“Cannabinoids (CBs) from Cannabis sativa provide relief for tumor-associated symptoms (including nausea, anorexia, and neuropathic pain) in the palliative treatment of cancer patients.
Additionally, they may decelerate tumor progression in breast cancer patients.
Indeed, the psychoactive delta-9-tetrahydrocannabinol (THC), non-psychoactive cannabidiol (CBD) and other CBs inhibited disease progression in breast cancer models.
The effects of CBs on signaling pathways in cancer cells are conferred via G-protein coupled CB-receptors (CB-Rs), CB1-R and CB2-R, but also via other receptors, and in a receptor-independent way.
THC is a partial agonist for CB1-R and CB2-R; CBD is an inverse agonist for both.
In breast cancer, CB1-R expression is moderate, but CB2-R expression is high, which is related to tumor aggressiveness. CBs block cell cycle progression and cell growth and induce cancer cell apoptosis by inhibiting constitutive active pro-oncogenic signaling pathways, such as the extracellular-signal-regulated kinase pathway.
They reduce angiogenesis and tumor metastasis in animal breast cancer models. CBs are not only active against estrogen receptor-positive, but also against estrogen-resistant breast cancer cells. In human epidermal growth factor receptor 2-positive and triple-negative breast cancer cells, blocking protein kinase B- and cyclooxygenase-2 signaling via CB2-R prevents tumor progression and metastasis.
Furthermore, selective estrogen receptor modulators (SERMs), including tamoxifen, bind to CB-Rs; this process may contribute to the growth inhibitory effect of SERMs in cancer cells lacking the estrogen receptor.
In summary, CBs are already administered to breast cancer patients at advanced stages of the disease, but they might also be effective at earlier stages to decelerate tumor progression.”
“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.
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.”
“Novel pharmacological treatments are needed for Tourette syndrome.
Our goal was to examine the current evidence base and biological rationale for the use of cannabis-derived medications or medications that act on the cannabinoid system in Tourette syndrome.
There is a strong biological rationale regarding how cannabis-derived medications could affect tic severity. Anecdotal case reports and series have noted that many patients report that their tics improve after using cannabis. However, only two small randomized, placebo-controlled trials of Δ9-tetrahydrocannabinol have been published; these suggested possible benefits of cannabis-derived agents for the treatment of tics.
Trials examining other agents active on the cannabinoid system for tic disorders are currently ongoing.
Cannabinoid-based treatments are a promising avenue of new research for medications that may help the Tourette syndrome population.”
“Cannabinoids, commonly used for medicinal and recreational purposes, consist of various complex hydrophobic molecules obtained from Cannabis sativa L. Acting as an inhibitory molecule; they have been investigated for their antineoplastic effect in various breast tumor models. Lately, it was found that cannabinoid treatment not only stimulates autophagy-mediated apoptotic death of tumor cells through unfolded protein response (UPRER) activated downstream effectors, but also imposes cell cycle arrest. The exploitation of UPRER tumors as such is believed to be a major molecular event and is therefore employed in understanding the development and progression of breast tumor. Simultaneously, the data on clinical trials following administration of cannabinoid is currently being explored to find its role not only in palliation but also in the treatment of breast cancer. The present study summarizes new achievements in understanding the extent of therapeutic progress and highlights recent developments in cannabinoid biology towards achieving a better cure of breast cancer through the exploitation of different cannabinoids.”
“Synthetic cannabinoids (SCs) are a class of new psychoactive substances that have been rapidly evolving around the world throughout recent years. Many different synthetic cannabinoid analogues are on the consumer market and sold under misleading names, like “spice” or “incense.”
A limited number of studies have reported serious health effects associated with SC use. In this study, we compared clinical and subclinical psychopathological symptoms associated with SC use and natural cannabis (NC) use.
SC users scored higher than NC users on all used psychometric measures, indicating a higher likelihood of drug abuse, sleep problems, (hypo)manic symptoms, and the nine dimensions comprising the BSI, somatization, obsessive-compulsive behavior, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism.
This study shows that SC use is associated with increased mental health symptomatology compared to NC use.”
“While cannabis use usually induces psychotropic effects such as euphoria, relaxation, and a general pleasant feeling, the use of Synthetic Cannabinoid drugs is associated with more undesired effects including; agitation, irritability, confusion, hallucinations, delusions, psychosis, and death.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999798/
“These side effects (including psychosis, tachyarrhythmia, and seizures) are not typically seen with marijuana (Cannabis sativa) use.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726077/
“Dementia is increasing worldwide. No effective medication is currently available for the treatment of the underlying disease and accompanying behavioral symptoms. Cannabinoids might have a beneficial effect, but clinical studies with (low-dose) synthetic THC have not been conclusive.
Objective: To test the acceptability, practical aspects, and clinical outcomes of the introduction of a THC/CBD-based oral medication in severely demented patients in a specialized nursing home in Geneva.
Methods: This was a prospective observational study.
