Medicinal cannabis oil improves anxiety-like and depressive-like behaviors in CCS mice via the BDNF/TRPC6 signaling pathway.

BACKGROUND: Post-traumatic stress disorder (PTSD) refers to a chronic impairing psychiatric disorder occurring after exposure to the severe traumatic event. Studies have demonstrated that medicinal cannabis oil plays an important role in neuroprotection, but the mechanism by which it exerts anti-PTSD effects remains unclear. METHODS: The chronic complex stress (CCS) simulating the conditions of long voyage stress for 4 weeks was used to establish the PTSD mice model. After that, behavioral tests were used to evaluate PTSD-like behaviors in mice. Mouse brain tissue index was detected and hematoxylin-eosin staining was used to assess pathological changes in the hippocampus. The indicators of cell apoptosis and the BDNF/TRPC6 signaling activation in the mice hippocampus were detected by western blotting or real-time quantitative reverse transcription PCR experiments. RESULTS: We established the PTSD mice model induced by CCS, which exhibited significant PTSD-like phenotypes, including increased anxiety-like and depression-like behaviors. Medicinal cannabis oil treatment significantly ameliorated PTSD-like behaviors and improved brain histomorphological abnormalities in CCS mice. Mechanistically, medicinal cannabis oil reduced CCS-induced cell apoptosis and enhanced the activation of BDNF/TRPC6 signaling pathway. CONCLUSIONS: We constructed a PTSD model with CCS and medicinal cannabis oil that significantly improved anxiety-like and depressive-like behaviors in CCS mice, which may play an anti-PTSD role by stimulating the BDNF/TRPC6 signaling pathway.

Cannabis effectiveness on immunologic potency of pulmonary contagion.

Respiratory illnesses and its repercussions are becoming more prevalent worldwide. It is necessary to research both innovative treatment and preventative techniques. Millions of confirmed cases and fatalities from the COVID-19 epidemic occurred over the previous two years. According to the review research, cannabinoids are a class of medicines that should be considered for the treatment of respiratory conditions. Cannabinoids and inhibitors of endocannabinoid degradation have illustrated advantageous anti-inflammatory, asthma, pulmonary fibrosis, and pulmonary artery hypotension in numerous studies (in vitro and in vivo). It has been also noted that CB2 receptors on macrophages and T-helper cells may be particularly triggered to lower inflammation in COVID-19 patients. Since the majority of lung tissue contains cannabinoid receptors, cannabis can be an effective medical tool for treating COVID-19 as well as pulmonary infections. Notably, CB2 and CB1 receptors play a major role in immune system modulation and anti-inflammatory activities. In this review, we put forth the idea that cannabis might be helpful in treating pulmonary contagion brought on by viral integration, such as that caused by SARS-CoV-2, haemophilus influenza type b, Streptococcus pneumoniae, influenza virus, and respiratory syncytial virus. Also, a detailed overview of CB receptors, intricate mechanisms, is highlighted connecting link with COVID-19 viral structural modifications along with molecular basis of CB receptors in diminishing viral load in pulmonary disorders supported through evident literature studies. Further, futuristic evaluations on cannabis potency through novel formulation development focusing on in vivo/in vitro systems can produce promising results.

A randomised, placebo-controlled, double blind, crossover trial on the effect of a 20:1 cannabidiol: Δ9-tetrahydrocannabinol medical cannabis product on neurocognition, attention, and mood.

