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The National Institutes of Health (NIH) support of cannabinoid and cannabis research has increased over the past few years. Several NIH Institutes, Centers, and Offices (ICOs) have a growing interest in the therapeutic potential of cannabis, cannabinoids, and related compounds as well as their adverse effects on health and society. The National Center on Complementary (NCCIH) and Integrative Health (NCCIH) has become a focal point for research on the therapeutic potential of the heretofore understudied minor cannabinoids and terpenes found in cannabis for the management of pain. Also, NCCIH has become more actively involved in coordinating activities to stimulate new research programs and coordinating various cannabis-related activities across the NIH. This presentation will provide an update on the broad landscape of cannabis-related research at the NIH, summarize new areas of research interest and investment, including those of NCCIH, and describe a new multi-NIH ICO extramural program coordinating group to foster collaboration, share information, and expand and coordinate NIH cannabis and cannabinoid research activities. [ABSTRACT FROM AUTHOR]

Introduction: On the basis of both scientific progress and popular lore, there is growing optimism in the therapeutic potential of cannabis (marijuana) and cannabinoid-based chemicals for movement disorders. There is also notable skepticism regarding the scientific basis for this therapeutic optimism and significant concerns regarding the safety and regulation of cannabinoid products, particularly those available without prescription.Methods: In recognition of the high interest and controversial nature of this subject, the meeting committee of the International Parkinson and Movement Disorders Society arranged for a talk on cannabis at the 2019 annual meeting's Controversies in Movement Disorders plenary session. This paper summarizes the highlights of this session.Results: The endocannabinoid system is strongly tied to motor function and dysfunction, with basic research suggesting several promising therapeutic targets related to cannabinoids for movement disorders. Clinical research on cannabinoids for motor and nonmotor symptoms in Parkinson's disease, Huntington's disease, Tourette's syndrome, dystonia, and other movement disorders to date are promising at best and inconclusive or negative at worst. Research in other populations suggest efficacy for common symptoms like pain. While social campaigns against recreational cannabinoid use focus on cognitive changes in adolescents, the long-term sequelae of regulated medical use in older adults with movement disorders is unknown. The overall risks of cannabinoids may be similar to other commonly used medications and include falls and apathy.Conclusion: Further research is greatly needed to better understand the actual clinical benefits and long-term side effects of medical cannabis products for movement disorders indications and populations. [ABSTRACT FROM AUTHOR]

The phytocomplex of Cannabis is made up of approximately 500 substances: terpeno-phenols metabolites, including Δ-9-tetrahydrocannabinol and cannabidiol, exhibit pharmacological activity. Medical Cannabis has several pharmacological potential applications, in particular in the management of chronic and neuropathic pain. In the literature, a few data are available concerning cannabis pharmacokinetics, efficacy and safety. Thus, aim of the present study was the evaluation of cannabinoid pharmacokinetics in a cohort of patients, with chronic and neuropathic pain, treated with inhaled medical cannabis and decoction, as a galenic preparation. In this study, 67 patients were enrolled. Dried flower tops with different THC and CBD concentrations were used: Bedrocan® medical cannabis with THC level standardized at 19% and with a CBD level below 1%, Bediol® medical cannabis with THC and CBD level standardized at similar concentration of 6.5% and 8%, respectively. Cannabis was administered as a decoction in 47 patients and inhaled in 11 patients. The blood withdrawn was obtained before the new dose administration at the steady state and metabolites plasma concentrations were measured with an UHPLC-MS/MS method. Statistically significant differences were found in cannabinoids plasma exposure between inhaled and oral administration of medical cannabis , between male and female and cigarette smokers. For the first time, differences in cannabinoid metabolites exposures between different galenic formulations were suggested in patients. Therapeutic drug monitoring could be useful to allow for dose adjustment, but further studies in larger cohorts of patients are required in order to confirm these data. [Display omitted] • Cannabis shows different pharmacological applications, in particular in the management of pain. • Cannabinoids pharmacokinetics description in patients with chronic and neuropathic pain. • Differences in cannabinoids plasma exposure between route of administration. [ABSTRACT FROM AUTHOR]

In vivo solid-phase microextraction (SPME) is a minimally invasive, non-exhaustive sample-preparation technique that facilitates the direct isolation of low molecular weight compounds from biological matrices in living systems. This technique is especially useful for the analysis of phytocannabinoids (PCs) in plant material, both for forensic purposes and for monitoring the PC content in growing Cannabis spp. plants. In contrast to traditional extraction techniques, in vivo SPME enables continuous tracking of the changes in the level of PCs during plant growth without the need for plant material collection. In this study, in vivo SPME utilizing biocompatible C18 probes and liquid-chromatography coupled to quadrupole time-of flight mass spectrometry (LC-Q-TOF-MS) is proposed as a novel strategy for the extraction and analysis of the acidic forms of five PCs in growing medicinal cannabis plants. The SPME method was optimized by testing various parameters, including the extraction phase (coating), extraction and desorption times, and the extraction temperature. The proposed method was validated with satisfactory analytical performance regarding linearity (10–3000 ng/mL), limits of quantification, and precision (relative standard deviations below 5.5 %). The proposed method was then successfully applied for the isolation of five acidic forms of PCs, which are main components of growing medicinal cannabis plants. As a proof-of-concept, SPME probes were statically inserted into the inflorescences of two varieties of Cannabis spp. plants (i.e., CBD-dominant and Δ9-THC-dominant) cultivated under controlled conditions for 30 min extraction of tetrahydrocannabinolic acid (Δ9-THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabiviarinic acid (CBVA), and tetrahydrocannabivarinic acid (THCVA). The results confirmed that the developed SPME-LC-Q-TOF-MS method is a precise and efficient tool that enables direct and rapid isolation and analysis of PCs under in vivo conditions. The proposed methodology is highly appealing option for monitoring the metabolic pathways and compositions of multiple PCs in medicinal cannabis at different stages of plant growth. [Display omitted] • An analytical method to determine phytocannabinoids in Cannabis spp. is presented. • In vivo SPME allows direct isolation of acidic forms of phytocannabinoids from growing plants. • Precise tool for analysis of the composition of phytocannabinoids in in vivo conditions. • SPME-LC-Q-TOF-MS protocol for resolution and analysis of acidic forms of phytocannabinoids. • Monitoring of multiple phytocannabinoids at different stages of medicinal cannabis plant growth. [ABSTRACT FROM AUTHOR]

Conventional cannabis drying is time-consuming and energy intensive. A quick and dependable drying of cannabis is essential to ensure high-quality products to meet increasing demands. This study explored a combined microwave and infrared (MI) drying on cannabis comparing with control environmental (CE) drying. MI was very efficient with a short drying time of 16–200 min, high moisture diffusivity of 7.95×10−09-8.70×10−08 m2/s, and low energy consumption of 390.49–1611.42 kJ. The Page and Modified Page drying models fitted well to describe and predict the MI drying characteristics of cannabis. Microstructural images identified shrinkage in glandular trichomes of cannabis, whereas colorimetric assessment resulted in alteration of color attributes due to MI drying. It also facilitated the conversion of acidic cannabinoids to their neutral forms by decreasing tetrahydrocannabinolic acid (THCA) in g/g of dry matter from 20.15% to 7.57% and increasing tetrahydrocannabinol (THC) from 6.31% to 16.65% that insignificantly (p ≥0.05) affected the total THC level. MI drying resulted in a total terpenes concentration (%g/g of dry matters) of 0.541–0.730, insignificantly lower than CE drying (0.768). Overall, the study highlights MI as a rapid and energy-efficient drying for obtaining high quality cannabis, particularly for medicinal applications. [Display omitted] • The effects of microwave-infrared drying on medicinal cannabis were investigated. • Microwave-infrared drying was quite faster and saved 95.54–98.92% energy. • Scanning electron microscopy shows shrinkage and damage of cannabis trichomes. • Tetrahydrocannabinol content increased from 6.31% to 16.65%. • Total terpenes of dried samples were statistically similar but lower than fresh. [ABSTRACT FROM AUTHOR]

Cannabis sativa , widely known as 'Marijuana' poses a dilemma for being a blend of both good and bad medicinal effects. The historical use of Cannabis for both medicinal and recreational purposes suggests it to be a friendly plant. However, whether the misuse of Cannabis and the cannabinoids derived from it can hamper normal body physiology is a focus of ongoing research. On the one hand, there is enough evidence to suggest that misuse of marijuana can cause deleterious effects on various organs like the lungs, immune system, cardiovascular system, etc. and also influence fertility and cause teratogenic effects. However, on the other hand, marijuana has been found to offer a magical cure for anorexia, chronic pain, muscle spasticity, nausea, and disturbed sleep. Indeed, most recently, the United Nations has given its verdict in favour of Cannabis declaring it as a non-dangerous narcotic. This review provides insights into the various health effects of Cannabis and its specialized metabolites and indicates how wise steps can be taken to promote good use and prevent misuse of the metabolites derived from this plant. [ABSTRACT FROM AUTHOR]

