Routes of administration, reasons for use, and approved indications of medical cannabis in oncology: a scoping review.

INTRODUCTION: Some patients diagnosed with cancer use medical cannabis to self-manage undesirable symptoms, including nausea and pain. To improve patient safety and oncological care quality, the routes of administration for use of medical cannabis, patients' reasons, and prescribed indications must be better understood. METHODS: Based on the Joanna Briggs Institute guidelines, a scoping review was conducted to map the current evidence regarding the use of medical cannabis in oncological settings based on the experiences of patients diagnosed with cancer and their healthcare providers. A search strategy was developed with a scientific librarian which included five databases (CINAHL, Web of Science, Medline, Embase, and PsycINFO) and two grey literature sources (Google Scholar and ProQuest). The inclusion criteria were: 1) population: adults aged 18 and over diagnosed with cancer; 2) phenomena of interest: reasons for cannabis use and/or the prescribed indications for medical cannabis; 3) context: oncological setting. French- or English-language primary empirical studies, knowledge syntheses, and grey literature published between 2000 and 2021 were included. Data were extracted by two independent reviewers and subjected to a thematic analysis. A narrative description approach was used to synthesize and present the findings. RESULTS: We identified 5,283 publications, of which 163 met the eligibility criteria. Two main reasons for medical cannabis use emerged from the thematic analysis: limiting the impacts of cancer and its side effects; and staying connected to others. Our results also indicated that medical cannabis is mostly used for three approved indications: to manage refractory nausea and vomiting, to complement pain management, and to improve appetite and food intake. We highlighted 11 routes of administration for medical cannabis, with oils and oral solutions the most frequently reported. CONCLUSION: Future studies should consider the multiple routes of administration for medical cannabis, such as inhalation and edibles. Our review highlights that learning opportunities would support the development of healthcare providers' knowledge and skills in assessing the needs and preferences of patients diagnosed with cancer who use medical cannabis.

Use of Cannabis and Cannabinoids in Patients With Cancer.

OBJECTIVE: To review pharmacology, available dosage forms, efficacy, and safety of cannabis and cannabinoids in cancer patients. DATA SOURCES: In PubMed (1965 to June 2020) the search was conducted using the search terms cannabidiol, cannabis, CBD, dronabinol, endocannabinoids, medical marijuana, nabiximols, nabilone, THC, and cancer. Abstracts from article bibliographies were reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language studies conducted in humans evaluating cannabis and cannabinoids for cancer treatment or related symptoms were considered. Reference lists in relevant articles, package inserts, guidance documents, and addditional articles evaluating cannabis and cannabinoids were identified. DATA SYNTHESIS: Cannabis and cannabinoid effectiveness can be attributed to active components delta-9-tetrahydrocannabinol and cannabidiol. Multiple dosage forms exist, each with different properties contributing to efficacy and safety differences. No data supports use as anticancer agents, and mixed efficacy results have been reported when used in cancer patients with nausea, pain, and anorexia. Inclusion of medicinal and synthetic products, small sample sizes, varying patient populations, and different dosage forms, doses, and drug combinations. These products are well tolerated, and adverse effects depend on the main active component. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Healthcare professionals need to identify appropriateness, monitor, and document use of cannabis and cannabinoids similar to other drug therapies as well as educate the patients/ caregivers about potential benefits and risks. CONCLUSIONS: Current evidence for use of medical cannabis and cannabinoids in cancer patients is weak. However, healthcare professionals are in an ideal role to monitor and educate patients using medical cannabis and cannabinoids.

Clinical Data for the Use of Cannabis-Based Treatments: A Comprehensive Review of the Literature.