As cannabinoid-based medications gain popularity in the treatment of refractory medical conditions, it is crucial to examine the neurocognitive effects of commonly prescribed products to ensure associated safety profiles. The present study aims to investigate the acute effects of a standard 1 mL sublingual dose of CannEpil®, a medicinal cannabis oil containing 100 mg cannabidiol (CBD) and 5 mg Δ9-tetrahydrocannabinol (THC) on neurocognition, attention, and mood. A randomised, double-blind, placebo-controlled, within-subjects design assessed 31 healthy participants (16 female, 15 male), aged between 21 and 58 years, over a two-week experimental protocol. Neurocognitive performance outcomes were assessed using the Cambridge Neuropsychological Test Automated Battery, with the Profile of Mood States questionnaire, and the Bond-Lader Visual Analogue Scale used to assess subjective state and mood. CannEpil increased Total Errors in Spatial Span and Correct Latency (median) in Pattern Recognition Memory, while also increasing Efficiency Score (lower score indicates greater efficiency) relative to placebo (all p < .05). Subjective Contentedness (p < .01) and Amicability (p < .05) were also increased at around 2.5 h post dosing, relative to placebo. Drowsiness or sedative effect was reported by 23 % of participants between three to six hours post CannEpil administration. Plasma concentrations of CBD, THC, and their metabolites were not significantly correlated with any observed alterations in neurocognition, subjective state, or adverse event occurrence. An acute dose of CannEpil impairs select aspects of visuospatial working memory and delayed pattern recognition, while largely preserving mood states among healthy individuals. Intermittent reports of drowsiness and sedation underscore the inter-individual variability of medicinal cannabis effects on subjective state. (ANZCTR; ACTRN12619000932167; https://www.anzctr.org.au).

Assessment of education in a community hospital on healthcare providers' knowledge of and attitudes toward medical marijuana.

INTRODUCTION: Although medical marijuana usage continues to become more socially acceptable and is increasingly regarded as a legitimate treatment alternative for certain medical conditions such as cancer and epilepsy, stigma remains. METHODS: This study examined whether offering an educational session addressing several key aspects of medical marijuana (e.g., pharmacology, legality) to healthcare providers in a community hospital setting improved knowledge about and/or altered attitudes toward marijuana use. This information was collected through administration of pre- and post-education session surveys. Multiple choice questions were utilized to assess knowledge of marijuana pharmacotherapy, pharmacodynamic interactions, and regulations, whereas descriptive analyses via Likert-scale questions determined attitudes toward medical marijuana. A secondary outcome entailed analysis of drug interactions with marijuana users via retrospective chart review. RESULTS: A total of 43 healthcare providers participated in the study. There were statistically significant increases in healthcare provider knowledge post-education session across multiple occupations (physician, P < .01; nurse, P < .001; pharmacist, P < .01; and nurse technician, P < .05). A total of 72 patients (83%) who self-reported marijuana use for medical or recreational purposes had a potential drug-drug interaction with marijuana. CONCLUSIONS: As both medical and recreational marijuana continue to become legalized across the United States, formal education surrounding marijuana use and laws becomes increasingly important for healthcare providers and can be highly effective in preventing misinformation.

A semi-naturalistic open-label study examining the effect of prescribed medical cannabis use on simulated driving performance.

BACKGROUND: Despite increasing medical cannabis use, research has yet to establish whether and to what extent products containing delta-9-tetrahydrocannabinol (THC) impact driving performance among patients. Stable doses of prescribed cannabinoid products during long-term treatment may alleviate clinical symptoms affecting cognitive and psychomotor performance. AIM: To examine the effects of open-label prescribed medical cannabis use on simulated driving performance among patients. METHODS: In a semi-naturalistic laboratory study, 40 adults (55% male) aged between 23 and 80 years, consumed their own prescribed medical cannabis product. Driving performance outcomes including standard deviation of lateral position (SDLP), the standard deviation of speed (SDS), mean speed and steering variability were evaluated using the Forum8 driving simulator at baseline (pre-dosing), 2.5 h and 5 -h (post-dosing). Perceived driving effort (PDE) was self-reported after each drive. Oral fluid and whole blood samples were collected at multiple timepoints and analysed for THC via liquid chromatography-mass spectrometry. RESULTS: A significant main effect of time was observed for mean speed (p = 0.014) and PDE (p = 0.020), with patients displaying modest stabilisation of vehicle control, increased adherence to speed limits and reductions in PDE post-dosing, relative to baseline. SDLP (p = 0.015) and PDE (p = 0.043) were elevated for those who consumed oil relative to flower-based products. Detectable THC concentrations were observed in oral fluid at 6-h post-dosing (range = 0-24 ng/mL). CONCLUSIONS: This semi-naturalistic study suggests that the consumption of medical cannabis containing THC (1.13-39.18 mg/dose) has a negligible impact on driving performance when used as prescribed.