Objectives: Although there is a growing body of evidence suggesting that cannabinoids may relieve symptoms of some illnesses, they are relatively high-cost therapies compared with illicit growth and supply. This article aimed to comprehensively review economic evaluations of medicinal cannabis for alleviating refractory symptoms associated with chronic conditions.Methods: Seven electronic databases were searched for articles published up to September 6, 2020. The quality of reporting of economic evaluations was assessed using the Consolidated Health Economic Evaluation Reporting Standards checklist. The extracted data were grouped into subcategories according to types of medical conditions, organized into tables, and reported narratively.Results: This review identified 12 cost-utility analyses conducted across a variety of diseases including multiple sclerosis (MS) (N = 8), pediatric drug-resistant epilepsies (N = 2), and chronic pain (N = 2). The incremental cost-effectiveness ratio varied widely from cost saving to more than US$451 800 per quality-adjusted life-year depending on the setting, perspectives, types of medicinal cannabis, and indications. Nabiximols is a cost-effective intervention for MS spasticity in multiple European settings. Cannabidiol was found to be a cost-effective for Dravet syndrome in a Canadian setting whereas a cost-utility analysis conducted in a US setting deemed cannabidiol to be not cost-effective for Lennox-Gastaut syndrome. Overall study quality was good, with publications meeting 70% to 100% (median 83%) of the Consolidated Health Economic Evaluation Reporting Standards checklist criteria.Conclusions: Medicinal cannabis-based products may be cost-effective treatment options for MS spasticity, Dravet syndrome, and neuropathic pain, although the literature is nascent. Well-designed clinical trials and health economic evaluations are needed to generate adequate clinical and cost-effectiveness evidence to assist in resource allocation. [ABSTRACT FROM AUTHOR]

The public and health care providers are increasingly curious about the potential medical benefits of Cannabis. In vitro and in vivo studies of Cannabis have suggested it has favorable effects on regulating pain, pruritus, and inflammation, making it a potentially attractive therapeutic agent for many dermatologic conditions. The body of literature reporting on the role of cannabinoids in dermatology is in its infancy but growing. We review the current research, possible cutaneous adverse effects, and future directions for cannabinoids and their use in skin cancer, acne, psoriasis, pruritus, dermatitis, scleroderma, dermatomyositis, cutaneous lupus erythematous, epidermolysis bullosa, pain, and wound healing. [ABSTRACT FROM AUTHOR]

Background: Several systematic reviews (SRs) have summarized the potential effectiveness of medical cannabinoids, but it is unclear to what extent safety-related outcomes were incorporated.Objective: The objective of this study was to evaluate the cardiovascular toxicity associated with medical use of cannabinoids.Methods: A 2-stage systematic review (SR) approach was undertaken to assess the current evidence on cannabinoid-associated cardiovascular events reported among randomized controlled trials (RCTs). First, we searched for SRs in multiple sources until June 2019. Second, RCTs identified from the SRs were included if they assessed medical cannabis and reported cardiovascular events. The outcomes of interest were all types of cardiovascular events. Data were extracted by 2 independent reviewers. Study quality was assessed using the Cochrane risk of bias. A statistical test of heterogeneity was performed. The summary risk ratios (RRs) and 95% CIs were calculated using a random-effects model.Results: A total of 47 studies involving 2800 patients were included. The median duration of cannabinoid use was 15.8 days (range 1 to 322), and 45% of the studies excluded patients with underlying cardiovascular diseases. Cannabinoid use was significantly associated with increased risks of orthostatic hypotension (RR 3.16 [95% CI 2.27-4.40], I2 = 2.3%) and hypotension (3.55 [1.45-8.71], I2 = 31.8%), with a trend of increased risk of tachycardia (1.94 [0.81-4.64], I2 = 48.6%). No study reported serious cardiovascular events.Conclusions: Cannabinoid use was associated with tachycardia, hypotension, and orthostatic hypotension. There is a paucity of data for other cardiovascular events among medical cannabis users. More data, especially regarding long-term effects among patients with existing cardiovascular diseases, are needed. [ABSTRACT FROM AUTHOR]

• A safety-focused approach is necessary in each step of patient's cannabis journey. • Prior to initiation, screen for precautions, contraindications & drug interactions. • Patient risk factors guides choice of chemovar and route of administration. • Initiate cannabis using a low dose, slow titration method. • Set monitoring frequency, and adjust for adverse events or medication changes. Medical cannabis use is increasing worldwide. Clinicians are commonly asked by patients to provide guidance on its safety and efficacy. Although there has been an increase in research on the role of medical cannabis for a number of different conditions, we found that there was a paucity of clear safety guidance on its use. We aim to address this issue by answering two pertinent clinician safety questions: 1 Can medical cannabis be safely used in this patient? 2. What strategies can be used to ensure that any harms from medical cannabis are mitigated? To address these questions, we reviewed available evidence and provided expert clinical opinion to summarize the fundamental components for evaluating medical cannabis safety and strategies to reduce risk from its use. Our review resulted in a safety-focused framework for medical cannabis initiation and utilization. We provide clear recommendations for patients being considered for cannabis (e.g. precautions, contraindications and drug interactions). Risk mitigation strategies such as appropriate chemovar (strain) selection, routes of administration, and dosing are reviewed. As with any other pharmacotherapy, we review the key components of monitoring and address potential issues that may arise while using medical cannabis. We propose a structured assessment and monitoring strategy that can be used by clinicians recommending cannabis (CRC) to guide patients through each step of their cannabis journey. This framework can be used to ensure that medical cannabis utilization is associated with the lowest possible risk to the patient. [ABSTRACT FROM AUTHOR]

[Display omitted] Marijuana, dried and ground Cannabis , is the most consumed illicit drug in the world. Many undesirable and risky effects to human health are caused by its use. The medicinal use or legal recreational use of Cannabis has also been rising in many countries. These facts make traceability methodologies increasingly important whether for forensic use, such as drug trafficking eradication, or for quality control purposes of legal medicinal Cannabis. Consequently, the objective of this study was to analyze Cannabis by means of thermogravimetric analysis (TGA) in order to assess the capability of this technique to trace the geographical origin of Cannabis cultivated in Colorado, United States of America. TGA appears to be sensitive enough to detect the degradation/decarboxylation of cannabinoids and terpenes, at least to some extent; also, the degradation of cellulose, hemicellulose and lignin was indicated. Overall, the temperature ranges we analyzed using linear discriminant analysis showed high accuracies, with the 200 to 300 °C and 600 to 700 °C ranges achieving 100% accuracy. [ABSTRACT FROM AUTHOR]

Adequate evidence exists in the literature indicating a relatively positive shift with regards to the legal acceptance of cannabis and cannabis-derived products for medicinal purposes in some countries. Concomitantly, scientists are showing renewed interest in cannabis-related research work. Over the years, clinical and preclinical studies have demonstrated the therapeutic significance of cannabinoids for diverse indications. Additionally, efforts are being made to develop cannabis-related products into acceptable prescription products. FDA authorization for the commercial use of four cannabinoid-derived products, available as oral dosage forms is a significant progress already. However, there are certain drawbacks associated with the conventional delivery forms of cannabinoids. These include low oral bioavailability due to hepatic degradation, gastric instability, poor water solubility, and the side effects experienced upon the use of high doses of psychotropic cannabinoids associated with heightened plasma concentrations of the drug. These are however, limitable with the aid of transcutaneous drug delivery. Emerging topical and transdermal strategies could be exploited for the successful development of highly effective delivery systems for cannabinoids. This review discusses the feasibility of delivering therapeutic cannabinoids via skin and provides a comprehensive account of the supporting research studies that have been reported in the literature till date. [Display omitted] • Cannabis research is gaining renewed interest given favorable policy changes. • Delivery via the transcutaneous route is quite promising for cannabinoids. • Decrease in psychotropic side effects is anticipated with topical delivery. • Oleic acid, and ethanol alone or in solvents identify as good chemical enhancers. • Ethosomes, nanocryogel are viable controlled release strategies for cannabinoids. • Potential of microneedles and other active strategies is under utilized. [ABSTRACT FROM AUTHOR]