OBJECTIVE: To compile and synthesize the available literature describing medical cannabis use across various disease states. DATA SOURCES: PubMed, EBSCO, and Google Scholar searches were conducted using MeSH and/or keywords. STUDY SELECTION AND DATA EXTRACTION: Studies were included if they described the use of cannabis-based products and medications in the treatment of a predefined list of disease states in humans and were published in English. The extraction period had no historical limit and spanned through April 2019. DATA SYNTHESIS: Evidence was compiled and summarized for the following medical conditions: Alzheimer disease, amyotrophic lateral sclerosis, autism, cancer and cancer-associated adverse effects, seizure disorders, human immunodeficiency virus, inflammatory bowel disease, multiple sclerosis (MS), nausea, pain, posttraumatic stress disorder, and hospice care. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Based on identified data, the most robust evidence suggests that medical cannabis may be effective in the treatment of chemotherapy-induced nausea and vomiting, seizure disorders, MS-related spasticity, and pain (excluding diabetic neuropathy). Overall, the evidence is inconsistent and generally limited by poor quality. The large variation in cannabis-based products evaluated in studies limits the ability to make direct comparisons. Regardless of the product, a gradual dose titration was utilized in most studies. Cannabis-based therapies were typically well tolerated, with the most common adverse effects being dizziness, somnolence, dry mouth, nausea, and euphoria. CONCLUSIONS: As more states authorize medical cannabis use, there is an increasing need for high-quality clinical evidence describing its efficacy and safety. This review is intended to serve as a reference for clinicians, so that the risks and realistic benefits of medical cannabis are better understood.

Oral cannabinoid for the prophylaxis of chemotherapy-induced nausea and vomiting-a systematic review and meta-analysis.

INTRODUCTION: Chemotherapy-induced nausea and vomiting (CINV) is a burdensome adverse event frequently associated with chemotherapy treatment of cancer. Evidence suggests that cannabinoid CB2 receptors are present in brainstem neurons, and thus, there may exist a role for cannabinoids to counter CINV. The aim of this paper is to conduct a systematic review and meta-analysis of the efficacy and safety of oral cannabinoids compared with other treatments as documented in randomized controlled trials (RCTs). METHODS: A literature search was conducted using Ovid MEDLINE up until December 31, 2018; Embase Classic and Embase up until 2018 week 53; and Cochrane Central Register of Controlled Trials up until November 2018. Study data were extracted and included in this meta-analysis if they reported on at least one of the following efficacy endpoints: no nausea and no vomiting, no nausea, and no vomiting. The Mantel-Haenszel method and random effects analysis model were used, to generate odds ratio (OR) and accompanying 95% confidence intervals (CI). RESULTS: In the setting of prophylactic treatment against both nausea and vomiting, oral cannabinoid was more efficacious than placebo or other studied antiemetic treatments. When controlling for vomiting, oral cannabinoid was equally as efficacious as others. Against nausea, oral cannabinoid was equally as effective as other treatments. A greater percentage of patients administered oral cannabinoid for CINV experienced dysphoria, euphoria, and sedation. CONCLUSION: Although there exists some evidence suggesting that oral cannabinoids may have a role in controlling for emesis from a neurophysiological perspective, these conclusions are currently not mirrored in the published RCTs to date. However, there exists only a limited number of RCTs, comparisons with older treatment regimens and a lack of standard reporting practice across published literature. Further RCTs should investigate the efficacy and safety of oral cannabinoids, to secure a better picture of the efficacy of oral cannabinoids against CINV.

The Effectiveness of Cannabinoids in the Treatment of Posttraumatic Stress Disorder (PTSD): A Systematic Review.

Objectives: Posttraumatic stress disorder (PTSD) is a potentially debilitating mental health problem. There has been a recent surge of interest regarding the use of cannabinoids in the treatment of PTSD. We therefore sought to systematically review and assess the quality of the clinical evidence of the effectiveness of cannabinoids for the treatment of PTSD. Method: We included all studies published until December 2018 where a patient has had PTSD diagnosed and had been prescribed or were using a cannabinoid for the purpose of reducing PTSD symptoms. Our primary outcome measure was the reduction in PTSD symptoms using a validated instrument. In the absence of randomized controlled trials, we included the next best available levels of evidence including observational and retrospective studies and case reports. We assessed risk of bias and quality using validated tools appropriate for the study design. Results: We included 10 studies in this review, of which only one study was a pilot randomized, double-blind, placebo-controlled, crossover clinical trial. Every identified study had medium to high risk of bias and was of low quality. We found that cannabinoids may decrease PTSD symptomology, in particular sleep disturbances and nightmares. Conclusions: Most studies to date are small and of low quality, with significant limitations to the study designs precluding any clinical recommendations about its use in routine clinical practice. Evidence that cannabinoids may help reduce global PTSD symptoms, sleep disturbances, and nightmares indicates that future well-controlled, randomized, double-blind clinical trials are highly warranted.PROSPERO registration number: 121646.