Characterizing cannabis-prevalent terpenes for neuroprotection reveal a role for α and ß-pinenes in mitigating amyloid ß-evoked neurotoxicity and aggregation in vitro.

BACKGROUND: Cannabis sativa L. (C. sativa) can efficiently synthesize of over 200 terpenes, including monoterpenes, sesquiterpenes and triterpenes that may contribute to the known biological activities of phytocannabinoids of relevance for the burgeoning access to medicinal cannabis formulations globally; however, to date have been uncharacterized. We assessed twelve predominant terpenes in C. sativa for neuroprotective and anti-aggregative properties in semi-differentiated PC12 neuronal cell line that is robust and validated as a cell model responsive to amyloid ß (Aß1-42) protein exposure and oxidative stress. METHODS: Cell viability was assessed biochemically using the MTT assay in the presence of myrcene, ß-caryophyllene, terpinolene, limonene, linalool, humulene, α-pinene, nerolidol, ß-pinene, terpineol, citronellol and friedelin (1-200 µM) for 24 hr. Sub-toxic threshold test concentrations of each terpene were then applied to cells, alone or with concomitant incubation with the lipid peroxidant tert-butyl hyrdroperoxide (t-BHP; 0-250 µM) or amyloid ß (Aß1-42; 0-1 µM) to assess neuroprotective effects. Direct effects of each terpene on Aß fibril formation and aggregation were also evaluated using the Thioflavin T (ThT) fluorometric kinetic assay and transmission electron microscopy (TEM) to visualize fibril and aggregate morphology. RESULTS: Terpenes were intrinsically benign to PC12 cells up to 50 µM, with higher concentrations of ß-caryophyllene, humulene and nerolidol inducing some loss of PC12 cell viability. No significant protective effects of terpenes were observed following t-BHP (0-200 µM) administration, with some enhanced toxicity instead demonstrated from both ß-caryophyllene and humulene treatment (each at 50 µM). α-pinene and ß-pinene demonstrated a significant neuroprotective effect against amyloid ß exposure. α-pinene, ß-pinene, terpineol, terpinolene and friedelin were associated with a variable inhibition of Aß1-42 fibril and aggregate density. CONCLUSIONS: The outcomes of this study underline a neuroprotective role of α-pinene and ß-pinene against Aß-mediated neurotoxicity associated with an inhibition of Aß1-42 fibrilization and density. This demonstrates the bioactive potential of selected terpenes for consideration in the development of medicinal cannabis formulations targeting neurodegenerative diseases.

Exploring potential anti-inflammatory effects of medicinal cannabis.

PURPOSE: Inflammation is thought to play a key role in malignant disease and may play a significant part in the expression of cancer-related symptoms. Cannabidiol (CBD) is a bioactive compound in cannabis and is reported to have significant anti-inflammatory properties. METHOD: Serial C-reactive protein (CRP) levels were measured in all participants recruited to a randomised controlled trial of CBD versus placebo in patients with symptoms related to advanced cancer. A panel of inflammatory cytokines was measured over time in a subset of these patients. RESULTS: There was no difference between the two arms in the trajectory of CRP or cytokine levels from baseline to day 28. CONCLUSION: We were unable to demonstrate an anti-inflammatory effect of CBD in cancer patients. TRIAL REGISTRATION: ANZCTR 26180001220257, registered 20/07/2018.

Increased White Matter Coherence Following Three and Six Months of Medical Cannabis Treatment.