• Cannabinoid profiles by mass spectrometry identify dronabinol vs cannabis users. • This mass spectrometry-based method measures 11 cannabinoids in urine. • Urine cannabinoids were evaluated in control, cannabis and dronabinol users. • Cannabigerol and cannabidiol had the greatest sensitivity in detecting cannabis use. Dronabinol is used to treat a variety of conditions, including loss of appetite in people with AIDS and severe nausea and vomiting caused by cancer chemotherapy. Its therapeutic potential for pain management is now being explored in specific populations. Monitoring dronabinol compliance is challenging because its active ingredient, Δ-9-tetrahydrocannabinol (THC), is also present in cannabis. We developed a rapid LC-MS/MS assay with minimal specimen preparation to quantitate 11 cannabinoids in urine. Using this assay coupled with urine samples from normal controls, cannabis, and dronabinol users, we show the ability to differentiate cannabis from dronabinol use. Residual clinical urine samples from 55 cannabinoid positive subjects and 31 negative controls, as well as prospective samples from 5 patients receiving dronabinol therapy were obtained for analysis. In the dronabinol group, only the THC metabolites 11-nor-9-carboxy-tetrahydrocannabinol (THC-COOH) and 11-hydroxy-Δ-9-tetrahydrocannabinol (THC-OH) were detected. Minor cannabinoids were detected in 91% of cannabis group samples and their detection was more frequent in samples with increased THC metabolite concentrations. Of minor cannabinoids evaluated, cannabigerol (CBG) and cannabidiol (CBD) had the greatest sensitivity in detecting cannabis use. This method has a high sensitivity for the detection of cannabis use with implications for evaluating dronabinol compliance. [ABSTRACT FROM AUTHOR]

Posttraumatic stress disorder (PTSD) is an often chronic condition for which currently available medications have limited efficacy. Medical cannabis is increasingly used to treat patients with PTSD; however, evidence for the efficacy and safety of cannabinoids is scarce. To learn more about patients' opinions on and experiences with medical cannabis, we organized a focus group discussion among military veterans (N = 7) with chronic PTSD who were treated with medical cannabis. Afterwards, some of their partners (N = 4) joined the group for an evaluation, during which they shared their perspective on their partner's use of medical cannabis. Both sessions were audio-recorded, transcribed verbatim, and analyzed by means of qualitative content analysis. Five overarching themes were identified. The first four themes related to the different phases of medical cannabis use – namely, 1) Consideration; 2) Initiation; 3) Usage; and 4) Discontinuation. The fifth theme related to several general aspects of medical cannabis use. Patients used medical cannabis to manage their symptoms and did not experience an urge to "get high." They used a variety of different cannabis strains and dosages and reported several therapeutic effects, including an increased quality of sleep. Furthermore, discussions about the experienced stigma surrounding cannabis generated insights with implications for the initiation of medical cannabis use. These results underscore the value of qualitative research in this field and are relevant for the design of future clinical trials on the use of medical cannabis for the treatment of PTSD. [ABSTRACT FROM AUTHOR]

Objective: To describe marijuana's clinical role for urologic symptoms.Methods: Studies related to marijuana, voiding dysfunction, lower urinary tract symptoms (LUTS), and pain through January 2019 from PubMed were evaluated for relevance and quality.Results: Forty-eight studies were reviewed. Cannabinoids have mixed efficacy for neurogenic LUTS and little evidence for non-neurogenic LUTS, chronic non-cancer-related and perioperative pain. For cancer-related pain, high-level studies demonstrate cannabinoids are well-tolerated with unclear benefit.Conclusion: Cannabinoids appear well-tolerated in the short-term, but their efficacy and long-term impact is unproven and unknown in urologic discomfort. Cannabinoids for urologic symptoms should be further explored with well-designed randomized controlled trials. [ABSTRACT FROM AUTHOR]

Medical marijuana is becoming widely available to patients in the United States, and with recreational marijuana now legalized in many states, patient interest is on the rise. The endocannabinoid system plays an important role in skin homeostasis in addition to broader effects on neurogenic responses such as pruritus and nociception, inflammation, and immune reactions. Numerous studies of in vitro and animal models have provided insight into the possible mechanisms of cannabinoid modulation on pruritus, with the most evidence behind neuronal modulation of peripheral itch fibers and centrally acting cannabinoid receptors. In addition, human studies, although limited due to differences in the cannabinoids used, disease models, and delivery method, have consistently shown significant reductions in both scratching and symptoms in chronic pruritus. Clinical studies have shown a reduction in pruritus in several dermatologic (atopic dermatitis, psoriasis, asteatotic eczema, prurigo nodularis, and allergic contact dermatitis) and systemic (uremic pruritus and cholestatic pruritus) diseases. These preliminary human studies warrant controlled trials to confirm the benefit of cannabinoids for treatment of pruritus and to standardize treatment regimens and indications. In patients who have refractory chronic pruritus after standard therapies, cannabinoid formulations may be considered as an adjuvant therapy where it is legal. [ABSTRACT FROM AUTHOR]

Objectives: To summarize the history and evolution of cannabis use and policies and to review current therapeutic uses, safety, and the central role pharmacists can play.Summary: Cannabis regulation and use have evolved over the centuries and are becoming more widely accepted, with over two-thirds of states in the United States having an approved cannabis program. However, changing policy and a paucity of controlled clinical trials has led to questions on the safety and effectiveness of cannabinoid therapies. Although there are conditions for which cannabinoids may be helpful, potential contraindications, adverse effects, and drug-drug interactions should be taken into account.Conclusion: Pharmacists are in a unique position based on their accessibility, knowledge, and skills to guide product selection, dosing, and discuss drug interactions and adverse effects to educate patients on safe cannabis use, whether it be delta-9-tetrahydrocannabinol, cannabidiol, or a combination thereof. Pharmacists and pharmacy organizations, moreover, should advocate for an integral role in the medical cannabis movement to ensure patient safety and evaluate cannabinoid pharmacology, pharmacokinetics, drug-drug interactions, safety, and efficacy through rigorous investigations. [ABSTRACT FROM AUTHOR]

In response to the Canadian federal government's Cannabis Tracking and Licensing System compliance standards, a quantitative method was created for cannabis analysis, and validated using Eurachem V.2 (2014) guidelines. Cannabinol, cannabidiol, cannabigerol, cannabichromene, cannabidiolic acid, cannabigerolic acid, Δ-9-tetrahydrocannabinol, and Δ-9-tetrahydrocannabinolic acid A were all analysed by scheduled multiple reaction monitoring (MRM) via LC-MS/MS and isotope dilution. In addition, aflatoxins B1, B2, G1, and G2 were also analysed by scheduled MRM via LC-MS/MS and matrix matched calibration curves in order to achieve the reporting limits (≤2 μg kg−1) set out by the European Pharmacopoeia. The LODs/LOQs were 0.50/1.7, 2.0/6.7, 0.59/2.0, and 0.53/1.8 μg kg−1, for B1, B2, G1, and G2 respectively. Thirty one terpenes were analysed by selected reaction monitoring via GC-MS/MS and isotope dilution using β-myrcene-d 6 as a surrogate. All quantitative analyses can be accomplished using less than 1 g of material, with minimal solvent and consumable use, on low resolution instruments in less than 30 min of instrument time. Of important note is this method's power of selectivity, working ranges, and lack of need for extraction consumables such as SPE or QuEChERS, thereby minimising analytical costs and time. Image 1 • Validated method developed for analyses of organic chemicals in cannabis. • Cannabinoids and aflatoxins measured by LC/MS/MS; terpenes by GC/MS/MS. • Matrix effects evident for cannabinoids; isotope dilution needed to ensure accuracy. • Method achieves the reporting limits (≤2 μg kg−1) for aflatoxins. • Extractions performed on <1 g material with minimal solvent consumption. [ABSTRACT FROM AUTHOR]

