difficult to advise patients. Guidelines and additional research are needed.
Cannabis sativa L. may reduce aggressive behaviour towards humans in shelter dogs
Among the phytocomplex components of Cannabis sativa L., cannabidiol (CBD) has a recognised therapeutic effect on chronic pain. Little is known about the veterinary use of CBD in dogs. Even less is known on the effects of CBD on dog behaviour, especially in shelters. The purpose of this study was to determine if CBD affects stress related behaviour in shelter dogs. The sample consisted of 24 dogs divided into two groups that were created by assigning the dogs alternately: 12 dogs were assigned to the treatment group and 12 to the control group. Extra virgin olive oil, titrated to 5% in CBD was given to treated group; the placebo consisted of olive oil only, dispensed daily for 45 days. Behavioural data were collected using the 'focal animal' sampling method with 'all occurrences' and '1/0' methods for 3 h: before (T), after 15 days (T), after 45 days of treatment (T) and after 15 days from the end of the treatment (T). Treated dogs showed reduced aggressive behaviour toward humans following the treatment (Friedman Test: χ = 13.300; df = 3; N = 12; p = .004; adj. sig. p = 0.027), but the difference in the decrease of aggressive behaviour between the two groups was not significant (Mann-Whitney U test, T-T: Z = - 1.81; N = 24; p = 0.078). Other behaviours indicative of stress, such as displacing activities and stereotypes, did not decrease. Despite some non-significant results, our findings suggest that it is worth doing more research to further investigate the effect of CBD on dog behaviour; this would be certainly valuable because the potential for improving the welfare of dogs in shelters is priceless.
Safety and efficacy of low-dose medical cannabis oils in multiple sclerosis
The use of cannabis as medical therapy to treat chronic pain and spasticity in patients with multiple sclerosis (MS) is increasing. However, the evidence on safety when initiating treatment with medical cannabis oils is limited. The aim of this study was to investigate the safety of sublingual medical cannabis oils in patients with MS.
Cannabinoids in Neurologic Illnesses
Marijuana has been used to treat medical disease since well before the 1800s. Recently, increased use of cannabinoids, the chemical components of marijuana, have been seen to treat neurologic illness in children and adults. Unfortunately, data are lacking in treating most neurologic illnesses except in the field of epilepsy and pain from spasticity in multiple sclerosis. Therefore, formal conclusions about the potential efficacy, benefit, and adverse effects for most marijuana based products cannot be made at this time. Further research using gold standard scientific methodology should be performed to help address potential uses and safety for cannabinoids to treat neurologic illnesses.
Cannabidiol Interactions with Medications, Illicit Substances, and Alcohol: a Comprehensive Review
Cannabidiol, a non-intoxicating phytocannabinoid, has potential therapeutic effects over a broad range of disorders. Recently, there has been increased interest in CBD, as several studies showed promising anticonvulsant efficacy with few side effects. In 2018, a CBD-based oral solution, Epidiolex®, was approved by the FDA to treat two severe forms of pediatric epilepsy, Dravet syndrome, and Lennox-Gastaut syndrome. Although only these two syndromes are recognized indications for CBD, it has been consumed in an unregulated fashion for a variety of indications including chronic pain, muscle stiffness, inflammation, anxiety, smoking cessation, and even cancer. While CBD legislation in the USA is confusing due to the differences in state and federal laws, CBD has proliferated in the US market in several forms such as CBD oil or capsules, hemp oil/extract, and also as an ingredient in several dietary supplements, syrups, teas, and creams. With the ever-increasing use of CBD and its widespread availability to the general public, it is important to examine and report on possible drug-drug interactions between CBD and other therapeutic agents as well as addictive substances such as alcohol and tobacco. A detailed literature search for CBD's possible interactions was conducted using online databases. As expected, CBD has been reported to interact with anti-epileptic drugs, antidepressants, opioid analgesics, and THC, but surprisingly, it interacts with several other common medications, e.g. acetaminophen, and substances including alcohol. This review provides a comprehensive list of interacting drugs. The possible mechanisms for these drug-drug interactions are presented in table format. Given the growing popularity of CBD as a medication and the dearth of available information on CBD drug-drug interactions, it is critical to be aware of current drug-drug interactions and it will be important to investigate the impact of CBD upon concomitant medication use in future randomized, controlled trials.
Clinical Evidence of Magistral Preparations Based on Medicinal Cannabis
Cannabis has been widely used as a medicinal plant for millennia; however, studies related to its main components were first conducted in 1960. Subsequently, laboratories have produced new components and structures related to its active biological properties. Countries that have approved the medicinal use of cannabis impose regulations that govern its clinical and scientific use. One means of administering medicinal cannabis is via a magistral preparation that must have a medical prescription and be prepared in an establishment that meets quality standards to ensure the quantities of its main components, such as tetrahydrocannabinol (THC) and cannabidiol (CBD). Furthermore, suppliers must have a clear indication of its use in the patient before prescription. This review shows the published evidence regarding the clinical use of medicinal cannabis magistral preparations in the management of post-chemotherapy nausea and vomiting, neuropathic pain in multiple sclerosis, and anorexia and cachexia in patients with HIV.
Cannabis and its constituents for cancer: History, biogenesis, chemistry and pharmacological activities
Cannabis has long been used for healing and recreation in several regions of the world. Over 400 bioactive constituents, including more than 100 phytocannabinoids, have been isolated from this plant. The non-psychoactive cannabidiol (CBD) and the psychoactive Δ-tetrahydrocannabinol (Δ-THC) are the major and widely studied constituents from this plant. Cannabinoids exert their effects through the endocannabinoid system (ECS) that comprises cannabinoid receptors (CB1, CB2), endogenous ligands, and metabolizing enzymes. Several preclinical studies have demonstrated the potential of cannabinoids against leukemia, lymphoma, glioblastoma, and cancers of the breast, colorectum, pancreas, cervix and prostate. Cannabis and its constituents can modulate multiple cancer related pathways such as PKB, AMPK, CAMKK-β, mTOR, PDHK, HIF-1α, and PPAR-γ. Cannabinoids can block cell growth, progression of cell cycle and induce apoptosis selectively in tumour cells. Cannabinoids can also enhance the efficacy of cancer therapeutics. These compounds have been used for the management of anorexia, queasiness, and pain in cancer patients. Cannabinoid based products such as dronabinol, nabilone, nabiximols, and epidyolex are now approved for medical use in cancer patients. Cannabinoids are reported to produce a favourable safety profile. However, psychoactive properties and poor bioavailability limit the use of some cannabinoids. The Academic Institutions across the globe are offering training courses on cannabis. How cannabis and its constituents exert anticancer activities is discussed in this article. We also discuss areas that require attention and more extensive research.
