CANNABIDIOL

SCIENTIFIC PUBLICATIONS

Myrcene and terpene regulation of TRPV1
Jansen C, Shimoda LMN, Kawakami JK, Ang L, Bacani AJ, Baker JD, Badowski C, Speck M, Stokes AJ, Small-Howard AL and Turner H
Nociceptive Transient Receptor Potential channels such as TRPV1 are targets for treating pain. Both antagonism and agonism of TRP channels can promote analgesia, through inactivation and chronic desensitization. Since plant-derived mixtures of cannabinoids and the component myrcene have been suggested as pain therapeutics, we screened terpenes found in for activity at TRPV1. We used inducible expression of TRPV1 to examine TRPV1-dependency of terpene-induced calcium flux responses. Terpenes contribute differentially to calcium fluxes via TRPV1 induced by -mimetic cannabinoid/terpenoid mixtures. Myrcene dominates the TRPV1-mediated calcium responses seen with terpenoid mixtures. Myrcene-induced calcium influx is inhibited by the TRPV1 inhibitor capsazepine and Myrcene elicits TRPV1 currents in the whole-cell patch-clamp configuration. TRPV1 currents are highly sensitive to internal calcium. When Myrcene currents are evoked, they are distinct from capsaicin responses on the basis of I and their lack of shift to a pore-dilated state. Myrcene pre-application and residency at TRPV1 appears to negatively impact subsequent responses to TRPV1 ligands such as Cannabidiol, indicating allosteric modulation and possible competition by Myrcene. Molecular docking studies suggest a non-covalent interaction site for Myrcene in TRPV1 and identifies key residues that form partially overlapping Myrcene and Cannabidiol binding sites. We identify several non- plant-derived sources of Myrcene and other compounds targeting nociceptive TRPs using a data mining approach focused on analgesics suggested by non-Western Traditional Medical Systems. These data establish TRPV1 as a target of Myrcene and suggest the therapeutic potential of analgesic formulations containing Myrcene.
Cannabinoid interactions with ion channels and receptors
Watkins AR
Cannabidiol (CBD), the non-psychoactive component of Cannabis sativa, acts on a diverse selection of membrane proteins with promising therapeutic potential in epilepsy and chronic pain. One such protein is the voltage-gated sodium channel (Na). CBD shows a lack of specificity for sodium channels; however, the method of interaction is still unknown. In this review, we will outline the studies that report reproducible results of CBD and other cannabinoids changing membrane channel function, with particular interest on Na. Na are implicated in fatal forms of epilepsy and are also associated with chronic pain. This makes Na potential targets for CBD interaction since it has been reported to reduce pain and seizures. One potential method of interaction that is of interest in this review is whether CBD affects channel function by altering lipid bilayer properties, independent of any possible direct interaction with membrane channels. CBD's ability to interact with its targets is a novel and important discovery. This discovery will not only prompt further research towards CBD's characterization, but also promotes the application of cannabinoids as potentially therapeutic compounds for diseases like epilepsy and pain.
Myorelaxant Effect of Transdermal Cannabidiol Application in Patients with TMD: A Randomized, Double-Blind Trial
Nitecka-Buchta A, Nowak-Wachol A, Wachol K, Walczyńska-Dragon K, Olczyk P, Batoryna O, Kempa W and Baron S
(1) Background: The healing properties of cannabidiol (CBD) have been known for centuries. In this study, we aimed to evaluate the efficiency of the myorelaxant effect of CBD after the transdermal application in patients with myofascial pain. (2) Methods: The Polish version of the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD Ia and Ib) was used. A total of 60 patients were enrolled in the study and were randomly divided into two groups: Group1 and Group2. The average age in Group1 was 23.2 years (SD) = 1.6 years) and in Group2, it was 22.6 years (SD = 1.86). This was a parallel and double-blind trial. Group1 received CBD formulation, whereas Group2 received placebo formulation for topical use. The masseter muscle activity was measured on days 0 and 14, with surface electromyography (sEMG) (Neurobit Optima 4, Neurobit System, Gdynia, Poland). Pain intensity in VAS (Visual Analogue Scale) was measured on days 0 and 14. (3) Results: in Group1, the sEMG masseter activity significantly decreased (11% in the right and 12.6% in the left masseter muscles). In Group2, the sEMG masseter activity was recorded as 0.23% in the right and 3.3% in the left masseter muscles. Pain intensity in VAS scale was significantly decreased in Group1: 70.2% compared to Group2: 9.81% reduction. Patients were asked to apply formulation twice a day for a period of 14 days. (4) Conclusion: The application of CBD formulation over masseter muscle reduced the activity of masseter muscles and improved the condition of masticatory muscles in patients with myofascial pain.
Cannabidiol increases the nociceptive threshold in a preclinical model of Parkinson's disease
Crivelaro do Nascimento G, Ferrari DP, Guimaraes FS, Del Bel EA, Bortolanza M and Ferreira-Junior NC
Medications that improve pain threshold can be useful in the pharmacotherapy of Parkinson's disease (PD). Pain is a prevalent PD's non-motor symptom with a higher prevalence of analgesic drugs prescription for patients. However, specific therapy for PD-related pain are not available. Since the endocannabinoid system is expressed extensively in different levels of pain pathway, drugs designed to target this system have promising therapeutic potential in the modulation of pain. Thus, we examined the effects of the 6-hydroxydopamine- induced PD on nociceptive responses of mice and the influence of cannabidiol (CBD) on 6-hydroxydopamine-induced nociception. Further, we investigated the pathway involved in the analgesic effect of the CBD through the co-administration with a fatty acid amide hydrolase (FAAH) inhibitor, increasing the endogenous anandamide levels, and possible targets from anandamide, i.e., the cannabinoid receptors subtype 1 and 2 (CB1 and CB2) and the transient receptor potential vanilloid type 1 (TRPV1). We report that 6-hydroxydopamine- induced parkinsonism decreases the thermal and mechanical nociceptive threshold, whereas CBD (acute and chronic treatment) reduces this hyperalgesia and allodynia evoked by 6-hydroxydopamine. Moreover, ineffective doses of either FAAH inhibitor or TRPV1 receptor antagonist potentialized the CBD-evoked antinociception while an inverse agonist of the CB1 and CB2 receptor prevented the antinociceptive effect of the CBD. Altogether, these results indicate that CBD can be a useful drug to prevent the parkinsonism-induced nociceptive threshold reduction. They also suggest that CB1 and TRPV1 receptors are important for CBD-induced analgesia and that CBD could produce these analgesic effects increasing endogenous anandamide levels.
Cannabis Use Preferences and Decision-making Among a Cross-sectional Cohort of Medical Cannabis Patients with Chronic Pain
Boehnke KF, Scott JR, Litinas E, Sisley S, Clauw DJ, Goesling J and Williams DA
Cannabis is commonly used to manage chronic pain, but cannabis use patterns among individuals with chronic pain, has not been well-characterized. We report cannabinoid, administration route, and product selection preferences among medical cannabis users with chronic pain from an ongoing, online survey. We also examined whether these preferences are affected by differences in sex, intentions behind use (medical only [MED] vs medical + recreational [MEDREC]), and experience with cannabis (novice: <1 year vs experienced: ≥1 year). The survey was completed by 1,321 participants (59% female) 76.5% of whom used cannabis every day. 93.4% used 2 or more administration routes and 72.5% used 3 or more. Female, MED, and novice users were less likely to smoke or vaporize (all P < .0001), but more likely to rank edibles, tinctures, and topicals as a first-choice administration route than their counterparts. Female and MED users also preferred low THC: high cannabidiol ratios significantly more than their counterparts. Overall, only 2.6% of participants selected cannabis products with input from a medical professional, although 54.9% relied on advice from dispensary employees. More male, MEDREC, and experienced users selected products based on factors that reflected greater comfort with cannabis (eg, smell, visual properties, cannabis variety). The wide variability in cannabis use among these different groups indicates the need for further research to investigate how specific use routines relate to clinical outcomes. PERSPECTIVE: Medical cannabis users with chronic pain show distinct differences in cannabinoid preferences and administration associated with user sex, intentions behind use, and experience with cannabis. This article highlights the wide variability in cannabis preferences among medical cannabis users with chronic pain, which may be relevant for clinical outcomes.
Study protocol for a randomised, double-blind, placebo-controlled study evaluating the Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease: the EMERALD trial
Urbi B, Broadley S, Bedlack R, Russo E and Sabet A
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no known cure and with an average life expectancy of 3-5 years post diagnosis. The use of complementary medicine such as medicinal cannabis in search for a potential treatment or cure is common in ALS. Preclinical studies have demonstrated the efficacy of cannabinoids in extending the survival and slowing of disease progression in animal models with ALS. There are anecdotal reports of cannabis slowing disease progression in persons with ALS (pALS) and that cannabis alleviated the symptoms of spasticity and pain. However, a clinical trial in pALS with these objectives has not been conducted.
Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study
Capano A, Weaver R and Burkman E
: Chronic pain is highly prevalent in most of the industrialized nations around the world. Despite the documented adverse effects, opioids are widely used for pain management. Cannabinoids, and specifically Cannabidiol, is proposed as an opioid alternative, having comparable efficacy with better safety profile.: We aim to investigate the impact of full hemp extract cannabidiol (CBD) on opioid use and quality of life indicators among chronic pain patients.: An initial sample of 131 patients was recruited from a private pain management center's investigative population. Ninety-seven patients completed the 8-week study. The primary inclusion criteria included patients between 30 and 65 years old with chronic pain who have been on opioids for at least 1 year. Data were collected at three different time points: baseline, 4, and 8 weeks. Opioid and other medication use were evaluated via the medication and psychiatric treatment receipt. Improvement was evaluated using four indices: Pain Disability Index (PDI-4); Pittsburgh Sleep Quality Index (PSQI), Pain Intensity and Interference (PEG); and Patient Health Questionnaire (PHQ-4).: Over half of chronic pain patients (53%) reduced or eliminated their opioids within 8 weeks after adding CBD-rich hemp extract to their regimens. Almost all CBD users (94%) reported quality of life improvements. The results indicated a significant relationship between CBD and PSQI (p = 0.003), and PEG (p = 0.006). There was a trend toward improvement but no significant relationship between CBD use and PHQ and PDI.: CBD could significantly reduce opioid use and improve chronic pain and sleep quality among patients who are currently using opioids for pain management.: This is a prospective, single-arm cohort study for the potential role of cannabinoids as an alternative for opioids. The results indicate that using the CBD-rich extract enabled our patients to reduce or eliminate opioids with significant improvement in their quality of life indices.
Intraperitoneal cannabidiol attenuates neonatal germinal matrix hemorrhage-induced neuroinflamation and perilesional apoptosis
Abrantes De Lacerda Almeida T, Santos MV, Da Silva Lopes L, Goel G, Leonardo De Freitas R, De Medeiros P, Crippa JA and Machado HR
. As the survival of preterm infants has increased significantly, germinal matrix hemorrhage (GMH) has become an important public health issue. Nevertheless, treatment strategies for the direct neuronal injury are still scarce. The present study aims to analyze the neuroprotective properties of cannabidiol in germinal matrix hemorrhage. . 112 Wistar rat pups (P7) were submitted to an experimental collagenase induced model of GMH. Inflammatory response and neuronal death were analyzed both at the perilesional area as at the distant ipsilateral CA1 hippocampal area. Immunohistochemistry for GFAP and caspase 3 was used. The ipsilateral free water content was assessed for stimation of cerebral edema, and neurodevelopment and neurofunctional tests were conducted. . Reduction of reactive astrocytosis was observed both in the perilesional area 24 hours and 14 days after the hemorrhage lesion (p < 0.001) and in the of the ipsilateral hippocampal CA1 14 days after the hemorrhage lesion (p < 0.05) in the treated groups. Similarly, there was a reduction in the number of Caspase 3-positive astrocytes in the perilesional area in the treated groups 24 hours after the hemorrhage lesion (p < 0.001). Finally, we found a significant increase in the weight of the rats treated with cannabidiol. . The treatment of GMH with cannabidiol significantly reduced the number of apoptotic cells and reactive astrocytes in the perilesional area and the ipsilateral hippocampus. In addition, this response was sustained 14 days after the hemorrhage. These results corroborate our hypothesis that cannabidiol is a potential neuroprotective agent in the treatment of germinal matrix hemorrhage.
Medical cannabis and cannabinoids in rheumatology: where are we now?
Sarzi-Puttini P, Batticciotto A, Atzeni F, Bazzichi L, Di Franco M, Salaffi F, Marotto D, Ceribelli A, Ablin JN and Hauser W
: Clinicians involved in pain management can finally include cannabis or cannabis-related products in their therapeutic armamentarium as a growing number of countries have approved them for pain relief. Despite the several benefits attributed to analgesic, anti-inflammatory and immunomodulatory properties of cannabinoids, there are still significant areas of uncertainty concerning their use in many fields of medicine. The biosynthesis and inactivation of cannabinoids are regulated by a complex signaling system of cannabinoid receptors, endocannabinoids (the endogenous ligands of cannabinoid receptors) and enzymes, with a variety of interactions with neuroendocrinological and immunological systems. : A review of studies carried out during clinical development of cannabis and cannabis medical products in systemic rheumatic diseases was performed, highlighting the aspects that we believe to be relevant to clinical practice. : The growing public opinion, pushing toward the legalization of the use of cannabis in chronic pain and various rheumatological conditions, makes it necessary to have educational programs that modify the concerns and widespread preconceptions related to this topic in the medical community by increasing confidence. More extensive basic and clinical research on the mechanisms and clinical utility of cannabis and derivatives in various diseases and their long-term side effects is necessary.