Several new antiepileptic medicines became available for clinical use in the last two decades. However, the prognosis of epilepsy remains unchanged, with approximately one-third of patients continuing to have drug-resistant seizures. Because many of these patients are not candidates for curative epilepsy surgery, there is a need for new seizure medicines with better efficacy and safety profile. Recently, social media and public pressure sparked a renewed interest in cannabinoids, which had been used for epilepsy since ancient times. However, physicians have significant difficulty prescribing cannabinoids freely because of the paucity of sound scientific studies. Among the two most common cannabinoids, cannabidiol has better antiepileptic potential than tetrahydrocannabinol. The exact antiepileptic mechanism of cannabidiol is currently not known, but it modulates a number of endogenous systems and may have a novel anticonvulsant effect. However, it has broad drug-drug interactions with several agents, including inducer and inhibitor of CYP3A4 or CYP2C19. Cannabidiol can cause liver enzyme elevation, especially when co-administered with valproate. The US Food and Drug Administration (FDA) has approved pharmaceutical-grade cannabidiol oil for two childhood-onset catastrophic epilepsies: Dravet syndrome and Lennox-Gastaut syndrome. The Drug Enforcement Agency also reclassified this product as a schedule V agent. However, other cannabidiol products remain as a schedule I substance and are primarily used without regulation. Additionally, the FDA-approved pharmaceutical-grade cannabidiol oil is expensive, and insurance companies might approve this only for the designated indications. In despair, many individuals may resort to unregulated medical cannabis products in an attempt to control seizures. Rather than spontaneous treatment without medical supervision, adequate medical oversight is indicated to monitor and manage the proper dose, side effects, validity of the product, and drug-drug interactions. [ABSTRACT FROM AUTHOR]

• In this Review Article we highlight recent progress in research on terpene metabolites in cannabis. • This includes highlighting issues related to claims of medicinal properties of cannabis terpenes. • We also highlight issues related to so-called 'strains' and the need to establish properly genotyped cannabis varieties for research and use in the industry. • We highlight areas that require future research, including expanded genotyping and genetic transformation. Cannabis sativa (cannabis) produces a resin that is valued for its psychoactive and medicinal properties. Despite being the foundation of a multi-billion dollar global industry, scientific knowledge and research on cannabis is lagging behind compared to other high-value crops. This is largely due to legal restrictions that have prevented many researchers from studying cannabis, its products, and their effects in humans. Cannabis resin contains hundreds of different terpene and cannabinoid metabolites. Many of these metabolites have not been conclusively identified. Our understanding of the genomic and biosynthetic systems of these metabolites in cannabis, and the factors that affect their variability, is rudimentary. As a consequence, there is concern about lack of consistency with regard to the terpene and cannabinoid composition of different cannabis 'strains'. Likewise, claims of some of the medicinal properties attributed to cannabis metabolites would benefit from thorough scientific validation. [ABSTRACT FROM AUTHOR]

Growing nonmedical use of prescription opioids is a global problem, motivating research on ways to reduce use and combat addiction. Medical cannabis ("medical marijuana") legalization has been associated epidemiologically with reduced opioid harms and cannabinoids have been shown to modulate effects of opioids in animal models. This study was conducted to determine if Δ9-tetrahydrocannabinol (THC) enhances the behavioral effects of oxycodone. Male rats were trained to intravenously self-administer (IVSA) oxycodone (0.15 mg/kg/infusion) during 1 h, 4 h or 8 h sessions. Following acquisition rats were exposed to THC by vapor inhalation (1 h and 8 h groups) or injection (0–10 mg/kg, i.p.; all groups) prior to IVSA sessions. Fewer oxycodone infusions were obtained by rats following vaporized or injected THC compared with vehicle treatment prior to the session. Follow-up studies demonstrated parallel dose-dependent effects of THC, i.p., on self-administration of different per-infusion doses of oxycodone and a preserved loading dose early in the session. These patterns are inconsistent with behavioral suppression. Additional groups of male and female Wistar rats were assessed for nociception following inhalation of vaporized THC (50 mg/mL), oxycodone (100 mg/mL) or the combination. Tail withdrawal latency was increased more by the THC/oxycodone combination compared to either drug alone. Similar additive antinociceptive effects were produced by injection of THC (5.0 mg/kg, i.p.) and oxycodone (2.0 mg/kg, s.c.). Together these data demonstrate additive effects of THC and oxycodone and suggest the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids. • Δ9-tetrahydrocannabinol (THC) enhances the antinociceptive effects of oxycodone. • Vaporized and injected THC reduces oxycodone self-administration. • Cannabinoids may reduce opioid use for analgesia. • Cannabinoids may reduce nonmedical opioid use. [ABSTRACT FROM AUTHOR]

Analysis of cannabis has gained new importance worldwide, mainly for quality control within the legalized recreational and medical cannabis industry, but also for forensic differentiation between drug-type cannabis and legal products such as fiber hemp and CBD-rich/THC-poor cannabis. We herein present an HPLC-DAD method for quantitative analysis of major neutral and acidic cannabinoids in herbal cannabis and hashish: Δ9-tetrahydrocannabinol (THC), Δ9-tetrahydrocannabinolic acid A (THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), and cannabinol (CBN). Plant material was dried, homogenized and extracted with a mixture of methanol/hexane. Chromatographic separation of the analytes was achieved on a core-shell C8 column using gradient elution with water/acetonitrile containing 0.1% formic acid. The analytical run time was 13 min and analytes were detected at 210 nm. The method is selective, sensitive, accurate, and precise, as confirmed through validation according to ICH and AOAC guidelines. Linearity in herbal cannabis ranged from 0.04 to 4.00% for the neutral cannabinoids, and from 0.40 to 20% for the acids. Linear ranges in hashish samples were 0.13-13.33% and 1.33-66.66%, respectively. The presented method was successfully applied to characterize 110 cannabis samples seized by the Swiss police, demonstrating its applicability for routine cannabis potency testing in the forensic setting. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Neuropathic pain is a debilitating form of treatment-resistant chronic pain caused by damage to the nervous system. Cannabinoids have been known for suppressing neuropathic pain by modulating the endo cannabinoid system. Since the canonical Wnt/ β -catenin signaling has recently been implicated in pain sensation, we investigated the impact of major cannabinoids (1 – 6) from the leaves of Cannabis sativa and an epoxy derivative of compound 2 , here upon referred to as 2a , on modulating Wnt/ β -catenin signaling pathway. The results presented in this study show that compound 1 , 2 and 2a exhibited potent inhibitory activity against Wnt/ β -catenin pathway in a dose-dependent manner. Compound 2a was seen to inhibit this pathway at slightly lower concentrations than its parent molecule 2 , under similar conditions. Taken together, compound 1 , 2 and 2a , by virtue of their inhibition of Wnt /β -catenin signaling pathway, could be developed as effective neuroprotective agents for the management of neuropathic pain. [ABSTRACT FROM AUTHOR]

Highlights • Safer and more effective anti-seizure therapies for CDD are urgently needed. • Cannabis has increasing support from both medical professionals and the public. • The anticonvulsant mechanism of cannabinoids is complex and not completely known. • The efficacy and safety data for cannabis based preparations in CDD is limited. • Cannabidiol likely reduces seizures among children with CDD. Abstract Severe paediatric epilepsies such as CDKL5 Deficiency Disorder (CDD) are extremely debilitating, largely due to the early-onset and refractory nature of the seizures. Existing treatment options are often ineffective and associated with a host of adverse effects, causing those that are affected to seek alternative treatments. Cannabis based products have attracted significant attention over recent years, primarily driven by reports of miraculous cures and a renewed public preference for 'natural' therapies, thus placing intense pressure on health professionals and the government for regulatory change. This study provides a comprehensive overview of the potential role for cannabis in the treatment of CDD. Key areas discussed include the history, mechanism of action, efficacy and safety of cannabis based preparations as well as the burden related to CDD. The evidence supports the use of cannabinoids, especially cannabidiol, in similar forms of refractory epilepsy including Dravet and Lennox–Gastaut syndromes. Evidence for cannabinoids specifically in CDD is limited but growing, with multiple anecdotal reports and an open-label trial showing cannabidiol to be associated with a significant reduction in seizure activity. This review provides the first comprehensive overview of the potential role for cannabis based preparations in the treatment of CDD and provides justification for further clinical and observational research. [ABSTRACT FROM AUTHOR]

Medical cannabis is becoming increasingly popular for many different ailments and improvement of general well-being. Particularly CBD-rich extracts are easily available via online pharmacies, health stores or directly from producers. However, almost all of the extracts contain small amounts of THC. Thus, in case of continuous or heavy use of CBD rich cannabis, THC concentrations in hair may rise above accepted legal limits. In our study, we investigated THC, CBN and CBD in hair samples from regular CBD rich cannabis users. The goals were to determine levels of the cannabinoids in hair and to evaluate a possible correlation between regular CBD intake and CBD levels in hair. All participants consumed cannabis extracts from the same producer. It contained CBD at different concentrations and small amounts of THC with a CBD/THC concentration ratio of 30. The self-declared CBD dosage ranged from 4 to 128mg CBD/day, corresponding to a daily THC intake of 0.1 to 4.3mg. After extraction and derivatization, hair samples were analysed using a validated GC/MS-MS method. CBD concentrations ranged from 10 to 325pg/mg of hair, but no significant correlation was observed between CBD concentrations and the daily dose. THC was detected in one sample only at a concentration below our cut-off, whereas CBN was not detected. In this study, we showed that even after repeated consumption of CBD-rich cannabis extracts in medium to high doses, consumers are generally tested negative for THC in hair. [ABSTRACT FROM AUTHOR]