Cannabidiol: pharmacology and therapeutic targets
Cannabidiol (CBD) products lacking regulatory approval are being used to self-treat a myriad of conditions and for their unsubstantiated health benefits. The scientific evidence supporting these claims largely arises not from controlled clinical trials, but from the recognition that CBD has numerous biological targets. Yet, CBD is commonly consumed and often in over-the-counter products that are unapproved and of unknown composition. Epidiolex® is the only product that has undergone rigorous pharmacokinetic assessment and testing in clinical trials; it was approved as a non-scheduled drug by the U.S. Food and Drug Administration for the treatment of intractable childhood-onset seizures. However, studies investigating CBD for other medical conditions are limited in number and often lack the scientific rigor, controls, or sample sizes required to draw clinically meaningful conclusions. Although Epidiolex® is safe for human consumption, recent changes in regulation of commercially available CBD products have resulted in limited quality control and products marketed with unknown CBD bioavailability. Even scientifically rigorous studies have used different sources of CBD and different suspension vehicles for administration, making it difficult to compare results among studies and resolve mixed outcomes.
Cannabinoids in dermatologic surgery
Though known as a medicinal herb for centuries, the recent legalization of cannabinoids across many states has ushered in a new era where cannabinoids have become a popular treatment option among clinicians and patients alike. Cannabinoids have demonstrated efficacy in wound healing, reducing inflammation, ameliorating pain, and have shown potential as an antitumor agent. As a result, cannabinoids have been rapidly woven into the fabric of modern medicine. However, the utility of cannabinoids in dermatologic surgery has not been explored to date. In this article, we review the current literature to discuss the potential impact of cannabinoid use in dermatologic surgery.
The Role of Cannabinoids as Anticancer Agents in Pediatric Oncology
Cannabinoids are a group of chemicals that bind to receptors in the human body and, in turn, modulate the endocannabinoid system (ECS). They can be endogenously produced, synthetic, or derived from the plant . Research over the past several decades has shown that the ECS is a cellular communication network essential to maintain multiple biological functions and the homeostasis of the body. Indeed, cannabinoids have been shown to influence a wide variety of biological effects, including memory, pain, reproduction, bone remodeling or immunity, to name a few. Unsurprisingly, given these broad physiological effects, alterations of the ECS have been found in different diseases, including cancer. In recent years, the medical use of cannabis has been approved in different countries for a variety of human conditions. However, the use of these compounds, specifically as anticancer agents, remains controversial. Studies have shown that cannabinoids do have anticancer activity in different tumor types such as breast cancer, melanoma, lymphoma and adult brain cancer. Specifically, phytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) has been shown to induce apoptosis and inhibit proliferation of adult cancer cells, as well as modulate angiogenesis and metastasis. Despite increasing evidence that cannabinoids elicit antitumor effects in adult cancers, there is minimal data available on their effects in children or in pediatric cancers despite public and clinical demand for information. Here we describe a comprehensive and critical review of what is known about the effects of cannabinoids on pediatric cancers, highlight current gaps in knowledge and identify the critical issues that need addressing before considering these promising but controversial drugs for use in pediatric oncology.
Oropharyngeal Bleeding Due to Cannabidiol Oil Vape Use
Vaping has become an increasingly popular alternative to smoking in recent years. We present a rare and unusual case of upper airway bleeding caused by inhalation of a cannabidiol (CBD) oil-based vape due to a chemical burn. There are no case reports of this injury in the literature, and we discuss the clinical presentation, diagnosis and our management of this potentially life-threatening injury. A 27-year-old man presented to the accident and emergency department after using a CBD oil vape. After one inhalation of the CBD oil vape, the patient experienced immediate onset pain in the oropharynx, dyspnoea, expectoration of blood and hoarseness. The patient had used a CBD oil vape four hours earlier that evening for the first time, which was procured from an unregulated online source. The patient was referred to the Ear, Nose and Throat (ENT) team where the examination of oropharynx identified a posterior pharyngeal bleeding point. Flexible nasal endoscopy was undertaken showing profound erythema and inflammation throughout the oropharynx and posterior pharyngeal wall. The mucous membranes had been detached leaving an exposed bleeding submucosa. The patient was commenced on three cycles of back-to-back adrenaline nebulisers (1:1000 adrenaline in 5ml of 0.9% NaCl), 6.6mg dexamethasone intravenously and hydrogen peroxide gargles (5ml of 3% hydrogen peroxide in 10ml of water) three times a day. There were early involvement and review of the airway by the anaesthetic and intensive care teams, which was deemed safe at the time. A plan was made for a definitive airway if bleeding reoccurred. Upper airway bleeding can present as a rare form of vape-induced injury and should be considered part of the differential diagnosis particularly in those using CBD oil vapes. History taking is pertinent and patients should be questioned on the specific vape liquids used. Airway stabilisation is the priority with early involvement of the multi-disciplinary team including anaesthetists, intensive care specialists and ENT surgeons.
The Quality of Online Resources Available to Patients Regarding Cannabidiol for Symptomatic Relief of Hip or Knee Arthritis is Poor
This study aimed to assess the quality of online resources pertaining to cannabidiol (CBD) for the nonoperative management of hip and knee arthritis.
