“Epilepsy is a progressive neurological disease characterized by recurrent seizures and behavioral comorbidities. We investigated the antiseizure effect of cannabidiol (CBD) in a battery of acute seizure models. Additionally, we defined the disease-modifying potential of chronic oral administration of CBD on associated comorbidities in the reduced intensity status epilepticus-spontaneous recurrent seizures (RISE-SRS) model of temporal lobe epilepsy (TLE).
Author Archives: David Worrell
Social isolation as a promising animal model of PTSD comorbid suicide: neurosteroids and cannabinoids as possible treatment options.
“Post-traumatic stress disorder (PTSD) is a psychiatric condition characterized by drastic alterations in mood, emotions, social abilities and cognition. Notably, one aspect of PTSD, particularly in veterans, is its comorbidity with suicide. Elevated aggressiveness predicts high-risk to suicide in humans and despite the difficulty in reproducing a complex human suicidal behavior in rodents, aggressive behavior is a well reproducible behavioral trait of suicide. PTSD animal models are based on a peculiar phenotype, including exaggerated fear memory, anxiety- and depressive-like behaviors associated with neurochemical dysregulations in emotional brain circuitry. The endocannabinoid and the neurosteroid systems regulate emotions and stress responses, and recent evidence shows these two systems are interrelated and critically compromised in neuropsychiatric disorders. For instance, levels of the neurosteroid, allopregnanolone, as well as those of the endocannabinoids, anandamide and its congener, palmitoylethanolamide are decreased in PTSD. Similarly, the endocannabinoid system and neurosteroid biosynthesis are altered in suicidal individuals. Selective serotonin reuptake inhibitors (SSRIs), the only FDA-approved treatments for PTSD and depression, fail to help half of the treatment-seeking patients. This highlights the need for developing biomarker-based efficient therapies. One promising hypothesis points to stimulation of allopregnanolone biosynthesis as a valid end-point to predict treatment response in PTSD patients. This review highlights running findings on the role of the endocannabinoid and neurosteroid systems in PTSD and suicidal behavior both in a preclinical and clinical perspective. A specific focus is given to predictive PTSD/suicide animal models. Ultimately, we discuss the idea that disruption of neurosteroid and endocannabinoid biosynthesis may offer novel promising biomarker candidates to develop new treatments for PTSD and, perhaps, suicidal behavior.” https://www.ncbi.nlm.nih.gov/pubmed/30586627 https://www.sciencedirect.com/science/article/pii/S0278584618305839?via%3Dihub]]>
Knowledge, Attitudes, and Perceptions of Cannabinoids in the Dermatology Community
“Recent research has identified potential uses of cannabinoids in dermatology, including psoriasis, atopic dermatitis, and wound healing.
This study examined dermatology providers’ knowledge, attitudes, and perceptions on therapeutic cannabinoids using a 20-question online survey.
The response rate was 21% (n=531). Most responders thought cannabinoids should be legal for medical treatment (86%). Nearly all (94%) believed it is worthwhile to research dermatologic uses of cannabinoids. 55% reported at least one patient-initiated discussion about cannabinoids in the last year. Yet, 48% were concerned about a negative stigma when proposing cannabinoid therapies to patients. While most responders (86%) were willing to prescribe an FDA-approved cannabinoid as a topical treatment, fewer (71%) were willing to prescribe an oral form. 64% of respondents did not know that cannabidiol is not psychoactive and 29% did not know that tetrahydrocannabinol is psychoactive.
CONCLUSIONS:
Dermatology providers are interested in prescribing cannabinoids and patients are speaking about cannabinoids with their dermatologists. However, providers’ fund of knowledge on this subject is lacking. These results highlight the need for further education and research to detangle the dermatologic benefits and risks of cannabinoids.” https://www.ncbi.nlm.nih.gov/pubmed/30586258“Cannabinoid system in the skin – a possible target for future therapies in dermatology.” https://www.ncbi.nlm.nih.gov/pubmed/19664006
]]>An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia.