There is little research examining perceptions of cannabis use risk to mental health in countries with differing cannabis regulations. This study therefore examines such perceptions among youth between 2017 and 2021 in Canada (non-medical cannabis legalized in October 2018), England (highly-restricted medical cannabis legalized November 2018), and the US (non-medical cannabis legal in some states). Seven repeat cross-sectional online surveys were conducted between July 2017 to August 2021 among youth aged 16–19 in Canada (N=29,420), England (N=28,155), and the US (N=32,974). Logistic regression models, stratified by country, were used to examine perceptions of cannabis use risk to mental health over time, adjusting for age group, sex, race/ethnicity, cannabis use and, for the US only, state-level cannabis legalization. Perceptions that cannabis use posed "no risk" to mental health decreased between July 2017 and August 2021 in Canada (6.1–4.4%; AOR=0.64, 95% CI=0.52–0.78) and the US (14.0–11.3%; AOR=0.74, 0.65–0.84) but not England (3.7–4.5%; AOR=1.21, 0.97–1.52). No significant changes were observed from immediately before (August 2018) to after (August 2019) legalization of non-medical cannabis in Canada (AOR=0.99, 0.83–1.20) or highly-restricted medical cannabis in England (AOR=0.90, 0.70–1.17). In the US, perceptions of "no risk" were more likely in states where cannabis use was illegal (15.0%) compared with legal non-medical (12.2%) (AOR=0.68, 0.63–0.74). There were modest decreases in perceptions that cannabis use poses no risk to mental health in Canada and the US between 2017 and 2021 but no clear association with cannabis legalization status. • Trends in youth's perceptions of cannabis use risk to mental health were explored. • Data were from three countries with differing cannabis policies: Canada, England, US. • 89,158 youth aged 16–19 years were surveyed between 2017 and 2021. • Perceptions that cannabis posed no risk to mental health decreased in Canada and US. • There was no clear association between risk perceptions and legalization status. [ABSTRACT FROM AUTHOR]

Since ancient times, Cannabis and its preparations have found various applications such as for medical, recreational and industrial purposes. Subsequently the 1930s, legislation in many countries has restricted its use due to its psychotropic properties. More recently, the discovery of endocannabinoid system, including new receptors, ligands, and mediators, its role in maintaining the homeostasis of the human body and the possible implication in various physiological and pathophysiological processes has also been understood. Based on this evidence, researchers were able to develop new therapeutic targets for the treatment of various pathological disorders. For this purpose, Cannabis and cannabinoids were subjected for the evaluation of their pharmacological activities. The renewed interest in the medical use of cannabis for its potential therapeutic application has prompted legislators to take action to regulate the safe use of cannabis and products containing cannabinoids. However, each country has an enormous heterogeneity in the regulation of laws. Here, we are pleased to show a general and prevailing overview of the findings regarding cannabinoids and the multiple research fields such as chemistry, phytochemistry, pharmacology and analytics in which they are involved. [Display omitted] • The role of endocannabinoid system in maintaining the homeostasis of the human body. • Endocannabinoid system implication in pathophysiological processes. • Endocannabinoid system as therapeutic targets for various pathological disorders. • Pharmacological activities evaluation of Cannabis and cannabinoids. • Medical use of cannabis and cannabinoids for potential therapeutic application. [ABSTRACT FROM AUTHOR]

Whole-plant medical cannabis (MC) products are widely used for controlling symptoms associated with Parkinson's disease (PD). Despite its widespread use, few studies have investigated the long-term impact of MC on the progression of PD or its safety profile. This study examined the effects of MC on PD in a real-life setting. A retrospective case-control study of 152 idiopathic PD patients (mean age 69.1 ± 9.0 years), followed at the Sheba Medical Center Movement Disorders Institute (SMDI) from 2008 to 2022 was conducted. Seventy-six patients who used licensed whole-plant medical cannabis (MC) for at least a year were compared to a matched group who did not receive MC in terms of their Levodopa Equivalent Daily Dose (LEDD), Hoehn and Yahr (H&Y) stage, and cognitive, depressive, and psychotic symptoms. The median monthly dose of MC was 20 g (IQR: 20–30), with a median Tetrahydrocannabinol (THC) percentage of 10 (IQR: 9.5–14.15) and a median Cannabidiol (CBD) percentage of 4 (IQR: 2–10). There were no significant differences between the MC and the control groups for LEDD or H&Y stage progression (p = 0.90, 0.77, respectively). A Kaplan-Meier analysis showed no evidence of relative worsening of psychotic, depressive, or cognitive symptoms reported by patients to their treating physicians over time in the MC group (p = 0.16–0.50). Over the 1–3 years of follow-ups, the MC treatment regimens appeared to be safe. MC did not exacerbate neuropsychiatric symptoms and had no detrimental effects on disease progression. [Display omitted] • Cannabis use in PD was not associated with increased self-reported depressive/cognitive symptoms. • No link between cannabis use in PD patients and higher reported psychotic events. • Cannabis use did not enhance annual Hoehn and Yahr progression in PD patients. • Cannabis use did not accelerate the annual levodopa equivalent daily dose increase. • The median cannabis dose for PD was 20 g/month with a 10/4 THC/CBD% ratio. [ABSTRACT FROM AUTHOR]

Medicinal and recreational Cannabis sativa is a sector that has exploded in popularity both in academia and industry due to the relaxation in legislation concerning the controlled substance. This business is currently valued at $37 billion in annual sales. As cultivation of cannabis increases, waste from this sector will increase, providing a challenge, with legislative constraints of Δ9-tetrahydrocannabinol, and opportunity in sustainable management of this waste. Research into the waste management of cannabis production waste is vital as sustainability of waste management is a pressing issue and will provide opportunities for businesses to make use of said waste. This paper will use databases such as Scopus, Web of Science and Google scholar to identify literature to review related to cannabis waste and cannabis waste management systems. It has been discovered that the majority of plant biomass waste is generated during the cultivation period, with growing media being a large contributor to waste generated. Currently there are four methods for appropriate cannabis waste management, that are landfilling, composting, incineration and anaerobic digestion. Although there is this current information available further research is required to determine the most efficient method of disposal and pre-treatments, or novel approaches, to improving valorisation of this waste. • Waste streams from medicinal cannabis manufacturing are discussed. • Legislative cannabis challenges grant valorisation opportunities. • Cannabis management include incineration, composting and anaerobic digestion. • Hydrothermal processing cannabis waste has valorisation potential. • Limited literature in cannabis waste management requires development. [ABSTRACT FROM AUTHOR]

A generic liquid chromatographic method development workflow was developed and successfully applied to the analysis of phytocannabinoids and Cannabis sativa extracts. Our method development procedure consists in four steps: i) The screening of primary parameters (i.e. stationary phase nature, organic modifier nature and approximate mobile phase pH) was carried out with a generic gradient on a short narrow bore column, using a system able to accommodate numerous solvents/buffers and columns. Instead of complete peak tracking, the number of peaks which can be separated was considered as a response at this level, to save time. ii) The optimization of secondary parameters (i.e. gradient conditions, mobile phase temperature and pH within a narrow range) requires only 12 initial experiments and the use of HPLC modeling software for data treatment. It allows to find out the best retention and selectivity for the selected compounds. Peak tracking was performed with a single quadruple mass detector in single ion recording mode, and UV detection (in a broad wavelength range). iii) The refinement step allows to further adjust column efficiency, by tuning column length and mobile phase flow rate. This can also be done virtually using HPLC modeling software. iv) The robustness testing step was also evaluated from a virtual experimental design. Success rate and regression coefficients were estimated in about 1 min, without the need to perform any real experiment. At the end, this method development workflow was performed in less than 4 days and minimizes the costs of the method development in liquid chromatography. [ABSTRACT FROM AUTHOR]