Efficacy of topical interventions for temporomandibular disorders compared to placebo or control therapy: a systematic review with meta-analysis
This systematic review focused on the efficacy of topical products in reducing temporomandibular joint disorder (TMD)-associated pain, in comparison to placebo or control interventions. The EMBASE, Web of Science, Cochrane Library, and MEDLINE via PubMed databases were searched for randomized controlled trials (RCTs) using topical interventions in adults diagnosed with TMD. The pain intensity was the primary outcome, and other clinical findings were the secondary outcomes. The risk of bias was evaluated according to the Cochrane's handbook. The search up to February 7, 2020 identified a total of 496 unduplicated references. Nine RCTs with 355 adult patients diagnosed with TMD were included. The meta-analysis did not show a significant reduction in baseline pain intensity in the nonsteroidal anti-inflammatory drug (NSAIDs) group, when compared to the placebo group (P = 0.288). One study demonstrated a statistically significant pain score decrease for Theraflex-TMJ compared to placebo after 10 d of treatment (P = 0.003) and follow-up, 5 d after the last application (P = 0.027). Ping On reduced pain at 4 weeks of application (P < 0.001) but not after 7 d of application (P = 0.136). In one study, cannabidiol (CBD) significantly improved the pain intensity compared to placebo (P < 0.001). However, no differences were found with capsaicin in the two studies (P = 0.465). Evidence was of low quality because the studies were considered as having an unclear or a high risk of bias and a small number of studies were analyzed. The evidence is not sufficient to support the use of topical NSAIDs and capsaicin, and limited evidence was found for Threraflex-TMJ, bee venom, Ping On, and CBD, with only one study reporting for each. Additional studies are recommended to validate these results.
Diversity of molecular targets and signaling pathways for CBD
Cannabidiol (CBD) is the second most abundant component of the Cannabis plant and is known to have effects distinct from Δ -tetrahydrocannabinol (THC). Many studies that examined the behavioral effects of CBD concluded that it lacks the psychotomimetic effects attributed to THC. However, CBD was shown to have a broad spectrum of effects on several conditions such as anxiety, inflammation, neuropathic pain, and epilepsy. It is currently thought that CBD engages different targets and hence CBD's effects are thought to be due to multiple molecular mechanisms of action. A well-accepted set of targets include GPCRs and ion channels, with the serotonin 5-HT receptor and the transient receptor potential cation channel TRPV1 channel being the two main targets. CBD has also been thought to target G protein-coupled receptors (GPCRs) such as cannabinoid and opioid receptors. Other studies have suggested a role for additional GPCRs and ion channels as targets of CBD. Currently, the clinical efficacy of CBD is not completely understood. Evidence derived from randomized clinical trials, in vitro and in vivo models and real-world observations support the use of CBD as a drug treatment option for anxiety, neuropathy, and many other conditions. Hence an understanding of the current status of the field as it relates to the targets for CBD is of great interest so, in this review, we include findings from recent studies that highlight these main targets.
Medical Marijuana and Opioids (MEMO) Study: protocol of a longitudinal cohort study to examine if medical cannabis reduces opioid use among adults with chronic pain
In the USA, opioid analgesic use and overdoses have increased dramatically. One rapidly expanding strategy to manage chronic pain in the context of this epidemic is medical cannabis. Cannabis has analgesic effects, but it also has potential adverse effects. Further, its impact on opioid analgesic use is not well studied. Managing pain in people living with HIV is particularly challenging, given the high prevalence of opioid analgesic and cannabis use. This study's overarching goal is to understand how medical cannabis use affects opioid analgesic use, with attention to Δ9-tetrahydrocannabinol and cannabidiol content, HIV outcomes and adverse events.
Use of Cannabis for Self-Management of Chronic Pelvic Pain
Chronic pelvic pain (CPP) affects up to 15% of women in the United States. The endocannabinoid system is a potential pharmacological target for pelvic pain as cannabinoid receptors are highly expressed in the uterus and other nonreproductive tissues. We hypothesize that cannabis use is common for self-management of CPP, and our primary objective was to determine the prevalence of cannabis use in this population. A cross-sectional survey of women with pelvic and perineal pain, dyspareunia, or endometriosis was performed between March and August 2019. Subjects were recruited in an outpatient gynecology office. An anonymous, confidential, electronic survey was performed using a tablet. Statistical analysis was performed using JMP (SAS, Cary, NC). A total of 240 patients were approached, with 113 responses (47.1% response rate). There were 26 patients who used cannabis (23%). The majority used at least once per week ( = 18, 72%). Most users ( = 24, 96%) reported improvement in symptoms, including pain, cramping, muscle spasms, anxiety, depression, sleep disturbances, libido, and irritability. Over one-third (35%) stated that cannabis use decreased the number of phone calls or messages sent to their provider, and 39% reported decreased number of clinical visits. Side effects, including dry mouth, sleepiness, and feeling "high," were reported by 84% ( = 21). Almost one-quarter of patients with CPP report regular use of cannabis as an adjunct to their prescribed therapy. Although side effects are common, most users report improvement in symptoms. Our study highlights the potential of cannabis as a therapeutic option for patients with CPP.
In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa
The Cannabis sativa plant contains more than 120 cannabinoids. With the exceptions of ∆-tetrahydrocannabinol (∆-THC) and cannabidiol (CBD), comparatively little is known about the pharmacology of the less-abundant plant-derived (phyto) cannabinoids. The best-studied transducers of cannabinoid-dependent effects are type 1 and type 2 cannabinoid receptors (CB1R, CB2R). Partial agonism of CB1R by ∆-THC is known to bring about the 'high' associated with Cannabis use, as well as the pain-, appetite-, and anxiety-modulating effects that are potentially therapeutic. CB2R activation by certain cannabinoids has been associated with anti-inflammatory activities. We assessed the activity of 8 phytocannabinoids at human CB1R, and CB2R in Chinese hamster ovary (CHO) cells stably expressing these receptors and in C57BL/6 mice in an attempt to better understand their pharmacodynamics. Specifically, ∆-THC, ∆-tetrahydrocannabinolic acid (∆-THCa), ∆-tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDa), cannabidivarin (CBDV), cannabigerol (CBG), and cannabichromene (CBC) were evaluated. Compounds were assessed for their affinity to receptors, ability to inhibit cAMP accumulation, βarrestin2 recruitment, receptor selectivity, and ligand bias in cell culture; and cataleptic, hypothermic, anti-nociceptive, hypolocomotive, and anxiolytic effects in mice. Our data reveal partial agonist activity for many phytocannabinoids tested at CB1R and/or CB2R, as well as in vivo responses often associated with activation of CB1R. These data build on the growing body of literature showing cannabinoid receptor-dependent pharmacology for these less-abundant phytocannabinoids and are critical in understanding the complex and interactive pharmacology of Cannabis-derived molecules.