Nabilone for non-motor symptoms of Parkinson's disease: a randomized placebo-controlled, double-blind, parallel-group, enriched enrolment randomized withdrawal study (The NMS-Nab Study).

Although open-label observations report a positive effect of cannabinoids on non-motor symptoms (NMS) in Parkinson's disease (PD) patients, these effects remain to be investigated in a controlled trial for a broader use in NMS in PD patients. Therefore, we decided to design a proof-of-concept study to assess the synthetic cannabinoid nabilone for the treatment of NMS. We hypothesize that nabilone will improve NMS in patients with PD and have a favorable safety profile. The NMS-Nab Study is as a mono-centric phase II, randomized, placebo-controlled, double-blind, parallel-group, enriched enrollment withdrawal study. The primary efficacy criterion will be the change in Movement Disorders Society-Unified Parkinson's Disease-Rating Scale Part I score between baseline (i.e. randomization) and week 4. A total of 38 patients will have 80% power to detect a probability of 0.231 that an observation in the treatment group is less than an observation in the placebo group using a Wilcoxon rank-sum test with a 0.050 two-sided significance level assuming a true difference of 2.5 points between nabilone and placebo in the primary outcome measure and a standard deviation of the change of 2.4 points. The reduction of harm through an ineffective treatment, the possibility of individualized dosing, the reduction of sample size, and the possible evaluation of the influence of the placebo effect on efficacy outcomes justify this design for a single-centered placebo-controlled investigator-initiated trial of nabilone. This study should be the basis for further evaluations of long-term efficacy and safety of the use of cannabinoids in PD patients.

Randomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer's Disease.

OBJECTIVE: To investigate the efficacy and safety of nabilone for agitation in patients with moderate-to-severe Alzheimer's disease (AD). DESIGN: This 14-week randomized double-blind crossover trial compared nabilone to placebo (6 weeks each) with a 1-week washout between phases. SETTING: Patients were recruited from a long-term care facility and geriatric psychiatry clinics. PARTICIPANTS: Patients had AD (standardized Mini-Mental State Examination [sMMSE ≤24]) and agitation (Neuropsychiatric Inventory-Nursing Home version [NPI-NH]-agitation/aggression subscore ≥3). INTERVENTION: Nabilone (target 1-2 mg) versus placebo. MEASUREMENTS: The primary outcome was agitation (Cohen Mansfield Agitation Inventory [CMAI]). Secondary outcomes included NPI-NH total, NPI-NH caregiver distress, cognition (sMMSE and Severe Impairment Battery [SIB] or Alzheimer's Disease Assessment Scale of Cognition), global impression (Clinician's Global Impression of Change [CGIC]), and adverse events. RESULTS: Thirty-nine patients (mean ± SD age = 87 ± 10, sMMSE = 6.5 ± 6.8, CMAI = 67.9 ± 17.6, NPI-NH total = 34.3 ± 15.8, 77% male, nabilone dose = 1.6 ± 0.5 mg) were randomized. There were no crossover or treatment-order effects. Using a linear mixed model, treatment differences (95% CI) in CMAI (b = -4.0 [-6.5 to -1.5], t(30.2) = -3.3, p = 0.003), NPI-NH total (b = -4.6 [-7.5 to -1.6], t(32.9) = -3.1, p = 0.004), NPI-NH caregiver distress (b = -1.7 [-3.4 to -0.07, t(33.7) = -2.1, p = 0.041), and sMMSE (b = 1.1 [0.1-2.0], t(22.6) = 2.4, p = 0.026) all favored nabilone. However, in those who completed the SIB (n = 25) treatment differences favored placebo (b = -4.6 [-7.3 to -1.8], t(20.7) = -4.8, p = 0.003). CGIC improvement during nabilone (47%) and placebo (23%) was not significantly different (McNemar's test, exact p = 0.09). There was more sedation during nabilone (45%) compared to placebo (16%) phases (McNemar's test, exact p = 0.02), but treatment-limiting sedation was not significantly different (McNemar's test, exact p = 0.22). CONCLUSIONS: Nabilone may be an effective treatment for agitation. However, sedation and cognition should be closely monitored.