Background: The agreement between self-reported cannabis abstinence with urine cannabinoid concentrations in a clinical trials setting is not well characterized. We assessed the agreement between various cannabinoid cutoffs and self-reported abstinence across three clinical trials, one including contingency management for abstinence.Methods: Three cannabis cessation clinical trials where participants reported use and provided weekly urine samples for cannabis and creatinine concentration measurements were included. Bootstrapped data were assessed for agreement between self-reported 7+ day abstinence and urine cannabinoid tests using generalized linear mixed effects models for clustered binary outcomes. One study implemented contingency management for cannabis abstinence. Four hundred and seventy-three participants with 3787 valid urine specimens were included. Urine was analyzed for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol and creatinine using immunoassay methods Biological cutoffs of 50, 100, and 200 ng/ml, as well as changes in CN normalized THCCOOH (25%/50% decrease), were assessed for agreement with self-reported abstinence during the three clinical trials.Results: Agreement between measured THCCOOH and self-reported abstinence increases with increasing cutoff concentrations, while the agreement with self-reported non-abstinence decreases with increasing cutoff concentrations. Combining THCCOOH cutoffs with recent changes in CN-THCCOOH provides a better agreement in those self-reporting abstinence. Participants in the studies that received CM for abstinence had a lower agreement between self-reported abstinence and returned to use than those in studies that did not have a contingency management component.Conclusion: Using combinations of biological measurements and self-reported abstinence, confirmation of study related abstinence may be verifiable earlier and with greater accuracy than relying on a single measurement. [ABSTRACT FROM AUTHOR]

The National Academies of Sciences, Engineering and Medicine conducted a rapid turn-around comprehensive review of recent medical literature on The Health Effects of Cannabis and Cannabinoids . The 16-member committee adopted the key features of a systematic review process, conducting an extensive search of relevant databases and considered 10,000 recent abstracts to determine their relevance. Primacy was given to recently published systematic reviews and primary research that studied one of the committee's 11 prioritized health endpoints- therapeutic effects; cancer incidence; cardiometabolic risk; respiratory disease; immune function; injury and death; prenatal, perinatal and postnatal outcomes; psychosocial outcomes; mental health; problem Cannabis use; and Cannabis use and abuse of other substances. The committee developed standard language to categorize the weight of evidence regarding whether Cannabis or cannabinoids use for therapeutic purposes are an effective or ineffective treatment for the prioritized health endpoints of interest. In the Therapeutics chapter reviewed here, the report concluded that there was conclusive or substantial evidence that Cannabis or cannabinoids are effective for the treatment of pain in adults; chemotherapy-induced nausea and vomiting and spasticity associated with multiple sclerosis. Moderate evidence was found for secondary sleep disturbances. The evidence supporting improvement in appetite, Tourette syndrome, anxiety, posttraumatic stress disorder, cancer, irritable bowel syndrome, epilepsy and a variety of neurodegenerative disorders was described as limited, insufficient or absent. A chapter of the NASEM report enumerated multiple barriers to conducting research on Cannabis in the US that may explain the paucity of positive therapeutic benefits in the published literature to date. [ABSTRACT FROM AUTHOR]

In 1937, the United States of America criminalized the use of cannabis and as a result its use decreased rapidly. In recent decades, there is a growing interest in the wide range of medical uses of cannabis and its constituents; however, the laws and regulations are substantially different between countries. Laws differentiate between raw herbal cannabis, cannabis extracts, and cannabinoid-based medicines. Both the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) do not approve the use of herbal cannabis or its extracts. The FDA approved several cannabinoid-based medicines, so did 23 European countries and Canada. However, only four of the reviewed countries have fully authorized the medical use of herbal cannabis – Canada, Germany, Israel and the Netherlands, together with more than 50% of the states in the United States. Most of the regulators allow the physicians to decide what specific indications they will prescribe cannabis for, but some regulators dictate only specific indications. The aim of this article is to review the current (as of November 2017) regulations of medical cannabis use in Europe and North America. [ABSTRACT FROM AUTHOR]

Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised controlled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment. With the advent of pharmaceutical cannabis-based medicines (Sativex/nabiximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable. In this article, the authors endeavour to present concise data on cannabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30 mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance. CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks. Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities. [ABSTRACT FROM AUTHOR]

Outcomes 1. Identify indications for medical cannabis strongly or weakly supported by clinical evidence 2. Define the complexities of state and federal laws dictating the legality and availability of medical cannabinoids 3. Describe practical strategies for safely integrating medical cannabis into clinical practice Increasing numbers of patients living with serious illness are requesting access to medical cannabis and guidance about its use. Some palliative care clinics have incorporated cannabis into their therapeutic toolkit. Regardless of the legality of cannabis or clinician role in helping patients access medical cannabis where an individual clinician practices, all palliative clinicians will be asked questions about cannabis use in serious illness. Much is already known about the therapeutic benefits and limits of cannabinoids, and all palliative clinicians should be able to answer basic patient and family questions about cannabis/cannabinoid safety, side effects, and potential therapeutic benefits. In this session, outpatient palliative care providers who have incorporated cannabis as a therapeutic strategy in their clinics will address the evidence regarding cannabis and cannabinoids to treat pain, nausea, appetite, insomnia, mood, and other common symptoms in palliative care patients; review state and federal laws governing access to cannabis; and discuss practical advice approaches to counseling patients about the indications, contraindications, and safe use for medical cannabis in clinic. We will use an interactive "Jeopardy" game show approach to engage learners in this lively session. [ABSTRACT FROM AUTHOR]

Cannabinoid pharmacology has been intensely studied because of cannabis’ pervasive medicinal and non-medicinal uses as well as for the therapeutic potential of cannabinoid-based drugs for the treatment of pain, anxiety, substance abuse, obesity, cancer and neurodegenerative disorders. The identification of allosteric modulators of the cannabinoid receptor 1 (CB 1 ) has given a new direction to the development of cannabinoid-based therapeutics due to the many advantages offered by targeting allosteric site(s). Allosteric receptor modulators hold potential to develop subtype-specific and pathway-specific therapeutics. Here we briefly discuss the first-generation of allosteric modulators of CB 1 receptor, their structure-activity relationships, signaling pathways and the allosteric binding site(s) on the CB 1 receptor. This article is part of the Special Issue entitled “A New Dawn in Cannabinoid Neurobiology”. [ABSTRACT FROM AUTHOR]

Background: No effective pharmacotherapies exist for the treatment of crack cocaine use disorders. Emerging data suggests that cannabinoids may play a role in reducing cocaine-related craving symptoms. This study investigated the intentional use of cannabis to reduce crack use among people who use illicit drugs (PWUD).Methods: Data were drawn from three prospective cohorts of PWUD in Vancouver, Canada. Using data from participants reporting intentional cannabis use to control crack use, we used generalized linear mixed-effects modeling to estimate the independent effect of three pre-defined intentional cannabis use periods (i.e., before, during and after first reported intentional use to reduce crack use) on frequency of crack use.Results: Between 2012 and 2015, 122 participants reported using cannabis to reduce crack use, contributing a total of 620 observations. In adjusted analyses, compared to before periods, after periods were associated with reduced frequency of crack use (Adjusted Odds Ratio [AOR]=1.89, 95% Confidence Interval [CI]: 1.02-3.45), but not the intentional use periods (AOR=0.85, 95% CI: 0.51-1.41). Frequency of cannabis use in after periods was higher than in before periods (AOR=4.72, 95% CI: 2.47-8.99), and showed a tendency to lower frequency than in intentional cannabis use periods (AOR=0.56, 95% CI: 0.32-1.01).Conclusions: A period of intentional cannabis use to reduce crack use was associated with decreased frequency of crack use in subsequent periods among PWUD. Further clinical research to assess the potential of cannabinoids for the treatment of crack use disorders is warranted. [ABSTRACT FROM AUTHOR]

The endocannabinoid system has evolved as a key regulator in several pathological and physiological processes, including placentation, decidualization and implantation. In addition, it is known that Cannabis and cannabinoids negatively affect female reproduction. Although, the biological action of synthetic cannabinoids, such as WIN-55,212, in human fertility and pregnancy outcome remain to be unveiled. A tight balance between proliferation, differentiation and apoptosis of trophoblast cells is required for placental development and pregnancy outcome. Therefore, in this work, the effects of the synthetic cannabinoid WIN-55,212 in placental cytotrophoblast cells were explored. For that, it was used a human choriocarcinoma cell line, BeWo cells, and primary cultures of human cytotrophoblasts isolated from term placentas. Results demonstrate that this synthetic cannabinoid induces cell cycle arrest. We also observed that cell viability loss was associated with a disruption of mitochondrial membrane potential and activation of caspases -9 and -3/-7 independently of reactive oxygen species (ROS) production or recruitment of the endoplasmic reticulum stress marker CHOP . Moreover, these effects were prevented by pre-incubation with a selective cannabinoid receptor 1 (CBR1) antagonist (AM281). Thus, our results provide strong evidences of the apoptotic process induced by WIN-55,212 through the activation of the CBR1, which may reveal the impact of cannabinoids consumption during placental development. [ABSTRACT FROM AUTHOR]