CBD and THC: Do They Complement Each Other Like Yin and Yang?
Increased public access to cannabis calls for a deeper understanding of cannabis's constituents and how they interact to induce clinical effects. Whereas trans-Δ -tetrahydrocannabinol (THC) is considered the main psychoactive component in cannabis, producing the associated "high" or "euphoria," various findings demonstrate medical potential for cannabidiol (CBD), from anxiolytic to antiepileptic implications. This has translated into a public optimism and given way to the popular opinion that CBD can provide countless other therapeutic benefits, including the potential to mitigate some of the adverse side effects of THC, such as intoxication, psychomotor impairment, anxiety, and psychotic symptoms. This is particularly relevant for patients seeking to garner therapeutic benefits from cannabis without experiencing the burden of a significant subjective high. Thus, this article analyzes the scientific evidence available to support or disprove the idea that presence of CBD is beneficial and can exude a protective effect against THC. A thorough review of relevant literature, a basis from which to interpret such evidence through a critical mechanistic discussion, and the implications for patients are presented in this article.
Consensus-based recommendations for titrating cannabinoids and tapering opioids for chronic pain control
Opioid misuse and overuse have contributed to a widespread overdose crisis and many patients and physicians are considering medical cannabis to support opioid tapering and chronic pain control. Using a five-step modified Delphi process, we aimed to develop consensus-based recommendations on: 1) when and how to safely initiate and titrate cannabinoids in the presence of opioids, 2) when and how to safely taper opioids in the presence of cannabinoids and 3) how to monitor patients and evaluate outcomes when treating with opioids and cannabinoids.
Short-Term Medical Cannabis Treatment Regimens Produced Beneficial Effects among Palliative Cancer Patients
In the last decade the use of medical cannabis (MC) for palliative cancer treatment has risen. However, the choice between products is arbitrary and most patients are using Tetrahydrocannabinol (THC)-dominant cannabis products. In this study, we aimed to assess the short-term outcomes of MC treatment prescribed by oncologists in relation to the type of cannabis they receive. A comparative analysis was used to assess the differences in treatment effectiveness and safety between THC-dominant ( = 56, 52%), cannabidiol (CBD)-dominant ( = 19, 18%), and mixed ( = 33, 30%) MC treatments. Oncology patients ( = 108) reported on multiple symptoms in baseline questionnaires, initiated MC treatment, and completed a one-month follow-up. Most parameters improved significantly from baseline, including pain intensity, affective and sensory pain, sleep quality and duration, cancer distress, and both physical and psychological symptom burden. There was no significant difference between the three MC treatments in the MC-related safety profile. Generally, there were no differences between the three MC treatments in pain intensity and in most secondary outcomes. Unexpectedly, CBD-dominant oil treatments were similar to THC-dominant treatments in their beneficial effects for most secondary outcomes. THC-dominant treatments showed significant superiority in their beneficial effect only in sleep duration compared to CBD-dominant treatments. This work provides evidence that, though patients usually consume THC-dominant products, caregivers should also consider CBD-dominant products as a useful treatment for cancer-related symptoms.
Cannabis: are there any benefits?
Cannabis has been used as a medicine for millennia. Prohibition in the mid-20th century precluded early scientific investigation. 'Cannabis' describes three separate forms - herbal cannabis, 'hemp' products, pharmaceutical-grade regulated cannabinoid-based medical products (CBMP). In Australia, CBMP became available for prescription in November 2016. Herbal cannabis with Δ9-tetrahydrocannabinol (THC), which is illegal, and cannabidiol (CBD) in herbal extracts, are both unregulated and unreliable sources of cannabinoids. The endocannabinoid system (ECS), delineated in the late 1990s, has increased the understanding and interest in research for appropriate clinical indications. The ubiquitous ECS has homeostatic and anti-inflammatory effects and comprises cannabinoid receptors, endocannabinoids and degrading enzymes. Phytocannabinoids are partial agonists of the ECS. In pre-clinical studies, THC and CBD produce beneficial effects in chronic pain, anxiety, sleep and inflammation. Systematic reviews often conflate herbal cannabis and CBMP, confusing the evidence. Currently large randomised controlled trials are unlikely to be achieved. Other methodologies with quality end-points are required. Rich, valuable high-quality real-world evidence for the safe and effective use of CBMP provides an opportunity to examine benefits and potential harms. Evidence demonstrates benefit of CBMP in multiple sclerosis, chronic neuropathic pain, chemotherapy induced nausea and vomiting, resistant paediatric epilepsy, anxiety and insomnia. CBMP are well tolerated with few serious adverse events. Additional clinical benefits are promising in many other resistant chronic conditions. Pharmaceutical grade prescribed CBMP has proven clinical benefits and provides another clinical option in the physician's pharmacopeia.
Endocannabinoid system and cannabis hyperemesis syndrome: a narrative update
Cannabis use has been increasing in the United States and throughout the world. It is derived from one of the earliest plants cultivated by humans - Cannabis sativa. Cannabis (also called marijuana) is the most commonly used psychoactive substance worldwide. The cannabis plant has more than 400 chemicals, of which more than 100 cannabinoids (such as cannabigerol, cannabidiol, and cannabinol) have been identified. The endocannabinoid system (ECS) plays an essential role in the effects of cannabis on end organs. Although cannabis use has been reported for many decades, some of its unique adverse effects of nausea, vomiting, and abdominal pain, termed as cannabis hyperemesis syndrome (CHS), were noted recently. The legal status of cannabis in the United States has been rapidly changing from state to state. The incidence of CHS is expected to rise with rising access to cannabis in the United States. Furthermore, CHS is frequently underdiagnosed due to a lack of uniform criteria, subjective nature of symptoms, and overlap with cyclical vomiting syndrome (CVS). Understanding the ECS and its role in biphasic response (proemetic and antiemetic) of CHS is critical to explain its pathophysiology. As the use of cannabis increases globally, awareness of CHS is warranted for early recognition and prompt treatment to avoid complications. We describe the putative mechanism of CHS with an overview of the clinical features in these patients. Furthermore, we highlight the differences between CHS and CVS with important differentials to consider. We provide a narrative update on the current evidence on CHS pathophysiology, diagnosis, treatment, and identifying research gaps.