Background: Previous studies have demonstrated abnormal white matter (WM) microstructure in recreational cannabis consumers; however, the long-term impact of medical cannabis (MC) use on WM coherence is unknown. Accordingly, this study assessed the longitudinal impact of MC treatment on WM coherence. Given results from preclinical studies, we hypothesized that MC treatment would be associated with increased fractional anisotropy (FA) and reduced mean diffusivity (MD). Methods: As part of a larger, longitudinal investigation, patients interested in treating at least one medical condition with commercially available MC products of their choosing were assessed before initiating MC use (baseline n=37; female=25, male=12) and following three (n=31) and six (n=22) months of treatment. WM coherence was assessed via diffusion tensor imaging for bilateral regions of interest including the genu of the corpus callosum, anterior limb of the internal capsule, external capsule, and anterior corona radiata, as well as an occipital control region not expected to change over time. Results: In MC patients, FA values significantly increased bilaterally in several callosal regions relative to baseline following both 3 and 6 months of treatment; MD values significantly decreased in all callosal regions but only following 6 months of treatment. No significant changes in WM coherence were observed in the control region or in a pilot sample of treatment-as-usual patients (baseline n=14), suggesting that increased WM coherence observed in MC patients may be attributed to MC treatment as opposed to confounding factors. Interestingly, significant reductions in MD values correlated with higher cannabidiol (CBD) exposure but not Δ-9-tetrahydrocannabinol exposure. Conclusions: Overall, MC treatment was associated with increased WM coherence, which contrasts with prior research examining recreational cannabis consumers, likely related to inherent differences between recreational consumers and MC patients (e.g., product choice, age of onset). In addition, increased CBD exposure was associated with reduced MD following 6 months of treatment, extending evidence from preclinical research indicating that CBD may be neuroprotective against demyelination. However, additional research is needed to elucidate the clinical efficacy of MC treatment and the risks and benefits of long-term MC use.

Backgrounds and Trainings in Cannabis Therapeutics of Dispensary Personnel.

PURPOSE: A growing body of scientific research indicates that oncology teams tend to offer individuals with cancer little clinical advice regarding medicinal cannabis (MC) and that individuals with cancer instead turn to cannabis dispensaries for MC guidance. Our objective was to investigate dispensary personnel's backgrounds and trainings in MC advising. METHODS: The study design was semistructured interviews across 13 states with cannabis dispensary personnel in managerial or client-facing positions. Of 38 recruited, 26 (68%) completed interview. The primary outcome was training in MC advising. Researchers targeted thematic saturation and adhered to Consolidated Criteria for Reporting Qualitative Research. RESULTS: Of 26 participants, 54% were female, with an average age of 40 (range: 22-64) years. Half worked in client-facing roles; half worked in managerial ones. Study participants endorsed passionate commitment to their profession, often motivated by personal experience with MC therapeutics. Cannabis dispensaries often privileged sales skills over cannabis therapeutics knowledge when hiring, resulting in uneven baseline levels of cannabis therapeutics expertise among staff. Most participants reported workplace cannabis therapeutics training to be unstandardized and weak. They described dispensary personnel as resourceful in pursuing cannabis knowledge, self-financing learning in off-hours, sampling dispensary products, and exchanging knowledge. Nearly half the participants called for quality, standardized cannabis therapeutics training for dispensary personnel. CONCLUSION: The many oncology teams who defer to dispensary personnel regarding MC advising rely on a workforce who views themselves as unevenly trained. Further research should include a national survey of cannabis dispensary personnel to learn whether these findings hold true in a larger sample. If so, the oncology community must determine the best approach to clinically advising individuals with cancer about MC.

Medical cannabis and cannabidiol: A new harvest for Malawi.

In February 2020 parliament passed the Cannabis Regulation Bill (2020) which regulates the cultivation and production of industrial hemp and medical cannabis. The country will only fully benefit from this development if the medical and scientific community can take the lead in enabling the country to exploit the plant's potential to help address some of our economic and public health challenges. This special communication provides some basic information on cannabis and discusses its history and medical uses. Cannabidiol (CBD) has emerged as one of the most important cannabis-derived phytochemicals and has formed the basis for the growth of the medical cannabis industry. The scientific data on the mechanisms of the effects of CBD on the human neuroendocrine-immune network is reviewed and the first effective cannabis-based FDA-approved treatment for epilepsy discussed. Some clinical research that is being done on the antipsychotic and neuroprotective properties of CBD is also reviewed. A case is made for the potential of CBD as a neuroprotective adjunctive therapy for the prevention of neuropsychological sequelae associated with complicated malaria. The safety profile of CBD is reviewed and finally, the potential importance of the re-medicalization of cannabis-based therapies for the broader field of phytomedicine is pointed out.