“In this experimental randomized placebo-controlled 4-way crossover trial, we explored the analgesic effects of inhaled pharmaceutical-grade cannabis in twenty chronic pain patients with fibromyalgia. We tested four different cannabis varieties with exact knowledge on their [INCREMENT]-tetrahydrocannabinol (THC), and cannabidiol (CBD) content: Bedrocan® (22.4 mg THC, < 1 mg CBD), Bediol® (13.4 mg THC, 17.8 mg CBD), Bedrolite® (18.4 mg CBD, < 1 mg THC) and a placebo variety without any THC or CBD. Following a single vapor inhalation, THC and CBD plasma concentrations, pressure and electrical pain thresholds, spontaneous pain scores and drug high were measured for 3 hours. None of the treatments had an effect greater than placebo on spontaneous or electrical pain responses, although more subjects receiving Bediol® displayed a 30% decrease in pain scores compared to placebo (90% vs. 55% of patients, p = 0.01), with spontaneous pain scores correlating with the magnitude of drug high (ρ = -0.5, p < 0.001). Cannabis varieties containing THC caused a significant increase in pressure pain threshold relative to placebo (p < 0.01). CBD inhalation increased THC plasma concentrations but diminished THC-induced analgesic effects, indicative of a synergistic pharmacokinetic but antagonistic pharmacodynamic interactions of THC and CBD. This experimental trial shows the complex behavior of inhaled cannabinoids in chronic pain patients with just small analgesic responses after a single inhalation. Further studies are needed to determine long-term treatment effects on spontaneous pain scores, THC-CBD interactions and the role of psychotropic symptoms on pain relief.” https://www.ncbi.nlm.nih.gov/pubmed/30585986 https://insights.ovid.com/crossref?an=00006396-900000000-98794]]>
Long-term cannabidiol treatment in patients with Dravet syndrome: An open-label extension trial.
“Add-on cannabidiol (CBD) significantly reduced seizures associated with Dravet syndrome (DS) in a randomized, double-blind, placebo-controlled trial: GWPCARE1 Part B (NCT02091375). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or a second placebo-controlled trial, GWPCARE2 (NCT02224703), were invited to enroll in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5.
METHODS:
Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week period, with their existing medications. Based on response and tolerance, CBD could be reduced or increased up to 30 mg/kg/d.RESULTS:
By November 2016, a total of 278 patients had completed the original randomized trials, and 264 (95%) enrolled in this open-label extension. Median treatment duration was 274 days (range 1-512) with a mean modal dose of 21 mg/kg/d, and patients received a median of 3 concomitant antiepileptic medications. Adverse events (AEs) occurred in 93.2% of patients and were mostly mild (36.7%) or moderate (39.0%). Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Twenty-two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥3 times the upper limit of normal. In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to week 48 ranged from 38% to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient’s overall condition on the Subject/Caregiver Global Impression of Change scale.SIGNIFICANCE:
This trial shows that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.” https://www.ncbi.nlm.nih.gov/pubmed/30582156 https://onlinelibrary.wiley.com/doi/full/10.1111/epi.14628]]>Medical Cannabis in the Skilled Nursing Facility: A Novel Approach to Improving Symptom Management and Quality of Life.
“Throughout the millennia, the cannabis plant has been utilized as a recognized therapy for pain relief and symptom management.
Following the Prohibition-era stigmatization and criminalization of all forms of cannabis of the early 20th century, there has been a recent nationwide and worldwide resurgence in interest and use of the cannabinoid compounds extracted from the cannabis plant, that is, medical cannabis.
Although at the Federal level, cannabis remains a Schedule I substance, 31 states have already decriminalized possession and use of medical cannabis for specific diagnoses.
It is noteworthy that many of these indicated diagnoses are prevalent in the skilled nursing facility (SNF). This creates regulatory concerns as SNFs and other healthcare facilities must maintain compliance with Federal laws, while balancing the individual resident’s rights to utilize medical cannabis where indicated.