Reduction in Tamoxifen Metabolites Endoxifen and N-desmethyltamoxifen With Chronic Administration of Low Dose Cannabidiol: A CYP3A4 and CYP2D6 Drug Interaction
Cannabidiol (CBD) serves as a promising medicine, with few known adverse effects apart from the potential of drug interactions with the cytochrome P450 system. It has been hypothesized drug interactions may occur with chemotherapeutic agents, but no supporting evidence has been published to date.
Use and Perceptions of Cannabidiol Products in Canada and in the United States
This study aimed to characterize use and perceptions of cannabidiol (CBD) products. Participants aged 16-65 years in Canada (=15,042) and the United States (=30,288) completed measures on prevalence and patterns of CBD product use and perceptions of CBD oil as part of the 2019 International Cannabis Policy Study online survey. Past 12-month CBD product use was significantly more prevalent among respondents in the United States (26.1%) than in Canada (16.2%). Consumers in the United States and Canada reported using a range of CBD products, including drops (46.3% vs. 47.3%, respectively), topicals (26.0% vs. 16.7%), edibles/foods (23.8% vs. 17.6%), vape oils (18.9% vs. 13.3%), capsules (13.3% vs. 16.7%), and dried flower (10.1% vs. 16.1%). CBD was most commonly reported for management of pain, anxiety, and depression. Over half of CBD consumers in both countries reported that CBD oil was beneficial for health. Use of CBD products is common in both the United States and Canada, primarily to manage self-reported health conditions for which there is little or no evidence of efficacy. Clearer public health messaging regarding the therapeutic effects of CBD is warranted.
Cannabidiol for Pain Treatment: Focus on Pharmacology and Mechanism of Action
Cannabis has a long history of medical use. Although there are many cannabinoids present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two components found in the highest concentrations. CBD itself does not produce typical behavioral cannabimimetic effects and was thought not to be responsible for psychotropic effects of cannabis. Numerous anecdotal findings testify to the therapeutic effects of CBD, which in some cases were further supported by research findings. However, data regarding CBD's mechanism of action and therapeutic potential are abundant and omnifarious. Therefore, we review the basic research regarding molecular mechanism of CBD's action with particular focus on its analgesic potential. Moreover, this article describes the detailed analgesic and anti-inflammatory effects of CBD in various models, including neuropathic pain, inflammatory pain, osteoarthritis and others. The dose and route of the administration-dependent effect of CBD, on the reduction in pain, hyperalgesia or allodynia, as well as the production of pro and anti-inflammatory cytokines, were described depending on the disease model. The clinical applications of CBD-containing drugs are also mentioned. The data presented herein unravel what is known about CBD's pharmacodynamics and analgesic effects to provide the reader with current state-of-art knowledge regarding CBD's action and future perspectives for research.
Prescribing medicinal cannabis
The Australian Federal Government legalised access to medicinal cannabis in 2016 More than 100 different cannabis products are now available to prescribe. Most are oral preparations (oils) or capsules containing delta-9-tetrahydrocannabinol or cannabidiol. Dried-flower products are also available As most products are unregistered drugs, prescribing requires approval under the Therapeutic Goods Administration Special Access Scheme-B or Authorised Prescriber Scheme Special Access Scheme Category B applications can be made online, with approval usually being given within 24–48 hours. However, supply chain problems may delay dispensing by the pharmacy By the end of 2019, over 28,000 prescribing approvals had been issued to patients, involving more than 1400 doctors, mostly GPs. More than 70,000 approvals are projected by the end of 2020 Most prescriptions are for chronic non-cancer pain, anxiety, cancer-related symptoms, epilepsy and other neurological disorders. However, the evidence supporting some indications is limited Many doctors are cautious about prescribing cannabis. While serious adverse events are rare, there are legitimate concerns around driving, cognitive impairment and drug dependence with products containing delta-9-tetrahydrocannabinol. Cannabidiol-only products pose fewer risks
Chronic cannabis consumption and physical exercise performance in healthy adults: a systematic review
The effects of chronic cannabis consumption on physiological parameters of athletic performance are investigated to determine whether chronic cannabis consumption negatively affects athletic performance; improves performance, potentially via enhanced recovery; or has no effect at all.
A Critical Review of the Role of the Cannabinoid Compounds Δ-Tetrahydrocannabinol (Δ-THC) and Cannabidiol (CBD) and their Combination in Multiple Sclerosis Treatment
Many people with MS (pwMS) use unregulated cannabis or cannabis products to treat the symptoms associated with the disease. In line with this, Sativex, a synthetic combination of cannabidiol (CBD) and Δ-tetrahydrocannabinol (Δ-THC) has been approved to treat symptoms of spasticity. In animals, CBD is effective in reducing the amounts of T-cell infiltrates in the spinal cord, suggesting CBD has anti-inflammatory properties. By doing this, CBD has shown to delay symptom onset in animal models of multiple sclerosis and slow disease progression. Importantly, combinations of CBD and Δ-THC appear more effective in treating animal models of multiple sclerosis. While CBD reduces the amounts of cell infiltrates in the spinal cord, Δ-THC reduces scores of spasticity. In human studies, the results are less encouraging and conflict with the findings in animals. Drugs which deliver a combination of Δ-THC and CBD in a 1:1 ratio appear to be only moderately effective in reducing spasticity scores, but appear to be almost as effective as current front-line treatments and cause less severe side effects than other treatments, such as baclofen (a GABA-B receptor agonist) and tizanidine (an α2 adrenergic receptor agonist). The findings of the studies reviewed suggest that cannabinoids may help treat neuropathic pain in pwMS as an add-on therapy to already established pain treatments. It is important to note that treatment with cannabinoid compounds may cause significant cognitive dysfunction. Long term double-blind placebo studies are greatly needed to further our understanding of the role of cannabinoids in multiple sclerosis treatment.