Description and Disposition of Patients With Cancer Accessing a Novel, Pharmacist-Led Cannabis Consultation Service.

PURPOSE: The Cannabis Consultation Service (CCS) is an innovative pharmacist-led resource at the Sunnybrook Odette Cancer Centre. Its mandate is to provide education and guide patients through access and appropriate use of high-quality plant-derived cannabinoids (PDCs). Our objective was to describe the CCS, explain its processes, and characterize patient disposition with respect to use of PDCs. METHODS: We retrospectively reviewed the charts of patients referred to the CCS from July 13, 2020, to March 05, 2021. We used descriptive statistics to report on the patient population and service metrics. RESULTS: During the 34-week period, 96 patients accessed the CCS (median age, 61 years). The top reasons for CCS consultation were management of cancer pain, insomnia, and general interest. Medical cannabis was supported as an option in 44/96 patients. Reasons for not supporting PDC use included lack of indication, potential drug interaction/contraindication, or requiring treatment with first-line therapy. Of the 40 patients requiring a medical document, 22 initiated therapy. The most common product used was a 2:50 THC:CBD (Tetrahydrocannabinol:Cannabidiol) cannabis oil. At the date of last contact, few patients remained on therapy because of lack of benefit, patient choice, and/or hesitancy. CONCLUSION: Despite patients with cancer having interest in seeking PDCs for symptom management, only a few initiated and continued therapy. Pharmacists have an opportunity to advise patients and the oncology team on the risks and benefits of PDCs. These results can be used to support the development of medical cannabis programs by oncology centers and focus future research priorities.

Cannabinoids, Insomnia, and Other Sleep Disorders.

Sleep disturbances are often cited as a primary reason for medicinal cannabis use, and there is increasing clinical interest in the therapeutic potential of cannabinoids in treating sleep disorders. Burgeoning evidence suggests a role of the endocannabinoid system in regulating the circadian sleep-wake cycle, highlighting a potential avenue for developing novel therapeutics. Despite widespread use of cannabis products as sleep aids globally, robustly designed studies verifying efficacy in sleep-disordered populations are limited. Although some study outcomes have suggested cannabinoid utility in insomnia disorder and sleep apnea, most studies to date are limited by small sample sizes, lack of rigorously controlled study designs, and high risk of bias. This critical review summarizes the current evidence for the use of cannabinoids as a treatment for sleep disorders and provides an overview of endocannabinoid modulation of sleep-wake cycles, as well as the sleep-modulating effects of plant-derived cannabinoids such as delta-9-tetrahydrocannbinol, cannabidiol, and cannabinol. The review also discusses practical considerations for clinicians regarding cannabinoid formulations, routes of administration, respiratory concerns, dosing, potential side effects, drug interactions, and effects relevant to driving, tolerance, and withdrawal. Although current interest in, and uptake of, medicinal cannabis use for sleep disorders may have surpassed the evidence base, there is a strong rationale for continued investigation into the therapeutic potential of cannabinoids.

Oncology Fellows' Clinical Discussions, Perceived Knowledge, and Formal Training Regarding Medical Cannabis Use: A National Survey Study.