The effectiveness of self-directed medical cannabis treatment for pain
Li X, Vigil JM, Stith SS, Brockelman F, Keeling K and Hall B
The prior medical literature offers little guidance as to how pain relief and side effect manifestation may vary across commonly used and commercially available cannabis product types. We used the largest dataset in the United States of real-time responses to and side effect reporting from patient-directed cannabis consumption sessions for the treatment of pain under naturalistic conditions in order to identify how cannabis affects momentary pain intensity levels and which product characteristics are the best predictors of therapeutic pain relief. Between 06/06/2016 and 10/24/2018, 2987 people used the ReleafApp to record 20,513 cannabis administration measuring cannabis' effects on momentary pain intensity levels across five pain categories: musculoskeletal, gastrointestinal, nerve, headache-related, or non-specified pain. The average pain reduction was -3.10 points on a 0-10 visual analogue scale (SD = 2.16, d = 1.55, p < .001). Whole Cannabis flower was associated with greater pain relief than were other types of products, and higher tetrahydrocannabinol (THC) levels were the strongest predictors of analgesia and side effects prevalence across the five pain categories. In contrast, cannabidiol (CBD) levels generally were not associated with pain relief except for a negative association between CBD and relief from gastrointestinal and non-specified pain. These findings suggest benefits from patient-directed, cannabis therapy as a mid-level analgesic treatment; however, effectiveness and side effect manifestation vary with the characteristics of the product used.
[Cannabis-derived medicines for the treatment of chronic pain : Problems resulting from medical appraisals in the experience of the Medical Advisory Board of the Statutory Health Insurance Funds North]
Heidbreder M and van Treeck B
On March 10th 2017, the law amending narcotic and other regulations was expanded, thereby allowing physicians, irrespective of their specialization, to prescribe cannabis-derived medicines as magistral formulas or proprietary medicinal products at the expense of the German statutory health insurance (GKV). First prescription requires approval from the respective health insurance, which in turn commissions the Medical Advisory Board of the Statutory Health Insurance Funds (MDK) to prepare a medico-legal report.
Benefit of Tetrahydrocannabinol versus Cannabidiol for Common Palliative Care Symptoms
Casarett DJ, Beliveau JN and Arbus MS
To determine the relative contributions of tetrahydrocannabinol (THC) and cannabidiol (CBD) to patients' self-ratings of efficacy for common palliative care symptoms. This is an electronic record-based retrospective cohort study. Model development used logistic regression with bootstrapped confidence intervals (CIs), with standard errors clustered to account for multiple observations by each patient. This is a national Canadian patient portal. A total of 2,431 patients participated. Self-ratings of efficacy of cannabis, defined as a three-point reduction in neuropathic pain, anorexia, anxiety symptoms, depressive symptoms, insomnia, and post-traumatic flashbacks. We included 26,150 observations between October 1, 2017 and November 28, 2018. Of the six symptoms, response was associated with increased THC:CBD ratio for neuropathic pain (odds ratio [OR]: 3.58; 95% CI: 1.32-9.68;  = 0.012), insomnia (OR: 2.93; 95% CI: 1.75-4.91;  < 0.001), and depressive symptoms (OR: 1.63; 95% CI: 1.07-2.49;  = 0.022). Increased THC:CBD ratio was not associated with a greater response of post-traumatic stress disorder (PTSD)-related flashbacks (OR: 1.43; 95% CI: 0.60-3.41;  = 0.415) or anorexia (OR: 1.61; 95% CI: 0.70-3.73;  = 0.265). The response for anxiety symptoms was not significant (OR: 1.13; 95% CI: 0.77-1.64;  = 0.53), but showed an inverted U-shaped curve, with maximal benefit at a 1:1 ratio (50% THC). These preliminary results offer a unique view of real-world medical cannabis use and identify several areas for future research.
Patterns of Medical Cannabis Use among Cancer Patients from a Medical Cannabis Dispensary in New York State
Kim A, Kaufmann CN, Ko R, Li Z and Han BH
Research on the patterns of use of medical cannabis among cancer patients is lacking. To describe patterns of medical cannabis use by patients with cancer, and how patterns differ from patients without cancer. We performed secondary data analysis using data from a medical cannabis licensee in New York State, analyzing demographic information, qualifying conditions, and symptoms, and the medical cannabis product used, including tetrahydrocannabinol (THC) to cannabidiol (CBD) ratios. Adults age ≥18 who used New York State medical cannabis licensee products between January 2016 and December 2017. There were a total of 11,590 individuals with 1990 (17.2%) having cancer who used at least one cannabis product. Patients with cancer using cannabis were older and more likely to be female. The most common qualifying symptom for both cancer and noncancer patients was severe or chronic pain. Cancer patients were more likely to use the sublingual tincture form of cannabis ( = 1098, 55.2%), while noncancer patients were more likely to use the vaporization form ( = 4222, 44.0%). Over time, across all patients, there was an increase in the THC daily dose by a factor of 0.20 mg/week, yielding a corresponding increase in the THC:CBD daily ratio. Compared with noncancer patients, these trends were not different in the cancer group for THC daily dose, but there were less pronounced increases in the THC:CBD daily ratio over time among cancer patients. Our study found some key differences in demographics and medical cannabis product use between patients with cancer and without cancer.
Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis
Black N, Stockings E, Campbell G, Tran LT, Zagic D, Hall WD, Farrell M and Degenhardt L
Medicinal cannabinoids, including medicinal cannabis and pharmaceutical cannabinoids and their synthetic derivatives, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), have been suggested to have a therapeutic role in certain mental disorders. We analysed the available evidence to ascertain the effectiveness and safety of all types of medicinal cannabinoids in treating symptoms of various mental disorders.
The potential role of cannabinoids in dermatology
Sheriff T, Lin MJ, Dubin D and Khorasani H
Cannabis is increasingly being used world-wide to treat a variety of dermatological conditions. Medicinal cannabis is currently legalized in Canada, 31 states in America and 19 countries in Europe. The authors reviewed the literature on the pharmacology and use of cannabinoids in treating a variety of skin conditions including acne, atopic dermatitis, psoriasis, skin cancer, pruritus, and pain. Cannabinoids have demonstrated anti-inflammatory, antipruritic, anti-ageing, and antimalignancy properties by various mechanisms including interacting with the newly found endocannabinoid system of the skin thereby providing a promising alternative to traditional treatments.
Editorial: Brain Mediators of the Cannabis-Prodromal Psychosis Connection
Lange N
The article "Cannabis-Associated Psychotic-like Experiences Are Mediated by Developmental Changes in the Parahippocampal Gyrus" by Yu and Jia et al. in this issue investigates the role of a subregion of the parahippocampal gyrus called the right uncus ("hook") as a possible mediator of the known increase of psychotic-like experiences (PLEs) due to the consumption of cannabinoids (ie, cannabis). The authors chose a pattern of plausible inference worthy of pursuit. Cannabis continues to be one of the most widely used drugs globally, only behind alcohol, caffeine, and tobacco; 188 million people used cannabis worldwide in 2017. In January 2019, the WHO's Expert Committee on Drug Dependence (ECDD) recommended that cannabis be no longer classified as a Schedule IV drug (its medical potential is now deemed to outweigh its abuse potential). It should be noted that cannabidiol (CBD) is a non-psychoactive component of cannabis that has medicial uses in reducing pain and inflammation, controlling epileptic seizures, and possibly even treating mental illness and addiction. As more world governments legalize cannabis for recreational use, and owing to the widening availability of higher tetrahydrocannabinol content variants of cannabis, the number of cannabis users is increasing rapidly, which in turn increases the number of people having PLEs worldwide. Schizophrenia is one of the top 15 leading causes of disability worldwide. The estimated prevalence of schizophrenia and related psychotic disorders in the United States in 2005 ranged from 0.25% to 0.64%; a meta-analysis a decade later found the lifetime prevalence worldwide to be 0.48% with interquartile range 0.34% to 0.85%. The high variability of sampling domains, diagnostic criteria, data availability and analytic methods employed preclude reliable estimates of incidence and prevalence increases of schizophrenia at present.
A role for cannabinoids in the treatment of myotonia? Report of compassionate use in a small cohort of patients
Montagnese F, Stahl K, Wenninger S and Schoser B
The symptomatic treatment of myotonia and myalgia in patients with dystrophic and non-dystrophic myotonias is often not satisfactory. Some patients anecdotally report symptoms' relief through consumption of cannabis.
[High-dose dronabinol treatment vs. medicinal cannabis flowers]
Wendelmuth C and Gastmeier K
This article reports a case of pronounced, chronic lumboischialgia, which was not satisfactorily controlled by conventional analgesic treatment. The level of pain under high-dose dronabinol treatment with oral and inhalative administration as well as the way to reimburse the cost of medicinal cannabis flowers, the treatment success and criteria of the economic prescription procedure are presented.
Nutrition and immunology in mental health: Precision medicine and integrative approaches to address unmet clinical needs in psychiatric treatments
Chang JP and Su KP
The 'monoamine hypothesis' is insufficient in approaching the aetiology of psychiatric disorders or in developing novel therapies. Accumulating evidence suggests that inflammatory regulation plays an important role in pathophysiology and therapeutic mechanism across the major psychiatric disorders. "Inflammation theory" might not be the full answer for the big picture of mental disorders, but it might explain high occurrence of somatic symptoms and comorbidity of physical illness in certain subtypes of the heterogeneous groups. Due to the complexity of clinical manifestations and bio-psycho-social etiology, each single treatment shows only small effectiveness with limited effect sizes when compared with placebo. Unfortunately, clinicians are still struggling with trial-and-error practice without any reliable clinical or biological markers to predict therapeutic responses. Therefore, it is important to open up our minds to integrative approaches such dietary modification and nutraceutical prescription. In this special issue, we included 15 papers discussing the role of nutrition (blueberries, omega-3 polyunsaturated fatty acids, melatonergic agonist, S-Adenosyl-L-Methionine, Cannabidiol and Kratom) in the context of immunoregulation across different psychiatric disorders from depression, bipolar disorders, and schizophrenia to alcohol-induced dementia and anorexia nervosa. Moreover, we also included research in perinatal depression that highlight the role of estradiol and the component of breast milk and the association with the neurodevelopment of the offspring. In addition, several articles focused on the role of microbiota in mental health and pain as recent research has pointed to the gut-brain axis as a main regulator of brain, behaviour and immunity. Lastly, inflammatory mechanisms underlying psychiatric disorders including alcohol induced dementia and anorexia nervosa are also highlighted in the special issue.
Clinicians' Guide to Cannabidiol and Hemp Oils
VanDolah HJ, Bauer BA and Mauck KF
Cannabidiol (CBD) oils are low tetrahydrocannabinol products derived from Cannabis sativa that have become very popular over the past few years. Patients report relief for a variety of conditions, particularly pain, without the intoxicating adverse effects of medical marijuana. In June 2018, the first CBD-based drug, Epidiolex, was approved by the US Food and Drug Administration for treatment of rare, severe epilepsy, further putting the spotlight on CBD and hemp oils. There is a growing body of preclinical and clinical evidence to support use of CBD oils for many conditions, suggesting its potential role as another option for treating challenging chronic pain or opioid addiction. Care must be taken when directing patients toward CBD products because there is little regulation, and studies have found inaccurate labeling of CBD and tetrahydrocannabinol quantities. This article provides an overview of the scientific work on cannabinoids, CBD, and hemp oil and the distinction between marijuana, hemp, and the different components of CBD and hemp oil products. We summarize the current legal status of CBD and hemp oils in the United States and provide a guide to identifying higher-quality products so that clinicians can advise their patients on the safest and most evidence-based formulations. This review is based on a PubMed search using the terms CBD, cannabidiol, hemp oil, and medical marijuana. Articles were screened for relevance, and those with the most up-to-date information were selected for inclusion.
Cannabidiol (CBD) use in psychiatric disorders: A systematic review
Bonaccorso S, Ricciardi A, Zangani C, Chiappini S and Schifano F
Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the most represented phytocannabinoids in Cannabis sativa plants. However, CBD may present with a different activity compared with the psychotomimetic THC. Most typically, CBD is reported to be used in some medical conditions, including chronic pain. Conversely, the main aim of this systematic review is to assess and summarise the available body of evidence relating to both efficacy and safety of CBD as a treatment for psychiatric disorders, alone and/or in combination with other treatments. Eligible studies included randomized controlled trials (RCT) assessing the effect of CBD in a range of psychopathological conditions, such as substance use; psychosis, anxiety, mood disturbances, and other psychiatric (e.g., cognitive impairment; sleep; personality; eating; obsessive-compulsive; post-traumatic stress/PTSD; dissociative; and somatic) disorders. For data gathering purposes, the PRISMA guidelines were followed. The initial search strategy identified some n = 1301 papers; n = 190 studies were included after the abstract's screening and n = 27 articles met the inclusion criteria. There is currently limited evidence regarding the safety and efficacy of CBD for the treatment of psychiatric disorders. However, available trials reported potential therapeutic effects for specific psychopathological conditions, such as substance use disorders, chronic psychosis, and anxiety. Further large-scale RCTs are required to better evaluate the efficacy of CBD in both acute and chronic illnesses, special categories, as well as to exclude any possible abuse liability.