A Large-Scale Naturalistic Examination of the Acute Effects of Cannabis on Pain
Cannabis use for pain relief is commonly reported, yet laboratory studies and clinical trials suggest that cannabinoids are weak analgesics, and it is unclear whether perceived reductions in pain from before to after cannabis use relate to factors such as dose, method of administration, phytocannabinoid content, or the age or gender of the user. We determined whether inhalation of cannabis decreased self-reported pain ratings as well as whether user gender, age, time, method of administration, tetrahydrocannabinol (THC)/cannabidiol (CBD) content, or dose of cannabis contribute to changes in these ratings. We also examined whether tolerance may develop to the analgesic effects of cannabis over time. Archival data were obtained from Strainprint, a medical cannabis app that allows patients to track symptoms before and after using different strains and doses of cannabis. Latent change score models and multilevel models were used to analyze data from 131,582 sessions in which inhaled cannabis was used to treat "muscle pain," "joint pain," or "nerve pain." For all three pain symptoms, severity ratings decreased significantly after cannabis use. Women reported higher baseline and postcannabis pain severity than did men, and men reported larger decreases in pain than did women. Neither THC nor CBD content nor their interaction predicted reductions in pain ratings. However, vaping was associated with larger reductions in joint pain ratings than was smoking, and lower doses were associated with larger reductions in nerve pain ratings. Additionally, for all three pain symptoms, the dose of cannabis used to manage pain increased significantly over time. Inhaled cannabis reduces self-reported pain severity by ∼42-49%. However, these reductions appear to diminish across time, and patients use larger doses across time, suggesting that analgesic tolerance develops with continued use.
Ingestion of a THC-Rich Cannabis Oil in People with Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial
To determine the benefit of a tetrahydrocannabinol (THC)-rich cannabis oil on symptoms and quality of life of fibromyalgia patients.
Cannabidiol Oil-Associated Microscopic Colitis
Microscopic colitis (MC) is a chronic inflammation condition of the colon characterized by watery diarrhea and normal appearing mucosa. A 75-year-old female presented with one-year history of chronic diarrhea while taking cannabidiol (CBD) for pain. Colonoscopy with random colon biopsies revealed collagenous colitis. She started budesonide and stopped CBD. At six-week follow-up, her diarrhea improved, and the budesonide dose was decreased. She restarted CBD oil twice but had diarrhea both times. Her diarrhea resolved after taking budesonide and stopping CBD. We report a case of CBD-associated MC to make clinicians aware of this potential adverse effect in patients who chronically use CBD.
Therapeutic Efficacy of Cannabidiol (CBD): A Review of the Evidence from Clinical Trials and Human Laboratory Studies
Global policy changes have increased access to products containing cannabidiol (CBD), a primary constituent of hemp and cannabis. The CBD product industry has experienced tremendous growth, in part, because CBD is widely touted as an effective therapeutic for myriad health conditions. However, only 1 CBD product (Epidiolex®) has been approved by the U.S. Food and Drug Administration (FDA) to date. There is substantial interest among consumers and the medical and scientific communities regarding the therapeutic potential of CBD, including for novel indications that are not recognized by the FDA. The purpose of this review was to synthesize available evidence from clinical research regarding the efficacy of CBD as a therapeutic.
From an Alternative Medicine to a New Treatment for Refractory Epilepsies: Can Cannabidiol Follow the Same Path to Treat Neuropsychiatric Disorders?
Although cannabis has been known for ages as an "alternative medicine" to provide relief from seizures, pain, anxiety, and inflammation, there had always been a limited scientific review to prove and establish its use in clinics. Early studies carried out by Carlini's group in Brazil suggested that cannabidiol (CBD), a non-psychotropic phytocannabinoid present in , has anticonvulsant properties in animal models and reduced seizure frequency in limited human trials. Over the past few years, the potential use of cannabis extract in refractory epilepsy, including childhood epilepsies such as Dravet's syndrome and Lennox-Gastaut Syndrome, has opened a new era of treating epileptic patients. Thus, a considerable number of pre-clinical and clinical studies have provided strong evidence that phytocannabinoids has anticonvulsant properties, as well as being promising in the treatment of different neuropsychiatric disorders, such as depression, anxiety, post-traumatic stress disorder (PTSD), addiction, neurodegenerative disorders and autism spectrum disorder (ASD). Given the advances of cannabinoids, especially CBD, in the treatment of epilepsy, would the same expectation regarding the treatment of other neuropsychiatric disorders be possible? The present review highlights some contributions from Brazilian researchers and other studies reported elsewhere on the history, pre-clinical and clinical data underlying the use of cannabinoids for the already widespread treatment of refractory epilepsies and the possibility of use in the treatment of some neuropsychiatric disorders.
Constituents of Cannabis Sativa
The Cannabis sativa plant has been used medicinally and recreationally for thousands of years, but recently only relatively some of its constituents have been identified. There are more than 550 chemical compounds in cannabis, with more than 100 phytocannabinoids being identified, including Δ-tetrahydrocannabinol (THC) and cannabidiol (CBD). These phytocannabinoids work by binding to the cannabinoid receptors, as well as other receptor systems. Also within cannabis are the aromatic terpenes, more than 100 of which have been identified. Cannabis and its constituents have been indicated as therapeutic compounds in numerous medical conditions, such as pain, anxiety, epilepsy, nausea and vomiting, and post-traumatic stress disorder. This chapter provides an overview of some of the biological effects of a number of the cannabinoids and terpenes, as well as discussing their known mechanisms of action and evidence of potential therapeutic effects.
Cannabidiol as a Treatment for Chronic Pain: A Survey of Patients' Perspectives and Attitudes
Cannabis products have become easily available and accessible after decriminalization of cannabis for recreational and medicinal use in many states. Cannabidiol (CBD) has been of increasing interest to patients and is being used to self-medicate a variety of ailments. However, very limited information is available to patients and providers to form an educated opinion regarding its indicated use to treat the many conditions this substance has been implied to be helpful for. The aim of this survey was to learn about participants' attitudes and views towards cannabis-based medicine (CBM) with a focus on perception of "CBD" and its potential role for pain management.