PURPOSE: Evidence suggests that patients with cancer frequently use cannabis with medicinal intent and desire clinical guidance from providers. We aimed to determine whether oncology training adequately prepares fellows to discuss medical cannabis. METHODS: A national survey study was conducted from January to March 2021. A questionnaire assessing oncology fellows' practices regarding cannabis recommendations in cancer care and their knowledge of its effectiveness and risks compared with conventional care for cancer-related symptoms was developed and sent to 155 US-based oncology training programs to distribute to trainees. RESULTS: Forty programs from 25 states participated; of the 462 trainees across these programs, 189 responded (response rate of 40%). Of the participants, 52% were female; 52% were White, 33% Asian, and 5% Hispanic. Fifty-seven percent reported that they discussed medical cannabis with more than five patients in the preceding year; however, only 13% felt sufficiently informed to issue cannabis-related clinical recommendations. Twenty-four percent reported having received formal training regarding medical cannabis. Oncology fellows who reported having received prior training in medical cannabis were significantly more likely to discuss cannabis with patients (risk ratio: 1.37, 95% CI 1.06 to 1.75; P = .002) and feel sufficiently informed to discuss cannabis recommendations (risk ratio: 5.06; 95% CI, 2.33 to 10.99; P < .001). Many viewed the botanical as a useful adjunctive therapy that was at least as effective as conventional treatments for anorexia/cachexia (72%), nausea/vomiting (45%), and pain (41%). CONCLUSION: Most oncology trainees not only reported engaging in discussions regarding medical cannabis with patients but also considered themselves insufficiently informed to make cannabis-related clinical recommendations. The discrepancy between the frequency of cannabis inquiries/discussions at the patient level and comfort/knowledge at the trainee provider level represents an unmet curricular need with implications for both graduate medical education and patient care.

Clinical Approaches to Cannabis: A Narrative Review.

Cannabis use in the United States is growing at an unprecedented pace. Most states in the United States have legalized medical cannabis use, and many have legalized nonmedical cannabis use. In this setting, health care professionals will increasingly see more patients who have questions about cannabis use, its utility for medical conditions, and the risks of its use. This narrative review provides an overview of the background, pharmacology, therapeutic use, and potential complications of cannabis.

Cannabis Essentials: Tools for Clinical Practice.

Cannabis use in the United States is increasing annually in people of all ages. This increase is fueled by state-level legalization, decreased risk perception, and increased social acceptability. Cannabis and its active components, cannabinoids, have been studied for medical uses and marketed in many commercial forms. Cannabis can impair short-term memory, judgment, and coordination, and there is substantial evidence that it can adversely affect multiple organ systems. Cannabinoids have potential adverse drug interactions with commonly prescribed analgesic, psychotropic, and cardiovascular medications. Current evidence supports cannabinoid use only for a limited number of conditions (chemotherapy-induced nausea and vomiting, specific pain and spasticity syndromes, and certain forms of childhood epilepsy); thus, physicians recommending cannabinoids need to weigh the potential harms vs. perceived benefits. The U.S. Preventive Services Task Force recommends universal screening for unhealthy drug use, including cannabis, in adults 18 years and older. However, the American Academy of Family Physicians does not support this recommendation because of the lack of evidence of benefit in screening patients for unhealthy drug use, except for opioid use disorder. Treatment of cannabis use disorder is largely behavioral and requires a patient-centered, multifaceted approach with a focus on patient education. Pharmacotherapy for cannabis use disorder is limited and experimental. Harm reduction strategies and education about cannabis withdrawal syndrome should be provided to patients. Interpretation of urine drug testing for cannabis is challenging because of the persistence of metabolites for four to five days after a single use and for one month after chronic daily use.

Cannabis-Based Medicines and Medical Cannabis in the Treatment of Nociplastic Pain.

Nociplastic pain is defined as pain due to sensitization of the nervous system, without a sufficient underlying anatomical abnormality to explain the severity of pain. Nociplastic pain may be manifest in various organ systems, is often perceived as being more widespread rather than localized and is commonly associated with central nervous system symptoms of fatigue, difficulties with cognition and sleep, and other somatic symptoms; all features that contribute to considerable suffering. Exemplified by fibromyalgia, nociplastic conditions also include chronic visceral pain, chronic headaches and facial pain, and chronic musculoskeletal pain. It has been theorized that dysfunction of the endocannabinoid system may contribute to persistent pain in these conditions. As traditional treatments for chronic pain in general and nociplastic pain in particular are imperfect, there is a need to identify other treatment options. Cannabis-based medicines and medical cannabis (MC) may hold promise and have been actively promoted by the media and advocacy. The medical community must be knowledgeable of the current evidence in this regard to be able to competently advise patients. This review will briefly explain the understanding of nociplastic pain, examine the evidence for the effect of cannabinoids in these conditions, and provide simplified guidance for healthcare providers who may consider prescribing cannabinoids for these conditions.