High-Frequency Medical Cannabis Use Is Associated With Worse Pain Among Individuals With Chronic Pain
Boehnke KF, Scott JR, Litinas E, Sisley S, Williams DA and Clauw DJ
Cannabis is widely used for chronic pain. However, there is some evidence of an inverse dose-response relationship between cannabis effects and pain relief that may negatively affect analgesic outcomes. In this cross-sectional survey, we examined whether daily cannabis use frequency was associated with pain severity and interference, quality of life measures relevant to pain (eg, anxiety and depressive symptoms), and cannabis use preferences (administration routes and cannabinoid ratio). Our analysis included 989 adults who used cannabis every day for chronic pain. Participant use was designated as light, moderate, and heavy (1-2, 3-4, and 5 or more cannabis uses per day, respectively). The sample was also subgrouped by self-reported medical-only use (designated MED, n = 531, 54%) versus medical use concomitant with a past-year history of recreational use (designated MEDREC, n = 458, 46%). In the whole sample, increased frequency of use was significantly associated with worse pain intensity and interference, and worse negative affect, although high-frequency users also reported improved positive affect. Subgroup analyses showed that these effects were driven by MED participants. Heavy MED participant consumption patterns showed greater preference for smoking, vaporizing, and high tetrahydrocannabinol products. In contrast, light MED participants had greater preference for tinctures and high cannabidiol products. Selection bias, our focus on chronic pain, and our cross-sectional design likely limit the generalizability of our results. Our findings suggest that lower daily cannabis use frequency is associated with better clinical profile as well as lower risk cannabis use behaviors among MED participants. Future longitudinal studies are needed to examine how high frequency of cannabis use interacts with potential therapeutic benefits. PERSPECTIVE: Our findings suggest that lower daily cannabis use frequency is associated with better clinical profile as well as safer use behaviors (eg, preference for cannabidiol and noninhalation administration routes). These trends highlight the need for developing cannabis use guidelines for clinicians to better protect patients using cannabis.
The effects of cannabis, cannabinoids, and their administration routes on pain control efficacy and safety: A systematic review and network meta-analysis
Rabgay K, Waranuch N, Chaiyakunapruk N, Sawangjit R, Ingkaninan K and Dilokthornsakul P
To determine the effects of cannabis, cannabinoids, and their administration routes on pain and adverse euphoria events.
Cannabis Teratology Explains Current Patterns of Coloradan Congenital Defects: The Contribution of Increased Cannabinoid Exposure to Rising Teratological Trends
Reece AS and Hulse GK
Rising Δ9-tetrahydrocannabinol concentrations in modern cannabis invites investigation of the teratological implications of prenatal cannabis exposure. Data from Colorado Responds to Children with Special Needs (CRCSN), National Survey of Drug Use and Health, and Drug Enforcement Agency was analyzed. Seven, 40, and 2 defects were rising, flat, and falling, respectively, and 10/12 summary indices rose. Atrial septal defect, spina bifida, microcephalus, Down's syndrome, ventricular septal defect, and patent ductus arteriosus rose, and along with central nervous system, cardiovascular, genitourinary, respiratory, chromosomal, and musculoskeletal defects rose 5 to 37 times faster than the birth rate (3.3%) to generate an excess of 11 753 (22%) major anomalies. Cannabis was the only drug whose use grew from 2000 to 2014 while pain relievers, cocaine, alcohol, and tobacco did not. The correlation of cannabis use with major defects in 2014 (2019 dataset) was = .77, = .0011. Multiple cannabinoids were linked with summary measures of congenital anomalies and were robust to multivariate adjustment.
A systematic review of cannabidiol dosing in clinical populations
Millar SA, Stone NL, Bellman ZD, Yates AS, England TJ and O'Sullivan SE
Cannabidiol (CBD) is a cannabis-derived medicinal product with potential application in a wide-variety of contexts; however, its effective dose in different disease states remains unclear. This review aimed to investigate what doses have been applied in clinical populations, in order to understand the active range of CBD in a variety of medical contexts.
Therapeutic impact of orally administered cannabinoid oil extracts in an experimental autoimmune encephalomyelitis animal model of multiple sclerosis
Zhou T, Ahmad TK, Alrushaid S, Pozdirca M, Ethans K, Intrater H, Le T, Burczynski F, Kong J and Namaka M
There is a growing surge of investigative research involving the beneficial use of cannabinoids as novel interventional alternatives for multiple sclerosis (MS) and associated neuropathic pain (NPP). Using an experimental autoimmune encephalomyelitis (EAE) animal model of MS, we demonstrate the therapeutic effectiveness of two cannabinoid oil extract formulations (10:10 & 1:20 - tetrahydrocannabinol/cannabidiol) treatment. Our research findings confirm that cannabinoid treatment produces significant improvements in neurological disability scoring and behavioral assessments of NPP that directly result from their ability to reduce tumor necrosis factor alpha (TNF-α) production and enhance brain derived neurotrophic factor (BDNF) production. Henceforth, this research represents a critical step in advancing the literature by scientifically validating the merit for medical cannabinoid use and sets the foundation for future clinical trials.
Exposure to cannabinoids can lead to persistent cognitive and psychiatric disorders
Krebs MO, Kebir O and Jay TM
Cannabinoids are proposed in a wide array of medical indications. Yet, the evaluation of adverse effects in controlled clinical studies, following the evidence-based model, has partly been bypassed. On the other hand, studies on the consequences of recreational use of cannabis and experimental studies bring some insights on the potential long-term consequences of cannabinoids use.
The use of cannabinoids for sleep: A critical review on clinical trials
Kuhathasan N, Dufort A, MacKillop J, Gottschalk R, Minuzzi L and Frey BN
Cannabis and its pharmacologically active constituents, phytocannabinoids, have long been reported to have multiple medicinal benefits. One association often reported by users is sedation and subjective improvements in sleep. To further examine this association, we conducted a critical review of clinical studies examining the effects of cannabinoids on subjective and objective measures of sleep. PubMED, Web of Science, and Google Scholar were searched using terms and synonyms related to cannabinoids and sleep. Articles chosen included randomized controlled trials and open label studies. The Cochrane risk of bias tool was used to assess the quality of trials that compared cannabinoids with control interventions. The current literature focuses mostly on the use of tetrahydrocannabinol (THC) and/or cannabidiol (CBD) in the treatment of chronic health conditions such as multiple sclerosis, posttraumatic stress disorder (PTSD), and chronic pain. Sleep is often a secondary, rather than primary outcome in these studies. Many of the reviewed studies suggested that cannabinoids could improve sleep quality, decrease sleep disturbances, and decrease sleep onset latency. While many of the studies did show a positive effect on sleep, there are many limiting factors such as small sample sizes, examining sleep as a secondary outcome in the context of another illness, and relatively few studies using validated subjective or objective measurements. This review also identified several questions that should be addressed in future research. These questions include further elucidation of the dichotomy between the effects of THC and CBD, as well as identifying any long-term adverse effects of medicinal cannabinoid use. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Cannabidiol, cannabinol and their combinations act as peripheral analgesics in a rat model of myofascial pain
Wong H and Cairns BE
This study investigated whether local intramuscular injection of non-psychoactive cannabinoids, cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC) and their combinations can decrease nerve growth factor (NGF)-induced masticatory muscle sensitization in female rats.
[Medical Cannabis-Related Relapse in a Patient with a History of Alcohol Abuse]
Flöther L, Peitek K, Bucher M and Benndorf RA
 In this report, a 60-year old patient with a history of mixed nociceptive and neuropathic chronic pain after successful removal of oral squamous cell cancer is described who received outpatient pain treatment in our clinic. Moreover, the patient presented with a history of alcohol abuse as well as anorexia and weight loss.
Cannabis Use and Cognition in Adults Prescribed Opioids for Persistent Pain
Wildes M, Bigand TL, Layton ME and Wilson M
Adults with persistent pain frequently report cannabis use to help manage their symptoms. The impact of cannabis use on cognition in the presence of concurrent symptoms of depression and anxiety is poorly understood.
Cannabidiol (CBD) Consumption and Perceived Impact on Extrahepatic Symptoms in Patients with Autoimmune Hepatitis
Mathur K, Vuppalanchi V, Gelow K, Vuppalanchi R and Lammert C
Utilization and safety of cannabidiol (CBD) in patients with autoimmune hepatitis (AIH) are currently unknown. We aimed to identify the frequency of CBD use, impact on symptoms, and safety profile.
[Progress in cannabis research from a pharmaceutical chemist's point of view]
Müller CE
Preparations of hemp, Cannabis sativa, have been used for thousands of years as recreational and therapeutic drugs. The most important constituents are the psychoactive (-)-trans-∆-tetrahydrocannabinol (THC), a partial agonist at cannabinoid (CB) receptors CB and CB, and the non-psychoactive pleiotropic cannabidiol (CBD). Both compounds are highly lipophilic, like the endogenous CB receptor agonists, the arachidonic acid derivatives anandamide and arachidonoyl glycerol. The CB receptors belong to the family of G protein-coupled receptors, and the first X‑ray crystal structures of both CB receptors subtypes have recently been obtained, which will facilitate the rational design of novel synthetic ligands. Besides the already largely established indications such as chronic pain, chemotherapy-induced vomiting, multiple sclerosis-associated spasms, and cachexia, there is preliminary evidence for several further cannabinoid effects, which will have to be confirmed by clinical studies.
Cannabinoids: a new approach for pain control?
Lossignol D
To analyze available data related to the use of cannabinoids in medicine, with a special focus on pain management in cancer. The use of cannabis for medical purposes is growing but there are still numerous questions to be solved: effectiveness, safety, and specific indications.
Eicosanoid mediation of cannabinoid actions
Burstein SH
Interactions between cannabinoids and eicosanoids have been observed for the last several decades and account for a variety of cannabinoid actions. These were seen both in vitro and in vivo and may provide a molecular basis for these actions. Some of the topics included in this review are; effects on adenylate cyclase activity, alteration of behavioral responses, reduction of pain sensation, reduction and resolution of inflammation, hypotensive and vasorelaxant responses, anti-cancer and anti-metastatic activities, reduction of intraocular pressure and others. The most widely studied cannabinoids so far are tetrahydrocannabinol and cannabidiol. However, synthetic agents such as CP55,940, ajulemic acid, JWH-133 and WIN-55,212-2 were also investigated for interaction with eicosanoids. The endocannabinoids anandamide and 2-arachidonoylglycerol have been examined as well. Among the eicosanoids mediating cannabinoid actions are PGE, 15-deoxy-Δ-prostaglandin-J, lipoxin A, lipoxin B, and leukotriene B. Enzyme activities involved include monoacylglycerylipase, adenylatecyclase, phospholipase A, cyclooxygenases-1, 2 and 5, lipoxygenases-12 and 15. Receptors involved include CB1, CB2 and the EP3 and EP3 prostanoid receptors. While not all cannabinoid activities can be accounted for, many are best explained by eicosanoid participation. The recent surge in interest in "medical marijuana" makes understanding mechanisms of cannabinoid actions particularly important.
Cannabidiol attenuates mechanical allodynia in streptozotocin-induced diabetic rats via serotonergic system activation through 5-HT1A receptors
Jesus CHA, Redivo DDB, Gasparin AT, Sotomaior BB, de Carvalho MC, Genaro K, Zuardi AW, Hallak JEC, Crippa JA, Zanoveli JM and da Cunha JM
Most diabetic patients describe moderate to severe pain symptoms whose pharmacological treatment is palliative and poorly effective. Cannabidiol (CBD) has shown promising results in painful conditions. Then, we aimed to investigate the potential antinociceptive effect of CBD over the mechanical allodynia in streptozotocin-induced diabetic (DBT) rats, as well as its involved mechanisms. Wistar adult male diabetic rats were treated acutely or sub-chronically (for 14 days) with CBD (0.1, 0.3 or 3 mg/kg, intraperitoneal; i.p.) and had their mechanical threshold assessed using the electronic Von Frey. Acute treatment with CBD (at doses of 0.3 and 3 mg/kg) exerted a significant anti-allodynic effect, which is not associated with locomotor impairment. The antinociceptive effect of CBD (3 mg/kg) was not altered by the pre-treatment with CB or CB receptor antagonists (AM251 and AM630; respectively; both at a dose of 1 mg/kg, i.p.) nor by glycine receptor antagonist (strychnine hydrochloride, 10 μg/rat, intrathecal, i.t.). However, this effect was completely prevented by the pre-treatment with the selective 5-HT receptor antagonist WAY 100135 (3 μg/rat, i.t.). Sub-chronic treatment with CBD (0.3 or 3 mg/kg) induced a sustained attenuation of the mechanical allodynia in DBT rats. DBT rats presented significantly lower spinal cord levels of serotonin, which was prevented by the daily treatment with CBD (0.3 mg/kg). Taken together, our data suggest that CBD may be effective in the treatment of painful diabetic neuropathy and this effect seems to be potentially mediated by the serotonergic system activation through 5-HT receptors.
A Hemp oil, CBD, and Marijuana Primer: Powerful Pain, Insomnia, and Anxiety-relieving Tools!
Teitelbaum J
No Abstract Available.
Should Oncologists Recommend Cannabis?