Medicinal Applications of Cannabinoids Extracted from Cannabis sativa (L.): A New Route in the Fight Against COVID-19?
Cannabis sativa is a well-known plant that has been recognized for its benefits since ancient times by several medicinal systems, including those of China, India, Greece, and Egypt. Although C. sativa is one of the most investigated medicinal plants in the world, it faces some of the greatest controversies surrounding its legalization and use as a medication. C. sativa contains several hundred phytoconstituents, including the infamous "cannabinoids". It is necessary to properly understand the medicinal importance of these phytochemicals and spread awareness among the countries where cannabis is still facing legal obstacles. The current review focuses on the most recent literature pertaining to various applications of cannabinoids, with a special focus on the medicinal aspect of these phytochemicals. Peer-reviewed articles focusing on the importance of cannabis and cannabinoids are the target of this review. Articles were selected based on the relevance to the general scope of the work, i.e., application of cannabinoids. Cannabinoids can truly be regarded as wonder drugs, considering their immense diversity of usage. Unfortunately, however, many of the mares have never been researched biologically or pharmacologically due to their low yield in the plant. However, the approval of some cannabinoids by the FDA (along with other recognized national medical health systems) has opened the horizon for the use of these natural drugs in medicines such as Epidiolex® (cannabidiol, used for the treatment of severe forms of epilepsy) and Sativex®(Δ-tetrahydrocannabinol and cannabidiol, used for the treatment of spasticity caused by multiple sclerosis). Many pharmacological properties of C. sativa are attributed to cannabidiol (CBD), a non-psychoactive component, along with Δ9-tetrahydrocannabinol (Δ-THC), a psychoactive component. This review addresses the most important applications or current utilization of cannabinoids in a variety of treatments such as chronic pain, cancer, emesis, anorexia, irritable bowel syndrome, communicable diseases, glaucoma, and central nervous system disorders. The biosynthetic pathway of cannabinoids is also discussed. In short, cannabis has a myriad of bioactive compounds that have the potential to increase the list of approved cannabinoids suitable for therapy.
Pharmacological treatment of central neuropathic pain: consensus of the Brazilian Academy of Neurology
Central neuropathic pain (CNP) is often refractory to available therapeutic strategies and there are few evidence-based treatment options. Many patients with neuropathic pain are not diagnosed or treated properly. Thus, consensus-based recommendations, adapted to the available drugs in the country, are necessary to guide clinical decisions.
Safety and Tolerability of Cannabidiol in Parkinson Disease: An Open Label, Dose-Escalation Study
Cannabis is increasingly used in Parkinson disease (PD), despite little information regarding benefits and risks. To investigate the safety and tolerability of a range of doses of cannabidiol (CBD), a nonintoxicating component of cannabis, and it's effect on common parkinsonian symptoms. In this open-label study Coloradans with PD, substantial rest tremor, not using cannabis received plant-derived highly purified CBD (Epidiolex; 100 mg/mL). CBD was titrated from 5 to 20-25 mg/kg/day and maintained for 10-15 days. Fifteen participants enrolled, two were screen failures. All 13 participants (10 male), mean (SD) age 68.15 (6.05), with 6.1 (4.0) years of PD, reported adverse events, including diarrhea (85%), somnolence (69%), fatigue (62%), weight gain (31%), dizziness (23%), abdominal pain (23%), and headache, weight loss, nausea, anorexia, and increased appetite (each 5%). Adverse events were mostly mild; none serious. Elevated liver enzymes, mostly a cholestatic pattern, occurred in five (38.5%) participants on 20-25 mg/kg/day, only one symptomatic. Three (23%) dropped out due to intolerance. Ten (eight male) that completed the study had improvement in total and motor Movement Disorder Society Unified Parkinson Disease Rating Scale scores of 7.70 (9.39, mean decrease 17.8%, =0.012) and 6.10 (6.64, mean decrease 24.7%, =0.004), respectively. Nighttime sleep and emotional/behavioral dyscontrol scores also improved significantly. CBD, in the form of Epidiolex, may be efficacious in PD, but the relatively high dose used in this study was associated with liver enzyme elevations. Randomized controlled trials are needed to investigate various forms of cannabis in PD.
Neuropharmacological Effects of the Main Phytocannabinoids: A Narrative Review
Cannabis can synthetize more than 400 compounds, including terpenes, flavonoids, and more than 100 phytocannabinoids. The main phytocannabinoids are Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabis-based products are used as medicines in several countries. In this text, we present an overview of the main neurochemical mechanisms of action of the phytocannabinoids, especially THC and CBD. We also reviewed the indications and adverse effects of the main cannabis-based medicinal products. THC acts as a partial agonist at cannabinoid 1/2 receptors (CB). It is responsible for the characteristic effects of cannabis, such as euphoria, relaxation, and changes in perceptions. THC can also produce dysphoria, anxiety, and psychotic symptoms. THC is used therapeutically in nausea and vomiting due to chemotherapy, as an appetite stimulant, and in chronic pain. CBD acts as a noncompetitive negative allosteric modulator of the CB receptor, as an inverse agonist of the CB receptor, and as an inhibitor of the reuptake of the endocannabinoid anandamide. Moreover, CBD also activates 5-HT serotonergic receptors and vanilloid receptors. Its use in treatment-resistant epilepsy syndromes is approved in some countries. CBD does not produce the typical effects associated with THC and has anxiolytic and antipsychotic effects. Some of the most common adverse effects of CBD are diarrhea, somnolence, nausea, and transaminase elevations (with concomitant use of antiepileptics). The mechanisms of action involved in both the therapeutic and adverse effects of the phytocannabinoids are not fully understood, involving not only the endocannabinoid system. This "promiscuous" pharmacology could be responsible for their wide therapeutic spectrum.