Nabilone administration in refractory chronic diarrhea: a case series.

BACKGROUND: Daily cannabis assumption is currently associated with several physical and mental health problems, however in the past it was prescribed for a multitude of symptoms, including vomiting, abdominal pain and diarrhea. Through the years, the endocannabinoid system has been recognized in the homeostatic mechanisms of the gut, as well as in the physiological control of intestinal motility and secretion. Accordingly, cannabinoids may be a promising therapy against several gastrointestinal conditions, such as abdominal pain and motility-related disorders. CASE PRESENTATION: We retrospectively analysed the efficacy and safety of a CB1-receptor agonist administered in six patients with refractory chronic diarrhea, between April 2008 and July 2016. After three months of therapy, oral nabilone improved the health of nearly all patients, with visible improvements in reducing diarrheal symptoms and weight gain. Most of the benefits persisted through the three-month follow-up. Only one patient interrupted the treatment after one month, due to severe fatigue and mental confusion; the symptoms disappeared in the follow-up period. CONCLUSIONS: These findings encourage the study of cannabinoids acting on CB1 receptors in chronic gastrointestinal disorders, especially in refractory chronic diarrhea, offering a chance for a substantial improvement in the quality of life of selected patients, with a reasonable safety profile.

Safety and efficacy of nabilone for acute chemotherapy-induced vomiting prophylaxis in pediatric patients: A multicenter, retrospective review.

OBJECTIVES: To describe the safety and efficacy of nabilone given to pediatric patients to prevent acute chemotherapy-induced nausea and vomiting (CINV). METHODS: A multicenter, retrospective review of pediatric patients who received nabilone for acute CINV prophylaxis between December 1, 2010 and August 1, 2015 was undertaken. One course of nabilone was evaluated per patient. Adverse effects associated with nabilone use were noted. The proportion of patients who experienced complete acute chemotherapy-induced vomiting (CIV) control during the acute phase was determined. The acute phase was defined as starting with the first chemotherapy dose and continuing until 24 h after administration of the last chemotherapy dose of the chemotherapy block. RESULTS: One hundred ten eligible patients (median age: 14.0 years, range: 1.1-18.0 years; 65 male) were identified. Most (109/110) received nabilone plus a 5-HT3 antagonist for CINV prophylaxis. Adverse effects associated with nabilone were experienced by 34% (37/110) of children. All were of CTCAE Version 4.03 Grade 2 or less. Sedation (20.0%), dizziness (10.0%), and euphoria (3.6%) were the most commonly reported adverse events. Nabilone was discontinued in 10 patients due to an adverse event. The proportions of patients receiving highly or moderately emetogenic chemotherapy who experienced complete acute CIV control were 50.6% (42/83) and 53.8% (14/26), respectively. CONCLUSION: Adverse events associated with nabilone were common but of minor clinical significance. Acute CIV control in children receiving nabilone as a part of their antiemetic regimen was poor. Future work should focus on implementation of guideline-consistent CINV prophylaxis and treatment.

The Use of Medical Marijuana in Cancer.

The use of medical marijuana in cancer care presents a dilemma for both patients and physicians. The scientific evidence is evolving, yet much of the known information is still insufficient to adequately inform patients as to risks and benefits. In addition, evidence-based dosing and administration information on medical marijuana is lacking. Medical marijuana is now legal, on some level, in 24 states plus the District of Columbia, yet is not legal on the federal level. This review addresses the current state of the research, including potential indications, risks and adverse effects, preliminary data on anticancer effects, as well as legal and quality issues. A summary of the clinical trials underway on medical marijuana in the oncology setting is discussed.

[Efficacy, tolerability and safety of cannabinoids for chronic neuropathic pain: A systematic review of randomized controlled studies]. / Wirksamkeit, Verträglichkeit und Sicherheit von Cannabinoiden bei neuropathischen Schmerzsyndromen : Eine systematische Übersichtsarbeit von randomisierten, kontrollierten Studien.