Abrams DI
Cannabis is a useful botanical with a wide range of therapeutic potential. Global prohibition over the past century has impeded the ability to study the plant as medicine. However, delta-9-tetrahydrocannabinol (THC) has been developed as a stand-alone pharmaceutical initially approved for the treatment of chemotherapy-related nausea and vomiting in 1986. The indication was expanded in 1992 to include treatment of anorexia in patients with the AIDS wasting syndrome. Hence, if the dominant cannabinoid is available as a schedule III prescription medication, it would seem logical that the parent botanical would likely have similar therapeutic benefits. The system of cannabinoid receptors and endogenous cannabinoids (endocannabinoids) has likely developed to help us modulate our response to noxious stimuli. Phytocannabinoids also complex with these receptors, and the analgesic effects of cannabis are perhaps the best supported by clinical evidence. Cannabis and its constituents have also been reported to be useful in assisting with sleep, mood, and anxiety. Despite significant in vitro and animal model evidence supporting the anti-cancer activity of individual cannabinoids-particularly THC and cannabidiol (CBD)-clinical evidence is absent. A single intervention that can assist with nausea, appetite, pain, mood, and sleep is certainly a valuable addition to the palliative care armamentarium. Although many healthcare providers advise against the inhalation of a botanical as a twenty-first century drug-delivery system, evidence for serious harmful effects of cannabis inhalation is scant and a variety of other methods of ingestion are currently available from dispensaries in locales where patients have access to medicinal cannabis. Oncologists and palliative care providers should recommend this botanical remedy to their patients to gain first-hand evidence of its therapeutic potential despite the paucity of results from randomized placebo-controlled clinical trials to appreciate that it is both safe and effective and really does not require a package insert.
Efficacy and safety of cannabidiol followed by an open label add-on of tetrahydrocannabinol for the treatment of chronic pain in patients with rheumatoid arthritis or ankylosing spondylitis: protocol for a multicentre, randomised, placebo-controlled study
Hendricks O, Andersen TE, Christiansen AA, Primdahl J, Hauge EM, Ellingsen T, Horsted TI, Bachmann AG, Loft AG, Bojesen AB, Østergaard M, Lund Hetland M, Krogh NS, Roessler KK and Petersen KH
Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic, systemic, inflammatory diseases, primarily in the musculoskeletal system. Pain and fatigue are key symptoms of RA and AS. Treatment presents a clinical challenge for several reasons, including the progressive nature of the diseases and the involvement of multiple pain mechanisms. Moreover, side effects of pain treatment pose an implicit risk. Currently, no well-controlled studies have investigated how medical cannabis affects pain and cognitive functions in RA and AS. The present study aims to evaluate the efficacy and safety of medical cannabis in the treatment of persistent pain in patients with RA and AS with low disease activity.
leaf extract facilitates oligodendrocyte development
Kim JY, Yoon JY, Sugiura Y, Lee SK, Park JD, Song GJ and Yang HJ
Treatment of multiple sclerosis is effective when anti-inflammatory, neuroprotective and regenerative strategies are combined. () has anti-inflammatory, anti-oxidative properties, which may be beneficial for multiple sclerosis. However, there have been no reports on the effects of on myelination, which is critical for regenerative processes. To know whether benefits myelination, we checked differentiation and myelination of oligodendrocytes (OLs) in various primary culture systems treated with leaf EtOH extracts or control. extracts increased the OL membrane size in the mixed glial and pure OL precursor cell (OPC) cultures and changed OL-lineage gene expression patterns in the OPC cultures. Western blot analysis of -treated OPC cultures showed upregulation of MBP and phosphorylation of ERK1/2. In myelinating cocultures, extracts enhanced OL differentiation, followed by increased axonal contacts and myelin gene upregulations such as Myrf, CNP and PLP. Phytochemical analysis by LC-MS/MS identified multiple components from extracts, containing bioactive molecules such as quercetin, cannabidiol, etc. Our results suggest extracts enhance OL differentiation, followed by an increase in membrane size and axonal contacts, thereby indicating enhanced myelination. In addition, we found that extracts contain multiple bioactive components, warranting further studies in relation to finding effective components for enhancing myelination.
The Endocannabinoid System and its Modulation by Cannabidiol (CBD)
Corroon J and Felice JF
The endocannabinoid system (ECS) is an extensive endogenous signaling system with multiple elements, the number of which may be increasing as scientists continue to elucidate its role in human health and disease. The ECS is seemingly ubiquitous in animal species and is modulated by diet, sleep, exercise, stress, and a multitude of other factors, including exposure to phytocannabinoids, like Cannabidiol (CBD). Modulating the activity of this system may offer tremendous therapeutic promise for a diverse scope of diseases, ranging from mental health disorders, neurological and movement disorders, pain, autoimmune disease, spinal cord injury, cancer, cardiometabolic disease, stroke, TBI, osteoporosis, and others.
Prevalence and correlates of medical cannabis patients' use of cannabis for recreational purposes
Morean ME and Lederman IR
Rates of legal medical cannabis (MC) use are increasing, but little is known about the prevalence and correlates of recreational cannabis (RC) use among medical users (MC/R).
CBD as the New Medicine in the Pain Provider's Armamentarium
Piermarini C and Viswanath O
Analog Derivatization of Cannabidiol for Improved Ocular Permeation
Taskar P, Adelli G, Patil A, Lakhani P, Ashour E, Gul W, ElSohly M and Majumdar S
Cannabidiol (CBD), active component of plant , has anti-inflammatory properties that could potentially help treat diabetic retinopathy-induced pain and inflammation. However, CBD is a lipophilic molecule making its topical delivery to back of the eye challenging. This study aims at improving ocular penetration of CBD by means of analog derivatization. Analogs were designed using various ligands, such as amino acids (AAs) and dicarboxylic acids (DCAs) and their combinations. Select analogs were screened with respect to their stability in ocular tissue homogenates. Based on stability, analogs were selected for testing. Formulations containing these compounds were tested in rabbits to determine ocular tissue disposition of CBD and the analogs after topical application. The rabbits were sacrificed 90 min post-topical application and the aqueous humor, vitreous humor (VH), iris-ciliary bodies (IC), and retina-choroid (RC) were analyzed for CBD and analog content. CBD-divalinate-dihemisuccinate (CBD-Di-VHS) and CBD-divalinate (CBD-Di-Val) were stable in the ocular tissue homogenates. Post-topical application, CBD and CBD-Di-Val analog levels were detected only in RC. Dosing of CBD-Di-VHS nanoemulsion generated analog levels both in the VH and in the RC, respectively. In contrast, post dosing of CBD-monovalinate-monohemisuccinate (CBD-Mono-VHS), both the analog and CBD were detected in the IC and RC. The analogs demonstrated superior penetration into ocular tissues in comparison with CBD. CBD-Di-VHS and CBD-Mono-VHS exhibited better permeation properties, possibly due to improved stability and physicochemical characteristics imparted by AA and DCA combination derivatives.
An Update of Current Cannabis-Based Pharmaceuticals in Pain Medicine
Urits I, Borchart M, Hasegawa M, Kochanski J, Orhurhu V and Viswanath O
Cannabis users have long reported therapeutic properties of the plant for a variety of conditions, some of which include nausea, emesis, seizures, cancer, neurogenic diseases and pain control. Research has elucidated many cannabinoid pharmacodynamic and pharmacokinetic properties, expanding the potential use of cannabinoids as a medical therapy. Due to the inconsistent delivery and control of the active components involved with smoking, pharmaceutical companies are investigating and prioritizing routes other than smoke inhalation for therapeutic use of cannabinoids. In this relatively new field of pharmaceutical development, ongoing drug development promises great benefit from targeted endocannabinoid receptor agonism. Available in Canada and Europe, nabiximols, a specific extract from the Cannabis plant, has demonstrated great benefit in the treatment of pain related to spasticity in multiple sclerosis, cancer and otherwise chronic pain conditions. The cannabidiol oral solution Epidiolex®, which is available in the USA, is indicated for management of refractory epilepsy but may offer therapeutic relief to chronic pain conditions as well. Current investigative drugs, such as those developed by Cara Therapeutics and Zynerba Pharmaceuticals, are synthetic cannabinoids which show promise to specifically target neuropsychiatric conditions and chronic pain symptoms such as neuropathy and allodynia. The objective of this review is to provide clinicians with an update of currently available and promising developmental cannabis pharmaceutical derivatives which may stand to greatly benefit patients with otherwise difficult-to-treat chronic conditions.
Joints for joints: cannabinoids in the treatment of rheumatoid arthritis
Lowin T, Schneider M and Pongratz G
An increasing number of patients with rheumatoid arthritis (RA) are using cannabis to treat their symptoms, although systematic studies regarding efficacy in RA are lacking. Within this review we will give an overview on the overall effects of cannabinoids in inflammation and why they might be useful in the treatment of RA.
Tetrahydrocannabinol - friend or foe? - Debate
Temple LM and Leikin JB
Tetrahydrocannabinol (THC) is a psychoactive cannabinoid that has been used to treat various conditions. However, due to various adverse effects, its widespread promotion and use has been controversial. It is this aspect (encouraged by various state legislatures) that forms the basis for an edited debate between an Integrative Family Medicine physician and a Medical Toxicologist.
Dark Classics in Chemical Neuroscience: Δ-Tetrahydrocannabinol
Banister SD, Arnold JC, Connor M, Glass M and McGregor IS
Cannabis ( Cannabis sativa) is the most widely used illicit drug in the world, with an estimated 192 million users globally. The main psychoactive component of cannabis is (-)- trans-Δ-tetrahydrocannabinol (Δ-THC), a compound with a diverse range of pharmacological actions. The unique and distinctive intoxication caused by Δ-THC primarily reflects partial agonist action at central cannabinoid type 1 (CB) receptors. Δ-THC is an approved therapeutic treatment for a range of conditions, including chronic pain, chemotherapy-induced nausea and vomiting, and multiple sclerosis, and is being investigated in indications such as anorexia nervosa, agitation in dementia, and Tourette's syndrome. It is available as a regulated pharmaceutical in products such as Marinol, Sativex, and Namisol as well as in an ever-increasing range of unregistered medicinal and recreational cannabis products. While cannabis is an ancient medicament, contemporary use is embroiled in legal, scientific, and social controversy, much of which relates to the potential hazards and benefits of Δ-THC itself. Robust contemporary debate surrounds the therapeutic value of Δ-THC in different diseases, its capacity to produce psychosis and cognitive impairment, and the addictive and "gateway" potential of the drug. This review will provide a profile of the chemistry, pharmacology, and therapeutic uses of Δ-THC as well as the historical and societal import of this unique, distinctive, and ubiquitous psychoactive substance.
Safety, efficacy, and mechanisms of action of cannabinoids in neurological disorders
Friedman D, French JA and Maccarrone M
In the past two decades, there has been an increasing interest in the therapeutic potential of cannabinoids for neurological disorders such as epilepsy, multiple sclerosis, pain, and neurodegenerative diseases. Cannabis-based treatments for pain and spasticity in patients with multiple sclerosis have been approved in some countries. Randomised controlled trials of plant-derived cannabidiol for treatment of Lennox-Gastaut syndrome and Dravet syndrome, two severe childhood-onset epilepsies, provide evidence of anti-seizure effects. However, small clinical trials of cannabinoids in other neurological disorders such as Huntington's disease, attention deficit hyperactivity disorder, and dementia, have not found any effect. Despite positive results in these two severe epilepsy syndromes, further studies are needed to determine if the anti-seizure effects of cannabidiol extend to other forms of epilepsy, to overcome pharmacokinetic challenges with oral cannabinoids, and to uncover the exact mechanisms by which cannabidiol or other exogenous and endogenous cannabinoids exert their therapeutic effects.
[Use of cannabidiol oil in children]
Wolff D and Reijneveld SA
Useof cannabidiol oil in children The use of cannabidioloil (CBD oil), a cannabis-derived chemical, is increasing. CBD oil is freely available in the Netherlands, but its composition and quality are not monitored. However, the alternative, pharmacist-prepared oil, is more expensive and difficult to acquire. Common reasons for CBD oil use in children include impulsive behaviour, itch, epilepsy, stress, pain and sleeping problems. However, evidence of its effectiveness is scarce and focuses primarily on the effectiveness of the oil in reducing epileptic seizures. Known side-effects are vomiting, diarrhoea, fever, sleepiness, and abnormal liver function test results. We advise medical professionals who encounter young patients who may potentially be using CBD oil, to discuss its questionable quality and potential side effects and interactions. If a patient presents with poorly-understood fever, diarrhoea, vomiting or drowsiness, then the side effects of CBD oil should be considered. Finally, CBD should be differentiated from delta-THC, a cannabis-derived chemical with a psychoactive effect, the use of which should be discouraged in children.