Cannabis and cannabinoids are known to affect female reproduction. However, the role of the endocannabinoid system in mouse uterine contractility in the dioestrus and oestrus phases has not been previously investigated. The present study aimed at filling this gap. Endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were measured in mouse uterus at dioestrus and oestrus phases by liquid chromatography-mass spectrometry; quantitative reverse transcription-PCR and western blot were used to measured the expression of cannabinoid receptors and enzymes involved in the metabolism of endocannabinoids. Contractility was evaluated in vitro either on the spontaneous contractions or by stimulating the isolated uterus with exogenous spasmogens. The tissue concentrations of anandamide and 2-AG were reduced in the oestrus phase, compared to dioestrus. Uteri obtained in the dioestrus, but not oestrus, phase showed spontaneous phasic prostaglandin-mediated contractions that were reduced by ACEA (CB 1 receptor agonist) and to a lower extent by JWH133 (CB 2 receptor agonist). These inhibitory effects were counteracted by the corresponding selective antagonists. Neither ACEA nor JWH133 did affect the contractions induced by exogenous PGE 2 in the uterus from the oestrus phase. The FAAH inhibitor JNJ1661010 and, to a lower extent, the MAGL inhibitor JZL184 also reduced spontaneous contractions. It is concluded that the endocannabinoid system undergoes to adaptive changes between the oestrus and dioestrus phases. CB 1 and, to a lower extent, CB 2 receptor activation results in selective inhibition of myometrial contractility, without un-specific relaxing effects on the smooth muscle. These results might be of interest for female marijuana smokers as well as for the design of novel tocolytic agents. [ABSTRACT FROM AUTHOR]

Traffic policies show growing concerns about driving under the influence of cannabis, since cannabinoids are one of the most frequently encountered psychoactive substances in the blood of drivers who are drug-impaired and/or involved in accidents, and in the context of a legalization of medical marijuana and of recreational use. The neurobiological mechanisms underlying the effects of cannabis on safe driving remain poorly understood. In order to better understand its acute and long-term effects on psychomotor functions involved in the short term ability and long-term fitness to drive, experimental research has been conducted based on laboratory, simulator or on-road studies, as well as on structural and functional brain imaging. Results presented in this review show a cannabis-induced impairment of actual driving performance by increasing lane weaving and mean distance headway to the preceding vehicle. Acute and long-term dose-dependent impairments of specific cognitive functions and psychomotor abilities were also noted, extending beyond a few weeks after the cessation of use. Some discrepancies found between these studies could be explained by factors such as history of cannabis use, routes of administration, dose ranges, or study designs (e.g. treatment blinding). Moreover, use of both alcohol and cannabis has been shown to lead to greater odds of making an error than use of either alcohol or cannabis alone. Although the correlation between blood or oral fluid concentrations and psychoactive effects of THC needs a better understanding, blood sampling has been shown to be the most effective way to evaluate the level of impairment of drivers under the influence of cannabis. The blood tests have also shown to be useful to highlight a chronic use of cannabis that suggests an addiction and therefore a long-term unfitness to drive. Besides blood, hair and repeated urine analyses are useful to confirm abstinence. [ABSTRACT FROM AUTHOR]

Cannabis sativa L. is used to treat a wide variety of medical conditions, in light of its beneficial pharmacological properties of its cannabinoids and terpenes. At present, the quantitative chemical analysis of these active compounds is achieved through the use of laborious, expensive, and time-consuming technologies, such as high-pressure liquid-chromatography- photodiode arrays, mass spectrometer detectors (HPLC-PDA or MS), or gas chromatography-mass spectroscopy (GC-MS). Hence, we aimed to develop a simple, accurate, fast, and cheap technique for the quantification of major cannabinoids and terpenes using Fourier transform near infra-red spectroscopy (FT-NIRS). FT-NIRS was coupled with multivariate classification and regression models, namely partial least square-discriminant analysis (PLS-DA) and partial least squares regression (PLS-R) models. The PLS-DA model yielded an absolute major class separation (high-THC, high-CBD, hybrid, and high-CBG) and perfect class prediction. Using only three latent variables (LVs), the cross-validation and prediction model errors indicated a low probability of over-fitting the data. In addition, the PLS-DA model enabled the classification of chemovars with genetic-chemical similarities. The classification of high-THCA chemovars was more sensitive and more specific than the classifications of the remaining chemovars. The prediction of cannabinoid and terpene concentrations by PLS-R yielded 11 robust models with high predictive capabilities (R 2 CV and R 2 pred > 0.8, RPD >2.5 and RPIQ >3, RMSECV/RMSEC ratio <1.2) and additional 15 models whose performance was acceptable for initial screening purposes (R 2 CV > 0.7 and R 2 pred < 0.8, RPD >2 and RPIQ <3, 1.2 < RMSECV/RMSEC ratio <2). Our results confirm that there is sufficient information in the FT-NIRS to develop cannabinoid and terpene prediction models and major-cultivar classification models. Dried and homogenously ground cannabis inflorescence samples were directly analyzed using NIR spectrometer and then extracted with ethanol for the determination of cannabinoids and terpenes using HPLC-PDA and GC-MS, respectively. Finally, NIR spectra and the chemical composition of the samples were used to build PLS-R and PLS-DA models. [Display omitted] • FT-NIR based PLS-R model enables accurate quantification of cannabinoid and terpene. • FT-NIR based PLS-DA model enables accurate classification of cannabis chemovars. • FT-NIR has been proven as a promising fast alternative to chromatographic analysis. [ABSTRACT FROM AUTHOR]

In the last few years, there has been a boost in the use of cannabis-based extracts for medicinal purposes, although their preparation procedure has not been standardized but rather decided by the individual pharmacists. The present work describes the development of a simple and rapid high performance liquid chromatography method with UV detection (HPLC-UV) for the qualitative and quantitative determination of the principal cannabinoids (CBD-A, CBD, CBN, THC and THC-A) that could be applied to all cannabis-based medicinal extracts (CMEs) and easily performed by a pharmacist. In order to evaluate the identity and purity of the analytes, a high-resolution mass spectrometry (HPLC-ESI-QTOF) analysis was also carried out. Full method validation has been performed in terms of specificity, selectivity, linearity, recovery, dilution integrity and thermal stability. Moreover, the influence of the solvent (ethyl alcohol and olive oil) was evaluated on cannabinoids degradation rate. An alternative extraction method has then been proposed in order to preserve cannabis monoterpene component in final CMEs. [ABSTRACT FROM AUTHOR]

The article focuses on the medical use of marijuana or cannabis for pain management. Topics discussed include the specific actions and psychoactive effects of phytocannabinoids, delta-9 tetrahydrocannabinol (THC), and cannabidiol (CBD), the individualised dosing of whole-plant cannabis extracts, and the adverse events from medical or recreational use of cannabis.

Unlabelled: Since 2013 in the Italian market has been introduced the Nabiximols, a drug containing two of the main active cannabinoids: Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and cannabidiol (CBD). This drug has been approved in Italy in the treatment of Multiple Sclerosis (MS). It is an oral spray formulation and each puff of 100μl contains 2.7mg of Δ(9)-THC and 2.5mg of CBD. In the present study we analyzed urine and blood samples collected from a group of 20 patients treated with Nabiximols in order to evaluate: blood Δ(9)-THC concentrations in relation to the dose administered and the duration of treatment and the potentiality of this medication to be used for drug habit.Methods: The study was conducted on a sample group of patients affected by MS, of both sexes, age: 49-61 years, treated with Nabiximols for short (28 days) or long-term. The results of our study allow affirming that it is unlikely to use this medication for drug habit or to sale it in the black market because of the low blood concentrations available and of its high costs. These statements were confirmed by: (a) the low Δ(9)-THC concentrations in the pharmaceutical formulation; (b) the low blood concentrations produced by Nabiximols administration, more than 10 times smaller than the blood concentrations known to produce psychotropic effects; (c) the presence of CBD (Δ(9)-THC natural antagonist); (d) the route of administration (inhaled, not smoked). [ABSTRACT FROM AUTHOR]