BACKGROUND: Recently published systematic reviews came to different conclusions with respect to the efficacy, tolerability and safety of cannabinoids for treatment of chronic neuropathic pain. MATERIAL AND METHODS: A systematic search of the literature was carried out in MEDLINE, the Cochrane central register of controlled trials (CENTRAL) and clinicaltrials.gov up until November 2015. We included double-blind randomized placebo-controlled studies (RCT) of at least 2 weeks duration and with at least 9 patients per treatment arm comparing medicinal cannabis, plant-based or synthetic cannabinoids with placebo or any other active drug treatment in patients with chronic neuropathic pain. Clinical endpoints of the analyses were efficacy (more than 30 % or 50 % reduction of pain, average pain intensity, global improvement and health-related quality of life), tolerability (drop-out rate due to side effects, central nervous system and psychiatric side effects) and safety (severe side effects). Using a random effects model absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The methodological quality of RCTs was rated by the Cochrane risk of bias tool. RESULTS: We included 15 RCTs with 1619 participants. Study duration ranged between 2 and 15 weeks. Of the studies 10 used a plant-derived oromucosal spray with tetrahydrocannabinol/cannabidiol, 3 studies used a synthetic cannabinoid (2 with nabilone and 1 with dronabinol) and 2 studies used medicinal cannabis. The 13 studies with parallel or cross-over design yielded the following results with 95 % confidence intervals (CI): cannabinoids were superior to placebo in the reduction of mean pain intensity with SMD - 0.10 (95 % CI - 0.20- - 0.00, p = 0.05, 13 studies with 1565 participants), in the frequency of at least a 30 % reduction in pain with an RD of 0.10 [95 % CI 0.03-0.16, p = 0.004, 9 studies with 1346 participants, number needed to treat for additional benefit (NNTB) 14, 95 % CI 8-45] and in the frequency of a large or very large global improvement with an RD of 0.09 (95 % CI 0.01-0.17, p = 0.009, 7 studies with 1092 participants). There were no statistically significant differences between cannabinoids and placebo in the frequency of at least a 50 % reduction in pain, in improvement of health-related quality of life and in the frequency of serious adverse events. Patients treated with cannabinoids dropped out more frequently due to adverse events with an RD of 0.04 [95 % CI 0.01-0.07, p = 0.009, 11 studies with 1572 participants, number needed to treat for additional harm (NNTH) 19, 95 % CI 13-37], reported central nervous system side effects more frequently with an RD of 0.38 (95 % CI 0.18-0.58, p = 0.0003, 9 studies with 1304 participants, NNTH 3, 95 % CI 2-4) and psychiatric side effects with an RD of 0.11 (95 % CI 0.06-0.16, p < 0.0001, 9 studies with 1304 participants, NNTH 8, 95 % CI 7-12). CONCLUSION: Cannabinoids were marginally superior to placebo in terms of efficacy and inferior in terms of tolerability. Cannabinoids and placebo did not differ in terms of safety during the study period. Short-term and intermediate-term therapy with cannabinoids can be considered in selected patients with chronic neuropathic pain after failure of first-line and second-line therapies.

NHS-Reimbursed Cannabis Flowers for Cancer Palliative Care and the Management of Chemotherapy-Induced Nausea and Vomiting: An Autobiographical Case Report.

Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect of cancer treatment, affecting many patients. Cannabinoid agonists, such as nabilone and Δ9-tetrahydrocannabinol (THC), the main psychoactive component of Cannabis sativa L., have shown efficacy as antiemetics. Here, we report the case of Michael Roberts (MR), who we believe is the first British patient reimbursed by the National Health Service (NHS) England for the cost of medicinal cannabis flowers to manage CINV. Medical data were obtained from NHS records and individual funding request (IFR) forms. Patient-reported outcome measures (PROMs) were collected using validated questionnaires as part of the standard of care at the specialized private clinics where the prescription of medicinal cannabis was initiated. The patient presented with rectosigmoid adenocarcinoma with lung metastases. He received FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy and underwent an emergency Hartmann's procedure with subsequent second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy and lung ablation. MR reported severe nausea and vomiting associated with the initial FOLFIRI treatment. Antiemetics metoclopramide and aprepitant demonstrated moderated efficacy. Antiemetics ondansetron, levomepromazine, and nabilone were associated with intolerable side effects. Inhalation of THC-predominant cannabis flowers in association with standard medication improved CINV, anxiety, sleep quality, appetite, overall mood, and quality of life. Our results add to the available evidence suggesting that medicinal cannabis flowers may offer valuable support in cancer palliative care integrated with standard-of-care oncology treatment. The successful individual funding request in this case demonstrates a pathway for other patients to gain access to these treatments, advocating for broader awareness and integration of cannabis-based medicinal products in national healthcare services.