Future Aspects for Cannabinoids in Breast Cancer Therapy
Kisková T, Mungenast F, Suváková M, Jäger W and Thalhammer T
Cannabinoids (CBs) from provide relief for tumor-associated symptoms (including nausea, anorexia, and neuropathic pain) in the palliative treatment of cancer patients. Additionally, they may decelerate tumor progression in breast cancer patients. Indeed, the psychoactive delta-9-tetrahydrocannabinol (THC), non-psychoactive cannabidiol (CBD) and other CBs inhibited disease progression in breast cancer models. The effects of CBs on signaling pathways in cancer cells are conferred via G-protein coupled CB-receptors (CB-Rs), CB1-R and CB2-R, but also via other receptors, and in a receptor-independent way. THC is a partial agonist for CB1-R and CB2-R; CBD is an inverse agonist for both. In breast cancer, CB1-R expression is moderate, but CB2-R expression is high, which is related to tumor aggressiveness. CBs block cell cycle progression and cell growth and induce cancer cell apoptosis by inhibiting constitutive active pro-oncogenic signaling pathways, such as the extracellular-signal-regulated kinase pathway. They reduce angiogenesis and tumor metastasis in animal breast cancer models. CBs are not only active against estrogen receptor-positive, but also against estrogen-resistant breast cancer cells. In human epidermal growth factor receptor 2-positive and triple-negative breast cancer cells, blocking protein kinase B- and cyclooxygenase-2 signaling via CB2-R prevents tumor progression and metastasis. Furthermore, selective estrogen receptor modulators (SERMs), including tamoxifen, bind to CB-Rs; this process may contribute to the growth inhibitory effect of SERMs in cancer cells lacking the estrogen receptor. In summary, CBs are already administered to breast cancer patients at advanced stages of the disease, but they might also be effective at earlier stages to decelerate tumor progression.
Combined tetrahydrocannabinol and cannabidiol to treat pain in epidermolysis bullosa: a report of three cases
Schräder NHB, Duipmans JC, Molenbuur B, Wolff AP and Jonkman MF
Epidermolysis bullosa (EB) is a genetic blistering disorder characterized by intense pain related to disease pathology and care-based interventions. Opioid-based therapies underpin pain care in EB; however, they are unable to provide adequate analgesia in a significant proportion of patients. Cannabinoid-based medicines (CBMs) have been studied increasingly for pain conditions of various aetiologies and pose as a novel dimension for pain care in EB. We present three patients with EB who were prescribed pharmaceutical-grade sublingually administered CBMs comprising tetrahydrocannabinol and cannabidiol. All three patients reported improved pain scores, reduced pruritus and reduction in overall analgesic drug intake.
Impact of recreational and medicinal marijuana on surgical patients: A review
Bakshi C and Barrett AM
As medicinal and recreational marijuana use broadens across the United States, knowledge of its effects on the body will become increasingly important to all health care providers, including surgeons.
An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia
van de Donk T, Niesters M, Kowal MA, Olofsen E, Dahan A and van Velzen M
In this experimental randomized placebo-controlled 4-way crossover trial, we explored the analgesic effects of inhaled pharmaceutical-grade cannabis in 20 chronic pain patients with fibromyalgia. We tested 4 different cannabis varieties with exact knowledge on their [INCREMENT]-tetrahydrocannabinol (THC) and cannabidiol (CBD) content: Bedrocan (22.4-mg THC, <1-mg CBD; Bedrocan International BV, Veendam, the Netherlands), Bediol (13.4-mg THC, 17.8-mg CBD; Bedrocan International BV, Veendam, the Netherlands), Bedrolite (18.4-mg CBD, <1-mg THC; Bedrocan International BV, Veendam, the Netherlands), and a placebo variety without any THC or CBD. After a single vapor inhalation, THC and CBD plasma concentrations, pressure and electrical pain thresholds, spontaneous pain scores, and drug high were measured for 3 hours. None of the treatments had an effect greater than placebo on spontaneous or electrical pain responses, although more subjects receiving Bediol displayed a 30% decrease in pain scores compared to placebo (90% vs 55% of patients, P = 0.01), with spontaneous pain scores correlating with the magnitude of drug high (ρ = -0.5, P < 0.001). Cannabis varieties containing THC caused a significant increase in pressure pain threshold relative to placebo (P < 0.01). Cannabidiol inhalation increased THC plasma concentrations but diminished THC-induced analgesic effects, indicative of synergistic pharmacokinetic but antagonistic pharmacodynamic interactions of THC and CBD. This experimental trial shows the complex behavior of inhaled cannabinoids in chronic pain patients with just small analgesic responses after a single inhalation. Further studies are needed to determine long-term treatment effects on spontaneous pain scores, THC-CBD interactions, and the role of psychotropic symptoms on pain relief.
Cannabidiol: The Need for More Information About Its Potential Benefits and Side Effects
Hande K
Consumer demand for cannabidiol (CBD) oil has increased, with growing sales from dispensaries because of the alleged medicinal benefits. Although studies examining the specific therapeutic effects of CBD are increasing, clinical data do not support the popular uses of CBD for Parkinson disease, schizophrenia, cancer palliation and treatment, chronic pain and spasticity, depression, anxiety disorder, insomnia, and inflammation.
A Brief Background on Cannabis: From Plant to Medical Indications
Klumpers LE and Thacker DL
Cannabis has been used as a medicinal plant for thousands of years. As a result of centuries of breeding and selection, there are now over 700 varieties of cannabis that contain hundreds of compounds, including cannabinoids and terpenes. Cannabinoids are fatty compounds that are the main biological active constituents of cannabis. Terpenes are volatile compounds that occur in many plants and have distinct odors. Cannabinoids exert their effect on the body by binding to receptors, specifically cannabinoid receptors types 1 and 2. These receptors, together with endogenous cannabinoids and the systems for synthesis, transport, and degradation, are called the Endocannabinoid System. The two most prevalent and commonly known cannabinoids in the cannabis plant are delta-9-tetrahydrocannabinol (THC) and cannabidiol. The speed, strength, and type of effects of cannabis vary based on the route of administration. THC is rapidly distributed through the body to fatty tissues like the brain and is metabolized by the cytochrome P450 system to 11-hydroxy-THC, which is also psychoactive. Cannabis and cannabinoids have been indicated for several medical conditions. There is evidence of efficacy in the symptomatic treatment of nausea and vomiting, pain, insomnia, post-traumatic stress disorder, anxiety, loss of appetite, Tourette's syndrome, and epilepsy. Cannabis has also been associated with treatment for glaucoma, Huntington's Disease, Parkinson's Disease, and dystonia, but there is not good evidence to support its efficacy. Side effects of cannabis include psychosis and anxiety, which can be severe. Here, we provided a summary of the history of cannabis, its pharmacology, and its medical uses.
GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol
Laun AS, Shrader SH, Brown KJ and Song ZH
The G protein-coupled receptors 3, 6, and 12 (GPR3, GPR6, and GPR12) comprise a family of closely related orphan receptors with no confirmed endogenous ligands. These receptors are constitutively active and capable of signaling through G protein-mediated and non-G protein-mediated mechanisms. These orphan receptors have previously been reported to play important roles in many normal physiological functions and to be involved in a variety of pathological conditions. Although they are orphans, GPR3, GPR6, and GPR12 are phylogenetically most closely related to the cannabinoid receptors. Using β-arrestin2 recruitment and cAMP accumulation assays, we recently found that the nonpsychoactive phytocannabinoid cannabidiol (CBD) is an inverse agonist for GPR3, GPR6, and GPR12. This discovery highlights these orphan receptors as potential new molecular targets for CBD, provides novel mechanisms of action, and suggests new therapeutic uses of CBD for illnesses such as Alzheimer's disease, Parkinson's disease, cancer, and infertility. Furthermore, identification of CBD as a new inverse agonist for GPR3, GPR6, and GPR12 provides the initial chemical scaffolds upon which potent and efficacious agents acting on these receptors can be developed, with the goal of developing chemical tools for studying these orphan receptors and ultimately new therapeutic agents.
Cannabinoids: the lows and the highs of chemotherapy-induced nausea and vomiting
Mortimer TL, Mabin T and Engelbrecht AM
Despite remaining one of the most widely abused drugs worldwide, Cannabis sativa exhibits remarkable medicinal properties. The phytocannabinoids, cannabidiol and Δ-9-tetrahydrocannabinol, reduce nausea and vomiting, particularly during chemotherapy. This is attributed to their ability to reduce the release of serotonin from enterochromaffin cells in the small intestine, which would otherwise orchestrate the vomiting reflex. Although there are many preclinical and clinical studies on the effects of Δ-9-tetrahydrocannabinol during nausea and vomiting, little is known about the role that cannabidiol plays in this scenario. Since cannabidiol does not induce psychotropic effects, in contrast to other cannabinoids, its use as an anti-emetic is of great interest. This review aims to summarize the available literature on cannabinoid use, with a specific focus on the nonpsychotropic drug cannabidiol, as well as the roles that cannabinoids play in preventing several other adverse side effects of chemotherapy including organ toxicity, pain and loss of appetite.
Development of a validated method for the qualitative and quantitative analysis of cannabinoids in plant biomass and medicinal cannabis resin extracts obtained by super-critical fluid extraction
Elkins AC, Deseo MA, Rochfort S, Ezernieks V and Spangenberg G
The social push for the therapeutic use of cannabis extracts has increased significantly over recent years. Cannabis is being used for treatment for conditions such as epilepsy, cancer and pain management. There are a range of medicinal cannabis products available, but the use of cannabis resin obtained by super critical fluid extraction, often diluted in oil, is becoming increasingly more prominent. Much of the research on cannabis has focused on plant biomass or the final therapeutic product with a concerning lack of information on the intermediate resin. This study aims to bridge the gap between current methods of analysis for biomass and the final therapeutic product by describing a fully developed and validated ultra-high-performance-liquid-chromatography method with diode array detection (UHPLC-DAD) for the qualification and quantification of the cannabinoids CBDA, CBD, CBN, THC, CBC and THCA, in medicinal cannabis biomass and resin obtained by super-critical fluid extraction (SFE). The method was validated for specificity, linearity, limit of detection (LOD), limit of quantitation (LOQ), precision, accuracy, robustness, spike recovery and stability in accordance with the Validation of Analytical Procedures: Text and Methodology Q2 to meet the requirements of the International Council for Harmonisation (ICH), Therapeutic Goods Authority (TGA) and the Food and Drug Administration (FDA) test method validation regulations.
Sativex as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-blind, placebo-controlled randomised clinical trial
Markovà J, Essner U, Akmaz B, Marinelli M, Trompke C, Lentschat A and Vila C
Purpose/aim: To evaluate the efficacy of tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex) as add-on therapy to optimised standard antispasticity treatment in patients with moderate to severe multiple sclerosis (MS) spasticity.
Survey of Australian psychiatrists' and psychiatry trainees' knowledge about and attitudes towards medicinal cannabinoids
Jacobs NI, Montebello M, Monds LA and Lintzeris N
To assess Australian psychiatrists' and psychiatry trainees' knowledge about and attitudes towards medicinal cannabinoids, given the recent relaxation of cannabinoid-prescribing laws in Australia.
Exploring cannabis use by patients with multiple sclerosis in a state where cannabis is legal
Weinkle L, Domen CH, Shelton I, Sillau S, Nair K and Alvarez E
Studies suggest cannabis may improve symptoms like pain and muscle spasticity in patients with multiple sclerosis (PwMS). Despite cannabis' new-found legality and availability, few studies have explored the profile of PwMS cannabis users and characteristics of their use, particularly in a state where cannabis is legal both for recreational and medicinal use. The purpose of the current study was to evaluate cannabis use among PwMS at a large academic multiple sclerosis (MS) clinic, specifically: (1) prevalence, (2) products used (e.g., cannabidiol vs Δ-tetrahydocannabinol), (3) symptom treatment, and (4) patient characteristics.
Adherence to Consolidated Standards of Reporting Trials (CONSORT) Guidelines for Reporting Safety Outcomes in Trials of Cannabinoids for Chronic Pain: Protocol for a Systematic Review
Mohiuddin MM, Mizubuti G, Haroutounian S, Smith S, Campbell F, Park R and Gilron I
Chronic pain affects a significant proportion of the population and presents a major challenge to clinicians and pain specialists. Despite the availability of pharmacologic treatment options such as opioids, many patients continue to experience persistent pain. Cannabinoids present an alternative option with some data on efficacy; however, to date, a systematic review of adverse events (AEs) assessment and reporting in randomized clinical trials (RCTs) involving cannabinoids has not been performed. As a result, it is unclear whether a clear profile of cannabinoid-associated AEs has been accurately detailed in the literature. As cannabinoids are likely to become readily available for patients in the near future, it is important to study how well AEs have been reported in trials so that the safety profile of cannabinoids can be better understood.
Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain
De Gregorio D, McLaughlin RJ, Posa L, Ochoa-Sanchez R, Enns J, Lopez-Canul M, Aboud M, Maione S, Comai S and Gobbi G
Clinical studies indicate that cannabidiol (CBD), the primary nonaddictive component of cannabis that interacts with the serotonin (5-HT)1A receptor, may possess analgesic and anxiolytic effects. However, its effects on 5-HT neuronal activity, as well as its impact on models of neuropathic pain are unknown. First, using in vivo single-unit extracellular recordings in rats, we demonstrated that acute intravenous (i.v.) increasing doses of CBD (0.1-1.0 mg/kg) decreased the firing rate of 5-HT neurons in the dorsal raphe nucleus, which was prevented by administration of the 5-HT1A antagonist WAY 100635 (0.3 mg/kg, i.v.) and the TRPV1 antagonist capsazepine (1 mg/kg, i.v.) but not by the CB1 receptor antagonist AM 251 (1 mg/kg, i.v.). Repeated treatment with CBD (5 mg/kg/day, subcutaneously [s.c.], for 7 days) increased 5-HT firing through desensitization of 5-HT1A receptors. Rats subjected to the spared nerve injury model for 24 days showed decreased 5-HT firing activity, mechanical allodynia, and increased anxiety-like behavior in the elevated plus maze test, open-field test, and novelty-suppressed feeding test. Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity. Antiallodynic effects of CBD were fully prevented by capsazepine (10 mg/kg/day, s.c., for 7 days) and partially prevented by WAY 100635 (2 mg/kg/day, s.c., for 7 days), whereas the anxiolytic effect was blocked only by WAY. Overall, repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.