Results: Ten female demented patients with severe behavior problems received oral medication with on average 7.6 mg THC/13.2 mg CBD daily after 2 weeks, 8.8 mg THC/17.6 mg CBD after 1 month, and 9.0 mg THC/18.0 mg CBD after 2 months. The THC/CBD-based oil was preferred. Neuropsychiatric Inventory, Cohen-Mansfield Agitation Inventory score, and a behavior problem visual analog scale decreased by 40% after 2 months, rigidity score by 50%. Half of the patients decreased or stopped other psychotropic medications. The staff appreciated the decrease in rigidity, making daily care and transfers easier, the improved direct contact with the patients, the improvement in behavior, and the decrease in constipation with less opioids. There was no withholding of the medication for reasons of side effects, and the effects persisted after 2 months.
Conclusions: An oral cannabis extract with THC/CBD, in higher dosages than in other studies, was well tolerated and greatly improved behavior problems, rigidity, and daily care in severely demented patients.”
“Based on the traditional pain-relieving effect of Cannabis species an endogenous cannabinoid like system was discovered in the human body. Endocannabinoids have important role in the homeostasis of the body, such as stress response and mood control, feeding behaviour, energy balance and metabolism, immunological processes, and also play important role in controlling pain processing. Previous studies suggested that an endocannabinoid dysfunction, namely endocannabinoid deficit, might contribute to the development of migraine and its chronification. Although, the exact nature of the relationship between migraine and endocannabinoid system is not fully understood yet, in this brief review we summarise research results suggesting that the endocannabinoid system may be a potential drug target in the migraine therapy.”
“Drug-resistant epilepsy negatively impacts the quality of life and is associated with increased morbidity and mortality and high costs to the healthcare system. Cannabis-based treatments may be effective in reducing seizures in this population, but whether they are cost-effective is unclear. In this systematic review, we will search for cost-effectiveness analyses involving the treatment of pediatric drug-resistant epilepsy with cannabis-based products to inform decision-making by public healthcare payers about reimbursement of such products. We will also search for cost-effectiveness analyses of other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as estimates of healthcare resource use, costs, and utilities, for use in a subsequent cost-utility analysis to address this decision problem.
We will search the published and gray literature for economic evaluations of cannabis-based products and other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as resource utilization and utility studies. Two independent reviewers will screen the title and abstract of each identified record and the full-text version of any study deemed potentially relevant. Study and population characteristics, the incremental cost-effectiveness ratio (ICER), as well as total costs and benefits, will be extracted, and quality will be assessed by use of the Drummond and CHEERS checklists; context-specific issues will also be considered. From model-based cost-utility and cost-effectiveness analyses, we will extract and summarize the model structure, including health states, time horizon, and cycle length. From resource utilization studies, we will extract data about the frequency of resource use (e.g., neurology visits, emergency department visits, admissions to hospital). From utility studies, we will extract the utility for each health state, the source of the preferences (e.g., child, parent, patient, general public), and the method of elicitation.
Drug-resistant epilepsy in children is associated with important costs to the healthcare system, and decision-makers require high-quality evidence on which to base reimbursement decisions. The results of this review will be useful to both decision-makers considering the decision problem of whether to reimburse cannabis-based products through public formularies and to analysts conducting studies in this area.”
“Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy.
In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2-55 years) who had had 2 or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of 20 mg/kg of body weight (20-mg cannabidiol group) or 10 mg/kg (10-mg cannabidiolgroup) or matching placebo, administered in 2 equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period.
A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percentage reduction from baseline in drop seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group ( P = .005 for the 20-mg cannabidiol group vs placebo group, and P = .002 for the 10-mg cannabidiol group vs placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations.
Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 or 20 mg/kg/d to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560.) Long-Term Safety and Treatment Effects of Cannabidiol in Children and Adults With Treatment-Resistant Epilepsies: Expanded Access Program Results Szaflarski JP, Bebin EM, Comi AM, et al; CBD EAP Study Group. Epilepsia. 2018;59(8):1540-1548.
Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016.
Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2 to 10 mg/kg/d, titrated to a maximum dose of 25 to 50 mg/kg/d. Patient visits were every 2 to 4 weeks through 16 weeks and every 2 to 12 weeks thereafter. Efficacy end points included the percentage change from baseline in median monthly convulsive and total seizure frequency and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures versus baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation-carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit.
Of 607 patients in the safety data set, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. Cannabidiol was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%).
Results from this ongoing EAP support previous observational and clinical trial data, showing that add-on CBD may be an efficacious long-term treatment option for TRE. Randomized, Dose-Ranging Safety Trial of Cannabidiol in Dravet Syndrome Devinsky O, Patel AD, Thiele EA, et al; GWPCARE1 Part A Study Group. Neurology. 2018;90(14):e1204-e1211.
To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome.
Patients aged 4 to 10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, electrocardiograms, adverse events (AEs), seizure frequency, and suicidality.
Thirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and its metabolites was dose proportional (AUC0-t). Cannabidiol did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed.
Exposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. Cannabidiol resulted in more AEs than placebo but was generally well tolerated.
CLASSIFICATION OF EVIDENCE:
This study provides class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well tolerated.”