Subjective, cognitive and cardiovascular dose-effect profile of nabilone and dronabinol in marijuana smokers.

Marijuana dependence is a substantial public health problem, with existing treatments showing limited efficacy. In laboratory and clinical studies, the cannabinoid receptor 1 agonist oral Δ9tetrahydrocannabinol (THC; dronabinol) has been shown to decrease marijuana withdrawal but not relapse. Dronabinol has poor bioavailability, potentially contributing to its failure to decrease relapse. The synthetic THC analogue, nabilone, has better bioavailability than dronabinol. We therefore aimed to characterize nabilone's behavioral and physiological effects across a range of acute doses in current marijuana smokers and compare these with dronabinol's effects. Participants (4 female; 10 male) smoking marijuana 6.6 (standard deviation = 0.7) days/week completed this outpatient, within-subjects, double-blind, randomized protocol. Over seven sessions, the time-dependent subjective, cognitive and cardiovascular effects of nabilone (2, 4, 6, 8 mg), dronabinol (10, 20 mg) and placebo were assessed. Nabilone (4, 6, 8 mg) and dronabinol (10, 20 mg) increased ratings of feeling a good effect, a strong effect and/or 'high' relative to placebo; nabilone had a slower onset of peak subjective effects than dronabinol. Nabilone (6, 8 mg) modestly lowered psychomotor speed relative to placebo and dronabinol. There were dose-dependent increases in heart rate after nabilone, and nabilone (2 mg) and dronabinol (10 mg) decreased systolic blood pressure. Thus, nabilone produced sustained, dose-related increases in positive mood, few cognitive decrements and lawful cardiovascular alterations. It had a longer time to peak effects than dronabinol, and effects were more dose-related, suggesting improved bioavailability. Nabilone was well tolerated by marijuana smokers, supporting further testing as a potential medication for marijuana dependence.

The Safety of Dronabinol and Nabilone: A Systematic Review and Meta-Analysis of Clinical Trials.

Dronabinol, a natural cannabinoid, and its semi-synthetic derivative, nabilone, are marketed as medicines in several countries. The aim of our work was to systematically evaluate the frequency of adverse events related to dronabinol or nabilone treatment compared to placebo. Scientific databases were searched for placebo-controlled clinical studies of patients receiving either dronabinol or nabilone therapy with placebo control groups. This meta-analysis was reported following the PRISMA guidelines using the PICO format, and it was registered with the PROSPERO register. There were 16 trials included in the meta-analysis. In the nabilone studies, drowsiness was more than 7 times as frequent in patients treated with nabilone than in the placebo group (OR: 7.25; 95% CI: 1.64-31.95), and the risk of dizziness (OR: 21.14; 95% CI: 2.92-152.75) and dry mouth was also higher (OR: 17.23; 95% CI: 4.33-68.55). The frequency of headache was not different in the two groups. In case of dronabinol, the frequency of dry mouth (OR: 5.58; 95% CI: 3.19-9.78), dizziness (OR: 4.60 95% CI: 2.39-8.83) and headache (OR: 2.90; 95% CI: 1.07-7.85) was significantly higher in the dronabinol groups, whereas in case of nausea, drowsiness and fatigue there was no difference. The severity of adverse events was typically mild-to-moderate and transient. In a risk-benefit assessment, these adverse effects are acceptable compared to the achievable benefit. However, considering the diversity of the adverse effects, more studies are needed to provide a more accurate assessment on the side effect profiles of these two compounds.

Improved cyclobutyl nabilone analogs as potent CB1 receptor agonists.