Patient Counseling Guidelines for the Use of Cannabis for the Treatment of Chemotherapy-Induced Nausea/Vomiting and Chronic Pain
Makary P, Parmar JR, Mims N, Khanfar NM and Freeman RA
The use of cannabis medications has grown in recent years for the symptomatic relief of chemotherapy-induced nausea/vomiting (CINV) and chronic pain (cancer-related and non-cancer-related). As states legalize the use of cannabis, it is important for pharmacists and other health care professionals to be aware of how to counsel patients receiving prescriptions for cannabis medications. The aim of this study was to develop patient counseling guidelines for the use of cannabis products in treatment of CINV and chronic pain. A literature search was performed using Medline/PubMed resources and Google Scholar between July 2015 and August 2018 using broad search terms, e.g., cannabinoids adverse effects, cannabis, natural cannabinoids, and tetrahydrocannabinol. Using the American Society of Health-System Pharmacists patient counseling guidelines and medical information on cannabis medications gathered from drug databases, a comprehensive counseling guideline was developed. Medical evidence of the use of natural cannabis medications that are smoked or orally ingested have not been studied as extensively as oral therapeutic agents currently available. Cannabis medications have become more prevalent by approval of legislators in several states. Hence, pharmacists and health care professionals should counsel patients effectively on its use. This guideline needs to be tested to assess its utility in patients.
Natural Negative Allosteric Modulators of 5-HT₃ Receptors
Al Kury LT, Mahgoub M, Howarth FC and Oz M
Chemotherapy-induced nausea and vomiting (CINV) remain the most common and devastating side-effects associated with cancer chemotherapy. In recent decades, several lines of research emphasize the importance of 5-hydroxytryptamine3 (5-HT serotonin) receptors in the pathogenesis and treatment of CINV. 5-HT₃ receptors are members of ligand-gated ion channels that mediate the rapid and transient membrane-depolarizing effect of 5-HT in the central and peripheral nervous system. These receptors play important roles in nausea and vomiting, as well as regulation of peristalsis and pain transmission. The development of antagonists for 5-HT₃ receptor dramatically improved the treatment of CINV in cancer patients. In fact, the most common use of 5-HT₃ receptor antagonists to date is the treatment of nausea and vomiting. In recent years, there has been an increasing tendency to use natural plant products as important therapeutic entities in the treatment of various diseases. In this article, we examined the results of earlier studies on the actions of natural compounds on the functional properties of 5-HT₃ receptors. It is likely that these natural modulators of 5-HT₃ receptors can be employed as lead structures for the synthesis of therapeutic agents for treating CINV in future clinical studies.
Effect of cannabidiolic acid and ∆-tetrahydrocannabinol on carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain
Rock EM, Limebeer CL and Parker LA
Cannabidiol (CBD), a non-intoxicating component of cannabis, or the psychoactive Δ-tetrahydrocannabiol (THC), shows anti-hyperalgesia and anti-inflammatory properties.
Cannabidiol modulation of antinociceptive tolerance to Δ-tetrahydrocannabinol
Greene NZ, Wiley JL, Yu Z, Clowers BH and Craft RM
Humans typically self-administer cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) together repeatedly (as in cannabis, cannabis extract, or Sativex®) to relieve pain. It has been suggested that one benefit of the drug combination may be decreased tolerance development.
Medical Use of Cannabinoids
Fraguas-Sánchez AI and Torres-Suárez AI
Cannabinoid receptors, endocannabinoids and the enzymes responsible for their biosynthesis and degradation constitute the endocannabinoid system. In recent decades, the endocannabinoid system has attracted considerable interest as a potential therapeutic target in numerous pathological conditions. Its involvement in several physiological processes is well known, such as in energy balance, appetite stimulation, blood pressure, pain modulation, embryogenesis, nausea and vomiting control, memory, learning and immune response, among others, as well as in pathological conditions where it exerts a protective role in the development of certain disorders. As a result, it has been reported that changes in endocannabinoid levels may be related to neurological diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease and multiple sclerosis, as well as anorexia and irritable bowel syndrome. Alterations in the endocannabinoid system have also been associated with cancer, affecting the growth, migration and invasion of some tumours. Cannabinoids have been tested in several cancer types, including brain, breast and prostate cancers. Cannabinoids have shown promise as analgesics for the treatment of both inflammatory and neuropathic pain. There is also evidence for a role of the endocannabinoid system in the control of emotional states, and cannabinoids could prove useful in decreasing and palliating post-traumatic stress disorder symptoms and anxiolytic disorders. The role of the endocannabinoid system in addictions has also been examined, and cannabinoids have been postulated as alternative and co-adjuvant treatments in some abuse syndromes, mainly in ethanol and opioid abuses. The expression of the endocannabinoid system in the eye suggests that it could be a potential therapeutic target for eye diseases. Considering the importance of the endocannabinoid system and the therapeutic potential of cannabinoids in this vast number of medical conditions, several clinical studies with cannabinoid-based medications are ongoing. In addition, some cannabinoid-based medications have already been approved in various countries, including nabilone and dronabinol capsules for the treatment of nausea and vomiting associated with chemotherapy, dronabinol capsules for anorexia, an oral solution of dronabinol for both vomiting associated with chemotherapy and anorexia, a Δ-tetrahydrocannabinol/cannabidiol oromucosal spray for pain related to cancer and for spasticity and pain associated with multiple sclerosis, and an oral solution of cannabidiol for Dravet and Lennox-Gastaut syndromes. Here, we review the available efficacy, safety and tolerability data for cannabinoids in a range of medical conditions.
A UHPLC-MS/MS method for the quantification of Δ9-tetrahydrocannabinol and cannabidiol in decoctions and in plasma samples for therapeutic monitoring of medical cannabis
Barco S, Fucile C, Manfredini L, De Grandis E, Gherzi M, Martelli A, Tripodi G, Mattioli F and Cangemi G
Monitoring of blood levels of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is necessary for optimization of administration of medical cannabis. We describe the validation of a ultra-HPLC-MS/MS method for quantifying THC and CBD from plasma and decoctions and its application for therapeutic drug monitoring.Materials & methods: Analyses were performed by using a TSQ Quantiva™ Triple Quadrupole coupled to a Ultimate 3000 UHPLC system with atmospheric pressure chemical ionization after sample preparation with a straightforward method with deuterated internal standards.
Effect of Vaporized Cannabis on Exertional Breathlessness and Exercise Endurance in Advanced Chronic Obstructive Pulmonary Disease. A Randomized Controlled Trial
Abdallah SJ, Smith BM, Ware MA, Moore M, Li PZ, Bourbeau J and Jensen D
A series of studies conducted approximately 40 years ago demonstrated an acute bronchodilator effect of smoked cannabis in healthy adults and adults with asthma. However, the acute effects of vaporized cannabis on airway function in adults with advanced chronic obstructive pulmonary disease (COPD) remain unknown.
Report of Objective Clinical Responses of Cancer Patients to Pharmaceutical-grade Synthetic Cannabidiol
Kenyon J, Liu W and Dalgleish A
Cannabinoids are widely used in the management of pain, nausea and cachexia in cancer patients. However, there has been no objective clinical evidence of any anticancer activity yet. The aim of this study was to assess the effects of pharmaceutical-grade synthetic cannabidiol on a range of cancer patients.
Cannabinoid Delivery Systems for Pain and Inflammation Treatment
Bruni N, Della Pepa C, Oliaro-Bosso S, Pessione E, Gastaldi D and Dosio F
There is a growing body of evidence to suggest that cannabinoids are beneficial for a range of clinical conditions, including pain, inflammation, epilepsy, sleep disorders, the symptoms of multiple sclerosis, anorexia, schizophrenia and other conditions. The transformation of cannabinoids from herbal preparations into highly regulated prescription drugs is therefore progressing rapidly. The development of such drugs requires well-controlled clinical trials to be carried out in order to objectively establish therapeutic efficacy, dose ranges and safety. The low oral bioavailability of cannabinoids has led to feasible methods of administration, such as the transdermal route, intranasal administration and transmucosal adsorption, being proposed. The highly lipophilic nature of cannabinoids means that they are seen as suitable candidates for advanced nanosized drug delivery systems, which can be applied via a range of routes. Nanotechnology-based drug delivery strategies have flourished in several therapeutic fields in recent years and numerous drugs have reached the market. This review explores the most recent developments, from preclinical to advanced clinical trials, in the cannabinoid delivery field, and focuses particularly on pain and inflammation treatment. Likely future directions are also considered and reported.
Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor
Rodríguez-Muñoz M, Onetti Y, Cortés-Montero E, Garzón J and Sánchez-Blázquez P
Cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, exhibits therapeutic potential for various human diseases, including chronic neurodegenerative diseases, such as Alzheimer's and Parkinson's, ischemic stroke, epilepsy and other convulsive syndromes, neuropsychiatric disorders, neuropathic allodynia and certain types of cancer. CBD does not bind directly to endocannabinoid receptors 1 and 2, and despite research efforts, its specific targets remain to be fully identified. Notably, sigma 1 receptor (σ1R) antagonists inhibit glutamate N-methyl-D-aspartate acid receptor (NMDAR) activity and display positive effects on most of the aforesaid diseases. Thus, we investigated the effects of CBD on three animal models in which NMDAR overactivity plays a critical role: opioid analgesia attenuation, NMDA-induced convulsive syndrome and ischemic stroke. In an in vitro assay, CBD disrupted the regulatory association of σ1R with the NR1 subunit of NMDAR, an effect shared by σ1R antagonists, such as BD1063 and progesterone, and prevented by σ1R agonists, such as 4-IBP, PPCC and PRE084. The in vivo administration of CBD or BD1063 enhanced morphine-evoked supraspinal antinociception, alleviated NMDA-induced convulsive syndrome, and reduced the infarct size caused by permanent unilateral middle cerebral artery occlusion. These positive effects of CBD were reduced by the σ1R agonists PRE084 and PPCC, and absent in σ1R mice. Thus, CBD displays antagonist-like activity toward σ1R to reduce the negative effects of NMDAR overactivity in the abovementioned experimental situations.
Self-initiated use of topical cannabidiol oil for epidermolysis bullosa
Chelliah MP, Zinn Z, Khuu P and Teng JMC
Epidermolysis bullosa is a rare blistering skin disorder that is challenging to manage because skin fragility and repeated wound healing cause itching, pain, limited mobility, and recurrent infections. Cannabidiol, an active cannabinoid found in cannabis, is postulated to have antiinflammatory and analgesic effects. We report 3 cases of self-initiated topical cannabidiol use in patients with epidermolysis bullosa in an observational study. One patient was weaned completely off oral opioid analgesics. All 3 reported faster wound healing, less blistering, and amelioration of pain with cannabidiol use. Although these results demonstrate promise, further randomized, double-blind clinical trials are necessary to provide scientific evidence of our observed benefits of cannabidiol for the treatment of epidermolysis bullosa.
Plant-Based Cannabinoids for the Treatment of Chronic Neuropathic Pain
Casey SL and Vaughan CW
Chronic neuropathic pain is a prevalent condition that places a heavy burden on individuals and the healthcare system. Current medications have limitations and new approaches are needed, particularly given the current opioid crisis. There is some clinical evidence that the plant produces relief from neuropathic pain. However, current meta-analyses suggest that this efficacy is limited and there are problems with side effects. Most of this clinical research has examined whole cannabis, the psychoactive phytocannabinoid 9-tetrahydrocannabinol (THC), and nabiximols, which are a mixture of THC and the non-psychoactive phytocannabinoid cannabidiol. In the past, there has been little evidence based, preclinical animal research to guide clinical studies on phytocannabinoids. Recent animal studies indicate that while THC and high dose nabiximols are effective in animal neuropathic pain models, significant pain relief is only achieved at doses that produce substantial side effects. By contrast, cannabidiol and low dose nabiximols have moderate pain relieving efficacy, but are devoid of cannabinoid-like side effects. This animal data suggests that cannabidiol and low dose nabiximols warrant consideration for clinical studies, at least as adjuvants to current drugs. Preclinical research is also required to identify other phytocannabinoids that have therapeutic potential.
Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science
Baron EP
Comprehensive literature reviews of historical perspectives and evidence supporting cannabis/cannabinoids in the treatment of pain, including migraine and headache, with associated neurobiological mechanisms of pain modulation have been well described. Most of the existing literature reports on the cannabinoids Δ -tetrahydrocannabinol (THC) and cannabidiol (CBD), or cannabis in general. There are many cannabis strains that vary widely in the composition of cannabinoids, terpenes, flavonoids, and other compounds. These components work synergistically to produce wide variations in benefits, side effects, and strain characteristics. Knowledge of the individual medicinal properties of the cannabinoids, terpenes, and flavonoids is necessary to cross-breed strains to obtain optimal standardized synergistic compositions. This will enable targeting individual symptoms and/or diseases, including migraine, headache, and pain.