Plants have been the predominant source of medicines throughout the vast majority of human history, and remain so today outside of industrialized societies. One of the most versatile in terms of its phytochemistry is cannabis, whose investigation has led directly to the discovery of a unique and widespread homeostatic physiological regulator, the endocannabinoid system. While it had been the conventional wisdom until recently that only cannabis harbored active agents affecting the endocannabinoid system, in recent decades the search has widened and identified numerous additional plants whose components stimulate, antagonize, or modulate different aspects of this system. These include common foodstuffs, herbs, spices, and more exotic ingredients: kava, chocolate, black pepper, and many others that are examined in this review. [ABSTRACT FROM AUTHOR]

Background Drugs that induce psychosis may do so by increasing the level of task-irrelevant random neural activity or neural noise. Increased levels of neural noise have been demonstrated in psychotic disorders. We tested the hypothesis that neural noise could also be involved in the psychotomimetic effects of delta-9-tetrahydrocannabinol (Δ 9 -THC), the principal active constituent of cannabis. Methods Neural noise was indexed by measuring the level of randomness in the electroencephalogram during the prestimulus baseline period of an oddball task using Lempel-Ziv complexity, a nonlinear measure of signal randomness. The acute, dose-related effects of Δ 9 -THC on Lempel-Ziv complexity and signal power were studied in humans ( n = 24) who completed 3 test days during which they received intravenous Δ 9 -THC (placebo, .015 and .03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design. Results Δ 9 -THC increased neural noise in a dose-related manner. Furthermore, there was a strong positive relationship between neural noise and the psychosis-like positive and disorganization symptoms induced by Δ 9 -THC, which was independent of total signal power. Instead, there was no relationship between noise and negative-like symptoms. In addition, Δ 9 -THC reduced total signal power during both active drug conditions compared with placebo, but no relationship was detected between signal power and psychosis-like symptoms. Conclusions At doses that produced psychosis-like effects, Δ 9 -THC increased neural noise in humans in a dose-dependent manner. Furthermore, increases in neural noise were related with increases in Δ 9 -THC-induced psychosis-like symptoms but not negative-like symptoms. These findings suggest that increases in neural noise may contribute to the psychotomimetic effects of Δ 9 -THC. [ABSTRACT FROM AUTHOR]

Introduction Individuals report using cannabis for the promotion of sleep, and the effects of cannabis on sleep may vary by cannabis species. Little research has documented preferences for particular cannabis types or cannabinoid concentrations as a function of use for sleep disturbances. Methods 163 adults purchasing medical cannabis for a physical or mental health condition at a cannabis dispensary were recruited. They provided self-report of (a) whether cannabis use was intended to help with sleep problems (e.g. insomnia, nightmares), (b) sleep quality (PSQI), (c) cannabis use (including preferred type), and (d) symptoms of DSM-5 cannabis dependence. Results 81 participants reported using cannabis for the management of insomnia and 14 participants reported using cannabis to reduce nightmares. Individuals using cannabis to manage nightmares preferred sativa to indica strains (Fisher's exact test (2) = 6.83, p < 0.05), and sativa users were less likely to endorse DSM-5 cannabis dependence compared with those who preferred indica strains (χ 2 (2) = 4.09, p < 0.05). Individuals with current insomnia ( t (9) = 3.30, p < 0.01) and greater sleep latency ( F (3,6) = 46.7, p < 0.001) were more likely to report using strains of cannabis with significantly higher concentrations of CBD. Individuals who reported at least weekly use of hypnotic medications used cannabis with lower THC concentrations compared to those who used sleep medications less frequently than weekly ( t (17) = 2.40, p < 0.05). Conclusions Associations between sleep characteristics and the type of cannabis used were observed in this convenience sample of individuals using cannabis for the management of sleep disturbances. Controlled prospective studies are needed to better characterize the impact that specific components of cannabis have on sleep. [ABSTRACT FROM AUTHOR]

Recently, several countries approved the use of cannabis flowering tops with standardized amount of ∆9-tetrahydrocannabinol (THC), cannabidiol (CBD) to treat several diseases. Therapeutic monitoring of medical cannabis products administered to patients for the established pathologies is rarely carried out. Previous few investigations have been developed in conventional matrices like blood and urine. This is the first study involving hair analysis of THC, CBD and their metabolites in patients treated with medical cannabis. An ultra-high-performance liquid chromatography-tandem mass spectrometry method to quantify THC, CBD, and metabolites, i.e., 11-nor-9-carboxy-THC (THC-COOH), 11-hydroxy-THC (11-OH-THC) cannabidiol-7-oic acid (7-COOH-CBD), 7-hydroxycannabidiol (7-OH-CBD), 6-α-hydroxycannabidiol (6-α-OH-CBD) and 6-β-hydroxycannabidiol (6-β-OH-CBD) in hair samples was developed and fully validated. The validation results indicated that the method was accurate (average inter/intra-day error, <10%), precise (inter/intra-day imprecision, <10%), and fast (10 min run time). Average hair concentrations in four patients treated with different formulations of medical cannabis were 2.75 ng/mg THC, 2.87 ng/mg 11-OH-THC, and 0.32 ng/mg THC-COOH (n = 3); 1.65 ng/mg CBD, 2.73 ng/mg 7-OH-CBD, 1.29 ng/mg 7-COOH-CBD, 0.35 ng/mg 6-α-OH-CBD, and 0.03 ng/mg 6-β-OH-CBD. The proposed method proved suitable for a fast and sensitive determination of all target compounds allowing high throughput testing in individuals monitored for medical cannabis treatments. • We report the most comprehensive method to quantify THC, CBD and metabolites in hair. • The method is simple and fast, allowing high-throughput analyses. • Suitable for quantifying cannabinoids in hair from patients under medical cannabis treatment. [ABSTRACT FROM AUTHOR]

Cannabis is used to treat various medical conditions, and lines are commonly classified according to their total concentrations of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Based on their ratio of total THC to total CBD, cannabis cultivars are commonly classified into high-THC, high-CBD, and hybrid classes. While cultivars from the same class have similar compositions of major cannabinoids, their levels of other cannabinoids and their terpene compositions may differ substantially. Therefore, a more comprehensive and accurate classification of medicinal cannabis cultivars, based on a large number of cannabinoids and terpenes is needed. For this purpose, three different chemometric-based classification models were constructed using three sets of chemical profiles. We examined those models to determine which provides the most accurate "chemovar" classification. This was done by analyzing profiles of cannabinoids, terpenes, and the combination of these substances using the partial least square-discriminant analysis multivariate (PLS-DA) technique. The chemical profiles were selected from the three major classes of medicinal cannabis that are most commonly prescribed to patients in Israel: high-THC, high-cannabigerol (CBG), and hybrid. We studied the correlations between cannabinoids and terpenes to identify major bio-indicators representing the plant's terpene and cannabinoid content. All three PLS-DA models provided highly accurate classifications, utilizing six to nine latent variables with an overall accuracy ranging from 2 to 11% CV. The PLS-DA model applied to the combined cannabinoid-and-terpene profile did the best job of differentiating between the chemovars in terms of misclassification error, sensitivity, specificity, and accuracy. The combined cannabinoid-and-terpene PLS-DA profile had cross-validation and prediction misclassification errors of 4% and 0%, respectively. This is the first study to demonstrate the highly accurate classification of samples of medicinal cannabis based on their cannabinoid and terpene profiles, as compared to cannabinoid profiles alone. Furthermore, our correlation analysis indicated that 11 cannabinoids and terpenes might serve as bio-indicators for 32 different active compounds. These findings suggest that the use of multivariate statistics could assist in breeding studies and serve as a tool for minimizing the mislabeling of cannabis inflorescences. [Display omitted] • Classification of major cannabis classes was good for all data sets. • Terpene-cannabinoid–based PLS-DA provided the best chemovar classification. • Eleven potential bio-indicators predicted 32 cannabinoids and terpenes. [ABSTRACT FROM AUTHOR]

Despite the lack of clinical research, marijuana and synthetic cannabinoids have been approved to treat posttraumatic stress disorder (PTSD) in several states in the United States. This review critically examines preclinical research on the endocannabinoid system (ECS) in order to evaluate three key questions that are relevant to PTSD: (1) Does ECS dysfunction impact fear extinction? (2) Can stress-related symptoms be prevented by ECS modulation? (3) Is the ECS a potential target for enhancing PTSD treatment? Disruption of the ECS impaired fear extinction in rodents, and ECS abnormalities have been observed in PTSD. Targeting fear memories via the ECS had mixed results in rodents, whereas augmented cannabinoid receptor activation typically facilitated extinction. However, the translational value of these findings is limited by the paucity and inconsistency of human research. Further investigation is necessary to determine whether incorporating cannabinoids in treatment would benefit individuals with PTSD, with cautious attention to risks. [ABSTRACT FROM AUTHOR]