In earlier work, we explored the SAR for the C3 side chain pharmacophore in the hexahydrocannabinol template represented by the drug nabilone, which resulted in the development of AM2389. In an effort for further optimization, we have merged features of nabilone and AM2389 and explored the C3 side chain with varying chain lengths and terminal substitutions. Of the compounds described here, a nabilone analog, AM8936, with the C6'-cyano-substituted side chain, was identified as the most successful analog capable of serving as a potential candidate for further development and a valuable tool for further in vivo studies. AM8936 behaved as a balanced and potent CB1 agonist in functional assays and was a potent and efficacious CB1 agonist in vivo. Our SAR studies are highlighted with the docking of AM8936 on the crystal structure of the hCB1 receptor.

Effects of Nabilone on Sleep Outcomes in Patients with Parkinson's Disease: A Post-hoc Analysis of NMS-Nab Study.

Background: The synthetic tetrahydrocannabinol analogue nabilone improved overall non-motor symptom (NMS) burden in Parkinson's disease (PD) patients in comparison to placebo. Objectives: To characterize the effects of nabilone on different sleep outcomes in PD patients. Methods: We performed a post-hoc analysis of the controlled, double-blind, enriched enrollment randomized withdrawal NMS-Nab study to assess the effects of nabilone on sleep outcomes in study participants who reported clinically-relevant sleep problems (MDS-UPDRS-1.7 ≥ 2 points). Results: After open-label nabilone administration, 77.4% reported no relevant sleep problem. In the withdrawal phase of the trial, the MDS-UPDRS-1.7. and the NMS-Scale Domain 2 (i.e., Sleep/Fatigue) significantly worsened only in PD patients in the placebo group, which was mostly driven by a significant worsening of insomnia (question 5 of the NMS-Scale Domain 2). Conclusions: This post-hoc analysis of the NMS-Nab trial suggests that nabilone has beneficial effects on sleep outcomes in PD patients experiencing sleep problems at baseline.The original trial was registered with ClinicalTrials.gov (NCT03769896, https://clinicaltrials.gov/ct2/show/NCT03769896) and EudraCT (2017-000192-86).

Controversial Link between Cannabis and Anticancer Treatments-Where Are We and Where Are We Going? A Systematic Review of the Literature.

BACKGROUND AND OBJECTIVES: Cannabinoids are currently used in cancer patients primarily for their pain-relieving and antiemetic properties. The aim of our review was to synthesize all available data of studies evaluating the therapeutic efficacy of cannabis in combination with oncological treatments in cancer patients and to explore ongoing studies with different goals and medical areas registered in the field of oncology worldwide. MATERIALS AND METHODS: This study was performed in accordance with the PRISMA guidelines. A search using MEDLINE/PubMed database was performed between 1 January 2006 and 1 March 2022. Search terms included the following: cannabidiol, cannabis, CBD, dronabinol, endocannabinoids, medical marijuana, nabiximols, nabilone, THC, and cancer. All studies that examined the efficacy of cannabis administered during oncological treatments, regardless of cancer localization, subtype, and sample size, were considered eligible. RESULTS: In three studies, cannabis was administered to patients with glioblastoma, and in two other studies, cannabis was used in combination with immunotherapy in various cancer subgroups. The results of the clinical trials in cancer patients are not sufficient to draw conclusions at this time. Interestingly, several other studies addressing the systemic effects of cannabinoids in cancer patients are currently listed in the U.S. National Library of Medicine's registry on the ClinicalTrials.gov website. However, only one of the registered studies examined the efficacy of cannabinoids as a potential option for systemic cancer treatment. CONCLUSIONS: Although cannabis is touted to the public as a cancer cure, clinical trials need to clarify which combinations of chemotherapeutic agents with cannabinoids are useful for cancer patients.

Nabilone Impairs Spatial and Verbal Working Memory in Healthy Volunteers.