Duration of Neurocognitive Impairment With Medical Cannabis Use: A Scoping Review
While the recreational use of cannabis has well-established dose-dependent effects on neurocognitive and psychomotor functioning, there is little consensus on the degree and duration of impairment typically seen with medical marijuana use. Compared to recreational cannabis users, medical cannabis patients have distinct characteristics that may modify the presence and extent of impairment. The goal of this review was to determine the duration of acute neurocognitive impairment associated with medical cannabis use, and to identify differences between medical cannabis patients and recreational users. These findings are used to gain insight on how medical professionals can best advise medical cannabis patients with regards to automobile driving or safety-sensitive tasks at work. A systematic electronic search for English language randomized controlled trials (RCTs), clinical trials and systematic reviews (in order to capture any potentially missed RCTs) between 2000 and 2019 was conducted through Ovid MEDLINE and EMBASE electronic databases using MeSH terms. Articles were limited to medical cannabis patients using cannabis for chronic non-cancer pain or spasticity. After screening titles and abstracts, 37 relevant studies were subjected to full-text review. Overall, seven controlled trials met the inclusion/exclusion criteria and were included in the qualitative synthesis: six RCTs and one observational clinical trial. Neurocognitive testing varied significantly between all studies, including the specific tests administered and the timing of assessments post-cannabis consumption. In general, cognitive performance declined mostly in a THC dose-dependent manner, with steady resolution of impairment in the hours following THC administration. Doses of THC were lower than those typically reported in recreational cannabis studies. In all the studies, there was no difference between any of the THC groups and placebo on any neurocognitive measure after 4 h of recovery. Variability in the dose-dependent relationship raises the consideration that there are other important factors contributing to the duration of neurocognitive impairment besides the dose of THC ingested. These modifiable and non-modifiable factors are individually discussed.
Emerging role of cannabinoids and synthetic cannabinoid receptor 1/cannabinoid receptor 2 receptor agonists in cancer treatment and chemotherapy-associated cancer management
Cannabis was extensively utilized for its medicinal properties till the 19 century. A steep decline in its medicinal usage was observed later due to its emergence as an illegal recreational drug. Advances in technology and scientific findings led to the discovery of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis, that further led to the discovery of endogenous cannabinoids system consisting of G-protein-coupled receptors - cannabinoid receptor 1 and cannabinoid receptor 2 along with their ligands, mainly anandamide and 2-arachidonoylglycerol. Endocannabinoid (EC) is shown to be a modulator not only for physiological functions but also for the immune system, endocrine network, and central nervous system. Medicinal research and meta-data analysis over the last few decades have shown a significant potential for both THC and cannabidiol (CBD) to exert palliative effects. People suffering from many forms of advanced stages of cancers undergo chemotherapy-induced nausea and vomiting followed by severe and chronic neuropathic pain and weight loss. THC and CBD exhibit effective analgesic, anxiolytic, and appetite-stimulating effect on patients suffering from cancer. Drugs currently available in the market to treat such chemotherapy-induced cancer-related ailments are Sativex (GW Pharmaceutical), Dronabinol (Unimed Pharmaceuticals), and Nabilone (Valeant Pharmaceuticals). Apart from exerting palliative effects, THC also shows promising role in the treatment of cancer growth, neurodegenerative diseases (multiple sclerosis and Alzheimer's disease), and alcohol addiction and hence should be exploited for potential benefits. The current review discusses the nature and role of CB receptors, specific applications of cannabinoids, and major studies that have assessed the role of cannabinoids in cancer management.
Evaluation of Patient Reported Safety and Efficacy of Cannabis From a Survey of Medical Cannabis Patients in Canada
With the medical use of cannabis permitted in Canada since 2001, patients seek to use this botanical drug to treat a range of medical conditions. However, many healthcare practitioners express the need for further scientific evidence around the use of medical cannabis. This real-world evidence study aimed to address the paucity of scientific data by surveying newly registered medical cannabis patients, before beginning medical cannabis treatment, and at one follow up 6 weeks after beginning medical cannabis treatment. The goal was to collect data on efficacy, safety and cannabis product type information to capture the potential impact medical cannabis had on patient-reported quality of life (QOL) and several medical conditions over a 6-week period using validated questionnaires. The 214 participants were mainly male (58%) and 57% of the population was older than 50. The most frequently reported medical conditions were recurrent pain, post-traumatic stress disorder (PTSD), anxiety, sleep disorders [including restless leg syndrome (RLS)], and arthritis and other rheumatic disorders. Here we report that over 60% of our medical cannabis cohort self-reported improvements in their medical conditions. With the use of validated surveys, we found significant improvements in recurrent pain, PTSD, and sleep disorders after 6 weeks of medical cannabis treatment. Our findings from patients who reported arthritis and other rheumatic disorders are complex, showing improvements in pain and global activity sub-scores, but not overall changes in validated survey scores. We also report that patients who stated anxiety as their main medical condition did not experience significant changes in their anxiety after 6 weeks of cannabis treatment, though there were QOL improvements. While these results show that patients find cannabis treatment effective for a broad range of medical conditions, cannabis was not a remedy for all the conditions investigated. Thus, there is a need for future clinical research to support the findings we have reported. Additionally, while real-world evidence has not historically been utilized by regulatory bodies, we suggest changes in public policy surrounding cannabis should occur to reflect patient reported efficacy of cannabis from real-world studies due to the uniqueness of medical cannabis's path to legalization.
Cannabis in Parkinson's Disease: The Patients' View
Little is known about the patients' view on treatment with medical cannabis (MC) for Parkinson's disease (PD).
An Analysis of the Putative CBD Binding Site in the Ionotropic Cannabinoid Receptors
Cannabinoids have been long studied for their therapeutic properties, particularly for their use in the treatment of pain. As new therapies are sought after to treat conditions of chronic pain, so is a better understanding of the ligands and their target receptors or channels. A recently published cryo-EM structure showed the putative binding location of a well-known cannabinoid ligand, cannabidiol (CBD), in TRPV2, a channel that has been implicated in inflammation and chronic pain. TRPV2, along with TRPV1, TRPV3, TRPV4, TRPA1, and TRPM8 all have the capability to be modulated by cannabinoid ligands and are located in the peripheral nervous system. Here, we analyze the putative CBD binding site in each of these channels and compare structural and sequential information with experimental data.