Pain Modulation after Oromucosal Cannabinoid Spray (SATIVEX) in Patients with Multiple Sclerosis: A Study with Quantitative Sensory Testing and Laser-Evoked Potentials
Turri M, Teatini F, Donato F, Zanette G, Tugnoli V, Deotto L, Bonetti B and Squintani G
Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) (nabiximols or Sativex) is an oromucosal spray formulation containing THC and CBD at an approximately 1:1 fixed ratio. Its administration for the treatment of pain in patients with multiple sclerosis (MS) has been established. MS patients generally complain of different kinds of pain, including spasticity-related and neuropathic pain. In this study, we compared and evaluated pain modulation and thermal/pain threshold of MS patients before and after THC/CBD administration. 19 MS patients underwent clinical examination, numerical rating scale (NRS), quantitative sensory testing (QST), and laser-evoked potentials (LEPs) before and after 1 month of therapy. Psychophysiological and neurophysiological data were compared to sex- and age-matched controls. Patients reported a significant reduction in pain. We found statistically significant differences in LEP parameters between patients and controls but no significant change in LEP measures after THC/CBD therapy. Cold and heat detection thresholds were altered in patients but did not change after THC/CBD therapy. There was a significant increase in cold pain threshold by hand stimulation and a significant reduction in abnormal cold perception thresholds. Our results indicate that Sativex therapy provides pain relief in MS patients and suggest that it might modulate peripheral cold-sensitive TRP channels.
Priority areas for cannabis and cannabinoid product research in South Africa
Augustine TN, Cairns CJ, Chetty S, Dannatt LG, Gravett N, Grey G, Grobler G, Jafta Z, Kamerman P, Lopes J, Matsabisa MG, Mugabo P, Mulder M, Parry C, Rataemane S, Siegfried N, Steenkamp V, Thomas E and Van Zyl-Smit R
No abstract available.
Cannabinoids for Treatment of MS Symptoms: State of the Evidence
Rice J and Cameron M
Cannabis and cannabinoids have been used medically and recreationally for thousands of years and recently there has been a growing body of research in this area. With increased access now that medical marijuana is available in many jurisdictions, patients and providers want to know more about the evidence for benefits and risks of cannabinoid use. This paper provides an overview of the available cannabinoid-based formulations, a summary of the highest quality evidence for the use of cannabinoids for treating spasticity and pain associated with multiple sclerosis (MS), and a discussion of possible dosing regimens based on information from these studies.
Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort
Baron EP, Lucas P, Eades J and Hogue O
Medicinal cannabis registries typically report pain as the most common reason for use. It would be clinically useful to identify patterns of cannabis treatment in migraine and headache, as compared to arthritis and chronic pain, and to analyze preferred cannabis strains, biochemical profiles, and prescription medication substitutions with cannabis.
Evidence for the use of "medical marijuana" in psychiatric and neurologic disorders
Noel C
Cannabis is listed as a Schedule I substance under the Controlled Substances Act of 1970, meaning the US federal government defines it as an illegal drug that has high potential for abuse and no established medical use; however, half of the states in the nation have enacted "medical marijuana" (MM) laws. Clinicians must be aware of the evidence for and against the use of MM in their patients who may consider using this substance.
Cannabinoids, Pain, and Opioid Use Reduction: The Importance of Distilling and Disseminating Existing Data
Hutchison KE, Hagerty SL, Galinkin J, Bryan AD and Bidwell LC
The high prevalence of chronic pain conditions combined with an over-reliance on opioid prescriptions has resulted in an opioid epidemic and a desperate need for solutions. There is some debate about whether cannabis might play a role in addressing chronic pain conditions as well as the opioid epidemic. Recent surveys suggest that a large number of people are using cannabis as a treatment for pain and to reduce use of opioids, and cannabis-derived products demonstrate at least modest efficacy in the treatment of pain in randomized controlled trials. In addition, surveillance studies from countries that have approved the use of Sativex, which is a cannabis-based product, have demonstrated that a combination of Δ9-tetrahydrocannabinol and cannabidiol has low potential for harm, is well tolerated, and is helpful to patients. Given the number of people in the United States who are already using cannabis to manage pain and opioid use in state-regulated markets, it is imperative to conduct additional research in these areas, and to disseminate information on how to minimize harm and maximize any benefits of using cannabinoids to mitigate pain and reduce opioid use. The purpose of this article is to call attention to the fact that cannabis is being used in the management of chronic pain. Thus, this article also provides a set of guidelines on how to approach using cannabis to treat pain.
L. and Nonpsychoactive Cannabinoids: Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer
Pellati F, Borgonetti V, Brighenti V, Biagi M, Benvenuti S and Corsi L
In the last decades, a lot of attention has been paid to the compounds present in medicinal L., such as Δ-tetrahydrocannabinol (Δ-THC) and cannabidiol (CBD), and their effects on inflammation and cancer-related pain. The National Cancer Institute (NCI) currently recognizes medicinal as an effective treatment for providing relief in a number of symptoms associated with cancer, including pain, loss of appetite, nausea and vomiting, and anxiety. Several studies have described CBD as a multitarget molecule, acting as an adaptogen, and as a modulator, in different ways, depending on the type and location of disequilibrium both in the brain and in the body, mainly interacting with specific receptor proteins CB and CB. CBD is present in both medicinal and fibre-type plants, but, unlike Δ-THC, it is completely nonpsychoactive. Fibre-type (hemp) differs from medicinal , since it contains only few levels of Δ-THC and high levels of CBD and related nonpsychoactive compounds. In recent years, a number of preclinical researches have been focused on the role of CBD as an anticancer molecule, suggesting CBD (and CBD-like molecules present in the hemp extract) as a possible candidate for future clinical trials. CBD has been found to possess antioxidant activity in many studies, thus suggesting a possible role in the prevention of both neurodegenerative and cardiovascular diseases. In animal models, CBD has been shown to inhibit the progression of several cancer types. Moreover, it has been found that coadministration of CBD and Δ-THC, followed by radiation therapy, causes an increase of autophagy and apoptosis in cancer cells. In addition, CBD is able to inhibit cell proliferation and to increase apoptosis in different types of cancer models. These activities seem to involve also alternative pathways, such as the interactions with TRPV and GRP55 receptor complexes. Moreover, the finding that the acidic precursor of CBD (cannabidiolic acid, CBDA) is able to inhibit the migration of breast cancer cells and to downregulate the proto-oncogene c-fos and the cyclooxygenase-2 (COX-2) highlights the possibility that CBDA might act on a common pathway of inflammation and cancer mechanisms, which might be responsible for its anticancer activity. In the light of all these findings, in this review we explore the effects and the molecular mechanisms of CBD on inflammation and cancer processes, highlighting also the role of minor cannabinoids and noncannabinoids constituents of Δ-THC deprived hemp.
A Cross-Sectional Study of Cannabidiol Users
Corroon J and Phillips JA
Preclinical and clinical studies suggest that cannabidiol (CBD) found in Cannabis spp. has broad therapeutic value. CBD products can currently be purchased online, over the counter and at Cannabis-specific dispensaries throughout most of the country, despite the fact that CBD is generally deemed a Schedule I controlled substance by the U.S. Drug Enforcement Administration and renounced as a dietary supplement ingredient by the U.S. Food and Drug Administration. Consumer demand for CBD is high and growing, but few studies have examined the reasons for increasing CBD use. A self-selected convenience sample (n = 2409) was recruited via an online survey designed to characterize whom, how, and why individuals are currently using CBD. The anonymous questionnaire was accessed from October 25, 2017 to January 25, 2018. Participants were recruited through social media. Almost 62% of CBD users reported using CBD to treat a medical condition. The top three medical conditions were pain, anxiety, and depression. Almost 36% of respondents reported that CBD treats their medical condition(s) "very well by itself," while only 4.3% reported "not very well." One out of every three users reported a nonserious adverse effect. The odds of using CBD to treat a medical condition were 1.44 (95% confidence interval, 1.16-1.79) times greater among nonregular users of Cannabis than among regular users. Consumers are using CBD as a specific therapy for multiple diverse medical conditions-particularly pain, anxiety, depression, and sleep disorders. These data provide a compelling rationale for further research to better understand the therapeutic potential of CBD.
Preclinical and Clinical Evidence Supporting Use of Cannabidiol in Psychiatry
Calapai G, Mannucci C, Chinou I, Cardia L, Calapai F, Sorbara EE, Firenzuoli B, Ricca V, Gensini GF and Firenzuoli F
Cannabidiol (CBD) is a major chemical compound present in . CBD is a nonpsychotomimetic substance, and it is considered one of the most promising candidates for the treatment of psychiatric disorders.
Cannabis Therapeutics and the Future of Neurology
Russo EB
Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes. While cannabis-based medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis (MS), and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges remain. This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: intractable epilepsy, brain tumors, Parkinson disease (PD), Alzheimer disease (AD) and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE). Current basic science and clinical investigations support the safety and efficacy of such interventions in treatment of these currently intractable conditions, that in some cases share pathological processes, and the plausibility of interventions that harness endocannabinoid mechanisms, whether mediated via direct activity on CB and CB (tetrahydrocannabinol, THC, caryophyllene), peroxisome proliferator-activated receptor-gamma (PPARγ; THCA), 5-HT (CBD, CBDA) or even nutritional approaches utilizing prebiotics and probiotics. The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment.
The Effects of Dosage-Controlled Cannabis Capsules on Cancer-Related Cachexia and Anorexia Syndrome in Advanced Cancer Patients: Pilot Study
Bar-Sela G, Zalman D, Semenysty V and Ballan E
Cancer-related cachexia and anorexia syndrome (CACS) is a common phenomenon in cancer patients. Cannabis has been suggested to stimulate appetite but research on this issue has yielded mixed results. The current study aimed to evaluate the effect of dosage-controlled cannabis capsules on CACS in advanced cancer patients. The cannabis capsules used in this study contained two fractions of oil-based compounds. The planned treatment was 2 × 10 mg per 24 hours for six months of tetrahydrocannabinol (THC) 9.5 mg and cannabidiol (CBD) 0.5 mg. If patients suffered from side effects, dosage was reduced to 5 mg × 2 per day (THC 4.75 mg, CBD 0.25 mg). Participants were weighed on every physician visit. The primary objective of the study was a weight gain of ≥10% from baseline. Of 24 patients who signed the consent form, 17 started the cannabis capsules treatment, but only 11 received the capsules for more than two weeks. Three of six patients who completed the study period met the primary end-point. The remaining three patients had stable weights. In quality of life quaternaries, patients reported less appetite loss after the cannabis treatment (=0.05). Tumor necrosis factor-α (TNF-α) levels decreased after the cannabis treatment but without statistical significance. According to patients' self-reports, improvement in appetite and mood as well as a reduction in pain and fatigue was demonstrated. Despite various limitations, this preliminary study demonstrated a weight increase of ≥10% in 3/17 (17.6%) patients with doses of 5mgx1 or 5mgx2 capsules daily, without significant side effects. The results justify a larger study with dosage-controlled cannabis capsules in CACS.
Aplicaciones terapéuticas por acción de los cannabinoides
Plancarte-Sánchez R, Mansilla-Olivares A, De Los Reyes-Pacheco VA and Meneses-González F
The interest on cannabinoids became evident between the 1940 and 1950 decades. Although the active substance of the plant was not known, a series of compounds with cannabinomimetic activity were synthesized, which were investigated in animals and clinically. The most widely tested was Δ6a, 10a-THC hexyl. Δ6a, 10a-THC dimethylheptyl (DMHP) antiepileptic effects were studied in several children, with positive results being obtained in some cases. DMHP differs from sinhexyl in that its side chain is DMHP instead of n-hexyl. The first cannabinoid isolated from Cannabis sativa was cannabinol, although its structure was correctly characterized several years later. Cannabidiol was isolated some years later and was subsequently characterized by Mechoulam and Shvo. In 2013, the National Academy of Medicine and the Faculty of Medicine of the National Autonomous University of Mexico, through the Seminar of Studies on Entirety, decided to carry out a systematic review on a subject that is both complex and controversial: the relationship between marijuana and health. In recent years, studies have been conducted with cannabis in several diseases: controlled clinical trials on spasticity in multiple sclerosis and spinal cord injury, chronic, essentially neuropathic, pain, movement disorders (Gilles de Latourette, dystonia, levodopa dyskinesia), asthma and glaucoma, as well as non-controlled clinical trials on Alzheimer's disease, neuroprotection, intractable hiccups, epilepsy, alcohol and opioid dependence and inflammatory processes.