Background: Memory impairments and psychosis-like experiences can be adverse effects of cannabis use. However, reports on the cognitive impact of cannabis use are not consistent. There are also limited studies on the psychotomimetic effects of cannabinoid compounds to reveal the association between cannabis and psychosis. Therefore, we investigated the effect of acute cannabinoid intoxication on verbal working memory (VWM) and spatial working memory (SWM) following oral doses of the synthetic cannabinoid agonist, nabilone (1-2 mg, oral). We further investigated the effect of nabilone on psychosis-like experiences (schizotypy scores) and associations of schizotypy with VWM and SWM. Methods: Healthy participants (n=28) completed spatial and digit span tasks across different delay conditions (0, 6, 12, and 18 sec) after receiving nabilone (1-2 mg, PO) or placebo in a randomized, double-blind, counterbalanced, crossover manner. A subset of participants completed a short battery of schizotypy measures (n=25). Results: Nabilone impaired VWM (p=0.03, weak effect size η2=0.02) and SWM (p=0.00016, η2=0.08). Nabilone did not significantly change overall schizotypy scores. Schizotypy scores were negatively correlated with working memory (WM) averaged across all delays and both modalities, under placebo (ρ=-0.41, p=0.04). In addition, there were significant negative correlations between occasions of cannabis use and overall WM averaged scores across drug treatments (ρ=-0.49, p=0.007) and under placebo (ρ=-0.45, p=0.004). The results showed that the drug effect in the less frequent cannabis users was more pronounced on the SWM (p<0.01) and VWM (p<0.01), whereas there appeared to be little drug effect in the frequent cannabis users. Conclusion: Low doses of synthetic cannabinoid impaired SWM and VWM, indicating that exogenous activation of the cannabinoid system influences cognitive performance. Further, the results replicated previous findings that schizotypy is correlated with deficits in WM. Clinical Trial Registry Name: Nabilone and caffeine effects on the perceptions of visually, auditory, tactile and multimodal illusions in healthy volunteers. Clinical Trial Registration Number: CT-2018-CTN-02561 (Therapeutic Goods Administration Clinical Trial Registry) and ACTRN12618001292268 (The Australian New Zealand Clinical Trials Registry).

Eye Tracking in Patients with Parkinson's Disease Treated with Nabilone-Results of a Phase II, Placebo-Controlled, Double-Blind, Parallel-Group Pilot Study.

The topic of the therapeutic use of cannabinoids in Parkinson's disease (PD) is broadly discussed and frequently comes up in the outpatient clinic. So far, there are only a few randomized clinical trials assessing the effects of cannabinoids in PD. We are able to demonstrate a reduction in non-motor symptom (NMS) burden after the administration of nabilone. As impairment of attention and working memory have been described earlier as possible side effects, we assess cognitive performance using saccadic paradigms measured by an eye tracker. We do not observe a significant difference in any of the saccadic paradigms between PD patients on placebo versus those treated with nabilone. We, therefore, conclude that top-down inhibitory control is not affected by the tetrahydrocannabinol analogue. Nabilone did not significantly worsen cognitive performance and appears to be safe to use in selected PD patients who suffer from disabling NMS.

Use of cannabinoids for the treatment of patients with post-traumatic stress disorder.

OBJECTIVES: Post-traumatic Stress Disorder (PTSD) is a diagnosis of extreme anxiety caused by a traumatic event. Less than 10% of individuals who have experienced severe trauma will develop this disorder. Treatment options include various psychotherapies, but not all patients respond to them. Different pharmacological approaches have been explored as potential adjuvants, including using cannabinoids to target the endocannabinoid system to reduce the symptoms and enhance extinction training over the associated fear memories. This review was aimed to determine the effects of using cannabinoids for treatment of PTSD. CONTENT: For this review, four cohort studies, four randomized clinical trials, one case report, and one case series were obtained from PubMed within the last 10 years. Cannabis extracts, tetrahydrocannabinol (THC) and cannabidiol (CBD), and synthetic cannabinoids were used in the studies to target the cannabinoid receptors 1 and 2. Cannabinoids were shown to improve overall PTSD symptoms, including sleep quality and quantity, hyperarousal, and treatment-resistant nightmares. When participants were undergoing extinction training, cannabinoids given within the same time interval enhanced consolidation and retention. SUMMARY AND OUTLOOK: Cannabinoids have been shown to be an effective treatment option for patients with PTSD. Besides aiding to relieve the symptoms and enhance extinction training, they also are relatively well tolerated. Common adverse effects included light-headedness, forgetfulness, dizziness, and headaches.