The authors developed an innovative program that affords their residents the ability to participate in a state-approved medical cannabis program while remaining compliant with Federal law. As medical cannabis use becomes more widespread and accepted, clinicians providing medical care in healthcare facilities will encounter residents who may benefit from and request this alternative therapy.
Studies examining older adults that are utilizing medical cannabis legally have demonstrated significant decreases in prescription medication use, most notably a reduction in opioid analgesic usage. As such, medical cannabis should be viewed as an additional option in the clinician’s toolbox of therapeutic interventions for symptom relief.”
https://www.ncbi.nlm.nih.gov/pubmed/30580820
https://www.jamda.com/article/S1525-8610(18)30662-5/fulltext
Attenuation Effect of Cannabinoid Type 1 Receptor Activation on Methamphetamine-Induced Neurodegeneration and Locomotion Impairments among Male Rats.
“A number of neuroimaging studies on human addicts have revealed that abuse of Methamphetamine (METH) can induce neurodegenerative changes in various brain regions like the cerebral cortex and cerebellum. Although the underlying mechanisms of METH-induced neurotoxicity have been studied, the cellular and molecular mechanisms of METH-induced neurotoxicity remain to be clarified.
Previous studies implicated that cannabinoid type 1 receptors (CB1Rs) exert neuroprotective effects on several models of cerebral toxicity, but their role in METH-induced neurotoxicity has been rarely investigated. Moreover, the cerebellum was considered as a potential target to evaluate the effects of cannabinoids on locomotion activity as the CB1Rs are most widely distributed in the molecular layer of cerebellum. Therefore, the present study was carried out to evaluate whether neurodegeneration induced in the cerebellum tissue implicated in locomotion deficit induced by METH.
“A flowering plant of variegated ingredients and psychoactive qualities, Cannabis has long been used for medicinal and recreational purposes.
Regulatory approvals have been gained across a broad range of palliative and therapeutic indications, and in some cases, included in standard treatment guidelines.
Areas covered: The use of Cannabis and 
“Previous studies have shown that a cytosine (C) to thymine (T) single nucleotide polymorphism (SNP) of the human cannabinoid receptor 1 (CNR1) gene is associated with positive emotional processing.
C allele carriers are more sensitive to positive emotional stimuli including happiness. The effects of several gene polymorphisms related to sensitivity to emotional stimuli, such as that in the serotonin transporter gene-linked polymorphic region (5HTTLPR), on emotional processing have been reported to differ among cultures-e.g., between those that are independent and interdependent. Thus, we postulated that the effects of the CNR1 genotype on happiness might differ among different cultures because the concept of happiness varies by culture.
We recruited healthy male and female young adults in Japan, where favorable external circumstances determine the concept of happiness, and Canada, where the concept of happiness centers on positive inner feelings, and compared the effects of the CNR1 genotype on both subjective happiness levels (self-evaluation as being a happy person) and situation-specific happiness (happy feelings accompanying various positive events) by using a questionnaire.
We found that the effect of CNR1 on subjective happiness was different between the Japanese and Canadian groups. The subjective happiness level was the highest in Japanese individuals with the CC genotype, whereas in Canadian participants, it was the highest in individuals with the TT genotype. Furthermore, the effects of CNR1 genotype on situation-specific happiness were also different between the groups. Happiness accompanied with being surrounded by happy people was the highest among Japanese individuals with the CC genotype, whereas among Canadian individuals, it was the highest in TT genotype carriers.
These findings suggest that culture and CNR1 polymorphism interact to influence the perception of happiness.”
“A small body of work has started developing cannabis use “typologies” for use in treatment and prevention.
Two potentially relevant dimensions for classifying cannabis use typologies are medical versus recreational cannabis use and the co-use of cannabis and alcohol.
Here we compare alcohol use and related problems between cannabis users with and without medical cannabis recommendations.