Safety of Medical Cannabis in Neuropathic Chronic Pain Management.

Products derived from the plant Cannabis sativa are widely appreciated for their analgesic properties and are employed for the treatment of chronic neuropathic pain. Only nabiximols, a product composed of two extracts containing similar percentages of the two cannabinoids cannabidiol and delta-9-tetrahydrocannabinol, is approved by regulatory authorities for neuropathic pain and spasticity due to multiple sclerosis in many European countries and Canada. It is also included in pharmacovigilance systems monitoring the occurrence of adverse drug reactions. However, it is not the same for the great variety of other cannabis preparations widely used for medical purposes. This creates a situation characterized by insufficient knowledge of the safety of cannabis preparations and the impossibility of establishing a correct risk-benefit profile for their medical use in the treatment of chronic neuropathic pain. With the aim to explore this issue more deeply, we collected data on adverse reactions from published clinical studies reporting the use of cannabis for neuropathic relief.

Cannabinoid Formulations and Delivery Systems: Current and Future Options to Treat Pain.

The field of Cannabis sativa L. research for medical purposes has been rapidly advancing in recent decades and a growing body of evidence suggests that phytocannabinoids are beneficial for a range of conditions. At the same time impressing development has been observed for formulations and delivery systems expanding the potential use of cannabinoids as an effective medical therapy. The objective of this review is to present the most recent results from pharmaceutical companies and research groups investigating methods to improve cannabinoid bioavailability and to clearly establish its therapeutic efficacy, dose ranges, safety and also improve the patient compliance. Particular focus is the application of cannabinoids in pain treatment, describing the principal cannabinoids employed, the most promising delivery systems for each administration routes and updating the clinical evaluations. To offer the reader a wider view, this review discusses the formulation starting from galenic preparation up to nanotechnology approaches, showing advantages, limits, requirements needed. Furthermore, the most recent clinical data and meta-analysis for cannabinoids used in different pain management are summarized, evaluating their real effectiveness, in order also to spare opioids and improve patients' quality of life. Promising evidence for pain treatments and for other important pathologies are also reviewed as likely future directions for cannabinoids formulations.

Endocannabinoid Levels in Ulcerative Colitis Patients Correlate With Clinical Parameters and Are Affected by Cannabis Consumption.

Background: Inflammatory bowel diseases (IBDs) are chronic, idiopathic, inflammatory, gastrointestinal disorders. The endocannabinoid system may have a role in the pathogenesis of IBD. We aimed to assess whether cannabis treatment influences endocannabinoids (eCBs) level and clinical symptoms of IBD patients. Methods: Blood samples and biopsies were taken from IBD patients treated by either cannabis or placebo for 8 weeks. Immunohistochemistry for N-acyl-phosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH) expression was done on colon biopsies, and sample levels of anandamide (AEA), eCB2-arachidonylglycerol (2-AG), arachidonic acid (AA), palmitoylethanolamine (PEA), and oleoylethanolamine (OEA) were measured in patient's sera before and after cannabis treatment. Caco-2 cells were cultured with extracts of cannabis with/without tetrahydrocannabinol (THC) and their proteins extracted, and Western blotting for NAPE-PLD and FAAH expression was done. Results: Thirteen patients with Crohn's disease (CD) and nine patients with ulcerative colitis (UC) were treated with cannabis. Seventeen patients with CD and 10 with UC served as placebo groups. In all CD patients, the levels of eCBs remained unaltered during the treatment period. In UC patients treated with placebo, but not in those treated with cannabis, the levels of PEA, AEA, and AA decreased significantly. The percent reduction in bowel movements was negatively correlated with changes observed in the circulating AEA and OEA, whereas improvement in quality of life was positively correlated with the levels of 2-AG. In the biopsies from UC patients, FAAH levels increased over the study period. In Caco-2 cells, both cannabis extracts increased NAPE-PLD levels but reduced FAAH expression levels. Conclusion: Our study supports the notion that cannabis use affects eCB "tone" in UC patients and may have beneficial effects on disease symptoms in UC patients.