Effectiveness and tolerability of THC:CBD oromucosal spray as add-on measure in patients with severe chronic pain: analysis of 12-week open-label real-world data provided by the German Pain e-Registry
Ueberall MA, Essner U and Mueller-Schwefe GH
To evaluate effectiveness, tolerability and safety of an oromucosal spray containing Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), as add-on treatment in patients with severe chronic pain (SCP). Exploratory analysis of anonymized 12-week routine/open-label data provided by the German Pain e-Registry (GPR) on adult SCP patients treated with THC:CBD oromucosal spray in 2017. Among those 30.228 cases documented in the GPR in 2017, 800 (2.6%; 57% female, mean ± SD age: 46.3±9.7 years) received a treatment with THC:CBD. All patients fulfilled the legislative preconditions for a treatment with cannabis as medicine as defined by the German Act Amending Narcotics and Other Regulations. THC:CBD-treatment was followed by an aggregated nine-factor symptom relief (ASR-9) improvement at end of week 12 vs baseline of 39.0±26.5% (95%-CI: 36.9-41.1, median: 42, range -41 to 85). A full ASR-9 response (ie, a 50%-improvement in all 9 factors) was found for 123 patients (15.4%), while 488 patients (56.0%) presented with an ≥50% improvement in at least 5 of 9 ASR factors. With a 54.9±17.2% (median: 56%, range: -6 to 85) improvement was significantly superior in the neuropathic pain subgroup (n=497, 62.1%) vs those with mixed (n=249, 31.1%; ASR-9: 18.2±12.0, median: 19, range: -12 to 42%) or nociceptive pain (n=54, 6.8%; ASR-9: -11.9±10.5, median: -11, range: -41% to 12%; <0.001 for each). 159 patients (19.9%) reported at least one of 206 TEAEs, most of them of mild intensity (n=81.6%). Most frequently reported TEAEs were increased appetite (n=50, 6.3%) and dysgeusia (n=23, 2.9%). TEAE-related discontinuations were reported for 32 patients (4.0%). 113 (14.1%) patients discontinued due to inadequate pain relief, most of them with nociceptive pain (n=40, 74.1%), least with neuropathic pain (n=1, 0.2%; <0.001). THC:CBD oromucosal spray proved to be an effective and well-tolerated add-on treatment for patients with elsewhere refractory chronic pain - especially of neuropathic origin.
Oral Cannabidiol Prevents Allodynia and Neurological Dysfunctions in a Mouse Model of Mild Traumatic Brain Injury
Belardo C, Iannotta M, Boccella S, Rubino RC, Ricciardi F, Infantino R, Pieretti G, Stella L, Paino S, Marabese I, Maisto R, Luongo L, Maione S and Guida F
Neurological dysfunctions are the most impactful and persistent consequences of traumatic brain injury (TBI). Indeed, previous reports suggest that an association between TBI and chronic pain syndromes, as well anxio-depressive behaviors, tends to be more common in patients with mild forms of TBI. At present, no effective treatment options are available for these symptoms. In the present study, we used a weight drop mild TBI mouse model to investigate the effect of a commercially available 10% Cannabidiol (CBD) oil on both the sensorial and neuropsychiatric dysfunctions associated with mild TBI through behavioral and biomolecular approaches. TBI mice developed chronic pain associated with anxious and aggressive behavior, followed by a late depressive-like behavior and impaired social interaction. Such behaviors were related with specific changes in neurotransmitters release at cortical levels. CBD oral treatment restored the behavioral alterations and partially normalized the cortical biochemical changes. In conclusion, our data show some of the brain modifications probably responsible for the behavioral phenotype associated with TBI and suggest the CBD as a pharmacological tool to improve neurological dysfunctions caused by the trauma.
Cannabinoids and spinal cord stimulation for the treatment of failed back surgery syndrome refractory pain
Mondello E, Quattrone D, Cardia L, Bova G, Mallamace R, Barbagallo AA, Mondello C, Mannucci C, Di Pietro M, Arcoraci V and Calapai G
This study aimed to evaluate pain and its symptoms in patients with failed back surgery syndrome (FBSS) refractory to other therapies, treated with a combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), in association with spinal cord stimulation (SCS).
Cannabinoid Ligands Targeting TRP Channels
Muller C, Morales P and Reggio PH
Transient receptor potential (TRP) channels are a group of membrane proteins involved in the transduction of a plethora of chemical and physical stimuli. These channels modulate ion entry, mediating a variety of neural signaling processes implicated in the sensation of temperature, pressure, and pH, as well as smell, taste, vision, and pain perception. Many diseases involve TRP channel dysfunction, including neuropathic pain, inflammation, and respiratory disorders. In the pursuit of new treatments for these disorders, it was discovered that cannabinoids can modulate a certain subset of TRP channels. The TRP vanilloid (TRPV), TRP ankyrin (TRPA), and TRP melastatin (TRPM) subfamilies were all found to contain channels that can be modulated by several endogenous, phytogenic, and synthetic cannabinoids. To date, six TRP channels from the three subfamilies mentioned above have been reported to mediate cannabinoid activity: TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8. The increasing data regarding cannabinoid interactions with these receptors has prompted some researchers to consider these TRP channels to be "ionotropic cannabinoid receptors." Although CB1 and CB2 are considered to be the canonical cannabinoid receptors, there is significant overlap between cannabinoids and ligands of TRP receptors. The first endogenous agonist of TRPV1 to be discovered was the endocannabinoid, anandamide (AEA). Similarly, arachidonyl dopamine (NADA) and AEA were the first endogenous TRPM8 antagonists discovered. Additionally, Δ-tetrahydrocannabinol (Δ-THC), the most abundant psychotropic compound in cannabis, acts most potently at TRPV2, moderately modulates TRPV3, TRPV4, TRPA1, and TRPM8, though Δ-THC is not reported to modulate TRPV1. Moreover, TRP receptors may modulate effects of synthetic cannabinoids used in research. One common research tool is WIN55,212-2, a CB1 agonist that also exerts analgesic effects by desensitizing TRPA1 and TRPV1. In this review article, we aim to provide an overview and classification of the cannabinoid ligands that have been reported to modulate TRP channels and their therapeutic potential.
US Veterinarians' Knowledge, Experience, and Perception Regarding the Use of Cannabidiol for Canine Medical Conditions
Kogan L, Schoenfeld-Tacher R, Hellyer P and Rishniw M
Due to the myriad of laws concerning cannabis, there is little empirical research regarding the veterinary use of cannabidiol (CBD). This study used the Veterinary Information Network (VIN) to gauge US veterinarians' knowledge level, views and experiences related to the use of in the medical treatment of dogs. Participants ( = 2130) completed an anonymous, online survey. Results were analyzed based on legal status of recreational marijuana in the participants' state of practice, and year of graduation from veterinary school. Participants felt comfortable in their knowledge of the differences between Δ9-tetrahydrocannabinol (THC) and marijuana, as well as the toxic effects of marijuana in dogs. Most veterinarians (61.5%) felt comfortable discussing the use of CBD with their colleagues, but only 45.5% felt comfortable discussing this topic with clients. No differences were found based on state of practice, but recent graduates were less comfortable discussing the topic. Veterinarians and clients in states with legalized recreational marijuana were more likely to talk about the use of CBD products to treat canine ailments than those in other states. Overall, CBD was most frequently discussed as a potential treatment for pain management, anxiety and seizures. Veterinarians practicing in states with legalized recreational marijuana were more likely to advise their clients and recommend the use of CBD, while there was no difference in the likelihood of prescribing CBD products. Recent veterinary graduates were less likely to recommend or prescribe CBD. The most commonly used CBD formulations were oil/extract and edibles. These were most helpful in providing analgesia for chronic and acute pain, relieving anxiety and decreasing seizure frequency/severity. The most commonly reported side-effect was sedation. Participants felt their state veterinary associations and veterinary boards did not provide sufficient guidance for them to practice within applicable laws. Recent graduates and those practicing in states with legalized recreational marijuana were more likely to agree that research regarding the use of CBD in dogs is needed. These same groups also felt that marijuana and CBD should not remain classified as Schedule I drugs. Most participants agreed that both marijuana and CBD products offer benefits for humans and expressed support for use of CBD products for animals.
Pharmacology of Medical Cannabis
Amin MR and Ali DW
The Cannabis plant has been used for many of years as a medicinal agent in the relief of pain and seizures. It contains approximately 540 natural compounds including more than 100 that have been identified as phytocannabinoids due to their shared chemical structure. The predominant psychotropic component is Δ-tetrahydrocannabinol (Δ-THC), while the major non-psychoactive ingredient is cannabidiol (CBD). These compounds have been shown to be partial agonists or antagonists at the prototypical cannabinoid receptors, CB1 and CB2. The therapeutic actions of Δ-THC and CBD include an ability to act as analgesics, anti-emetics, anti-inflammatory agents, anti-seizure compounds and as protective agents in neurodegeneration. However, there is a lack of well-controlled, double blind, randomized clinical trials to provide clarity on the efficacy of either Δ-THC or CBD as therapeutics. Moreover, the safety concerns regarding the unwanted side effects of Δ-THC as a psychoactive agent preclude its widespread use in the clinic. The legalization of cannabis for medicinal purposes and for recreational use in some regions will allow for much needed research on the pharmacokinetics and pharmocology of medical cannabis. This brief review focuses on the use of cannabis as a medicinal agent in the treatment of pain, epilepsy and neurodegenerative diseases. Despite the paucity of information, attention is paid to the mechanisms by which medical cannabis may act to relieve pain and seizures.
Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs
Gamble LJ, Boesch JM, Frye CW, Schwark WS, Mann S, Wolfe L, Brown H, Berthelsen ES and Wakshlag JJ
The objectives of this study were to determine basic oral pharmacokinetics, and assess safety and analgesic efficacy of a cannabidiol (CBD) based oil in dogs with osteoarthritis (OA). Single-dose pharmacokinetics was performed using two different doses of CBD enriched (2 and 8 mg/kg) oil. Thereafter, a randomized placebo-controlled, veterinarian, and owner blinded, cross-over study was conducted. Dogs received each of two treatments: CBD oil (2 mg/kg) or placebo oil every 12 h. Each treatment lasted for 4 weeks with a 2-week washout period. Baseline veterinary assessment and owner questionnaires were completed before initiating each treatment and at weeks 2 and 4. Hematology, serum chemistry and physical examinations were performed at each visit. A mixed model analysis, analyzing the change from enrollment baseline for all other time points was utilized for all variables of interest, with a ≤ 0.05 defined as significant. Pharmacokinetics revealed an elimination half-life of 4.2 h at both doses and no observable side effects. Clinically, canine brief pain inventory and Hudson activity scores showed a significant decrease in pain and increase in activity ( < 0.01) with CBD oil. Veterinary assessment showed decreased pain during CBD treatment ( < 0.02). No side effects were reported by owners, however, serum chemistry showed an increase in alkaline phosphatase during CBD treatment ( < 0.01). This pharmacokinetic and clinical study suggests that 2 mg/kg of CBD twice daily can help increase comfort and activity in dogs with OA.
Music-Enhanced Analgesia and Antiseizure Activities in Animal Models of Pain and Epilepsy: Toward Preclinical Studies Supporting Development of Digital Therapeutics and Their Combinations With Pharmaceutical Drugs
Metcalf CS, Huntsman M, Garcia G, Kochanski AK, Chikinda M, Watanabe E, Underwood T, Vanegas F, Smith MD, White HS and Bulaj G
Digital therapeutics (software as a medical device) and mobile health (mHealth) technologies offer a means to deliver behavioral, psychosocial, disease self-management and music-based interventions to improve therapy outcomes for chronic diseases, including pain and epilepsy. To explore new translational opportunities in developing digital therapeutics for neurological disorders, and their integration with pharmacotherapies, we examined analgesic and antiseizure effects of specific musical compositions in mouse models of pain and epilepsy. The music playlist was created based on the modular progression of Mozart compositions for which reduction of seizures and epileptiform discharges were previously reported in people with epilepsy. Our results indicated that music-treated mice exhibited significant analgesia and reduction of paw edema in the carrageenan model of inflammatory pain. Among analgesic drugs tested (ibuprofen, cannabidiol (CBD), levetiracetam, and the galanin analog NAX 5055), music intervention significantly decreased paw withdrawal latency difference in ibuprofen-treated mice and reduced paw edema in combination with CBD or NAX 5055. To the best of our knowledge, this is the first animal study on music-enhanced antinociceptive activity of analgesic drugs. In the plantar incision model of surgical pain, music-pretreated mice had significant reduction of mechanical allodynia. In the corneal kindling model of epilepsy, the cumulative seizure burden following kindling acquisition was lower in animals exposed to music. The music-treated group also exhibited significantly improved survival, warranting further research on music interventions for preventing Sudden Unexpected Death in Epilepsy (SUDEP). We propose a working model of how musical elements such as rhythm, sequences, phrases and punctuation found in K.448 and K.545 may exert responses via parasympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. Based on our findings, we discuss: (1) how enriched environment (EE) can serve as a preclinical surrogate for testing combinations of non-pharmacological modalities and drugs for the treatment of pain and other chronic diseases, and (2) a new paradigm for preclinical and clinical development of therapies leading to drug-device combination products for neurological disorders, depression and cancer. In summary, our present results encourage translational research on integrating non-pharmacological and pharmacological interventions for pain and epilepsy using digital therapeutics.
Quantification of Eight Cannabinoids Including Cannabidiol in Human Urine Via Liquid Chromatography Tandem Mass Spectrometry
Scheidweiler KB and Barnes AJ
Medical and recreational cannabis legalization has highlighted the importance of being able to identify recent cannabis use and impairment. Monitoring minor plant cannabinoids has been proposed to assist in identifying recent cannabis use. Additionally, cannabidiol (CBD) has been proposed for epilepsy, pain, inflammatory disorder, anxiety, and addiction treatment; therefore, monitoring CBD is of increasing clinical importance. However, few methods exist capable of monitoring extensive panels of traditional cannabinoid analytes and minor cannabinoids (including CBD). This chapter details a liquid chromatography tandem mass spectrometry method capable of measuring Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC, 11-nor-9-carboxy-THC, cannabinol, cannabigerol, tetrahydrocannabivarin (THCV), and its metabolite, 11-nor-9-carboxy-THCV, in urine.
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