The endocannabinoid system as a target for addiction treatment: Trials and tribulations.

Posted on June 1, 2017 by David

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“Addiction remains a major public health concern, and while pharmacotherapies can be effective, clinicians are limited by the paucity of existing interventions. Endocannabinoid signaling is involved in reward and addiction, which raises the possibility that drugs targeting this system could be used to treat substance use disorders. This review discusses findings from randomized controlled trials evaluating cannabinergic medications for addiction.

Current evidence suggests that pharmacotherapies containing delta-9-tetrahydrocannabinol, such as dronabinol and nabiximols, are effective for cannabis withdrawal. Dronabinol may also reduce symptoms of opioid withdrawal. The cannabinoid receptor 1 (CB1) inverse agonist rimonabant showed promising effects for smoking cessation but also caused psychiatric side effects and currently lacks regulatory approval. Few trials have investigated cannabinergic medications for alcohol use disorder.

Overall, the endocannabinoid system remains a promising target for addiction treatment. Development of novel medications such as fatty acid amide hydrolase inhibitors and neutral CB1 antagonists promises to extend the range of available interventions.”

https://www.ncbi.nlm.nih.gov/pubmed/28564576

http://www.sciencedirect.com/science/article/pii/S0028390817302563

[Therapeutic potential of Cannabis sativa].

Posted on May 27, 2017 by David

SciELO - Scientific Electronic Library Online

“Cannabis sativa (marihuana) is considered an illicit drug due to its psychoactive properties. Recently, the Chilean government opened to the use cannabis in the symptomatic treatment of some patients. The biological effects of cannabis render it useful for the complementary treatment of specific clinical situations such as chronic pain. We retrieved scientific information about the analgesic properties of cannabis, using it as a safe drug. The drug may block or inhibit the transmission of nervous impulses at different levels, an effect associated with pain control. Within this context and using adequate doses, forms and administration pathways, it can be used for chronic pain management, considering its effectiveness and low cost. It could also be considered as an alternative in patients receiving prolonged analgesic therapies with multiple adverse effects.”

https://www.ncbi.nlm.nih.gov/pubmed/28548193

http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0034-98872017000300010&lng=en&nrm=iso&tlng=en

Single and combined effects of delta9 -tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy-induced neuropathic pain.

Posted on May 27, 2017 by David

British Journal of Pharmacology

“It has been suggested that the non-psychoactive phytocannabinoid cannabidiol (CBD) can impact the pharmacological effects of delta-9-tetrahydrocannabinol (THC). We tested the hypothesis that CBD and THC would significantly mitigate mechanical sensitivity in a mouse model of paclitaxel-induced neuropathic pain, and that CBD+THC combinations would produce synergistic effects. We also tested the hypothesis that CBD would attenuate oxaliplatin- and vincristine- induced mechanical sensitivity.

KEY RESULTS:

Both CBD and THC alone attenuated mechanical allodynia in mice treated with paclitaxel. Very low ineffective doses of CBD and THC were synergistic when given in combination. CBD also attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity, while THC significantly attenuated vincristine- but not oxaliplatin-induced mechanical sensitivity. The low dose combination significantly attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity.

CONCLUSIONS AND IMPLICATIONS:

CBD may be potent and effective at preventing the development of CIPN, and its clinical utility may be enhanced by co-administration of low doses of THC. These treatment strategies would increase the therapeutic window of Cannabis-based pharmacotherapies.”

https://www.ncbi.nlm.nih.gov/pubmed/28548225

http://onlinelibrary.wiley.com/doi/10.1111/bph.13887/abstract

Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities.

Posted on May 26, 2017 by David

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“Cannabinoid pharmacology has been intensely studied because of cannabis’ pervasive medicinal and non-medicinal uses as well as for the therapeutic potential of cannabinoid-based drugs for the treatment of pain, anxiety, substance abuse, obesity, cancer and neurodegenerative disorders. The identification of allosteric modulators of the cannabinoid receptor 1 (CB₁) has given a new direction to the development of cannabinoid-based therapeutics due to the many advantages offered by targeting allosteric site(s). Allosteric receptor modulators hold potential to develop subtype-specific and pathway-specific therapeutics. Here we briefly discuss the first-generation of allosteric modulators of CB₁ receptor, their structure-activity relationships, signaling pathways and the allosteric binding site(s) on the CB₁ receptor.”

https://www.ncbi.nlm.nih.gov/pubmed/28527758

http://www.sciencedirect.com/science/article/pii/S0028390817302307

In silico gene expression profiling in Cannabis sativa.

Posted on May 26, 2017 by David

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“The cannabis plant and its active ingredients (i.e., cannabinoids and terpenoids) have been socially stigmatized for half a century. Luckily, with more than 430,000 published scientific papers and about 600 ongoing and completed clinical trials, nowadays cannabis is employed for the treatment of many different medical conditions. Nevertheless, even if a large amount of high-throughput functional genomic data exists, most researchers feature a strong background in molecular biology but lack advanced bioinformatics skills. In this work, publicly available gene expression datasets have been analyzed giving rise to a total of 40,224 gene expression profiles taken from cannabis plant tissue at different developmental stages. The resource presented here will provide researchers with a starting point for future investigations with Cannabis sativa.” https://www.ncbi.nlm.nih.gov/pubmed/28529696

“Today, cannabis and its derivatives are successfully employed for treatment of a large number of different pathological conditions. Cannabis sativa is a versatile plant – it is being used for medical as well as for industrial purposes. Like in other plants, the cannabis genome is highly redundant and difficult to resolve. It is very likely that false negatives have caused important transcripts to still be missing. Nevertheless, these 40,224 gene expression profiles will provide researchers with a valuable resource and important genomic insights for future investigations with Cannabis sativa.” https://f1000research.com/articles/6-69/v1

Pharmacogenetics of Cannabinoids.

Posted on May 26, 2017 by David

European Journal of Drug Metabolism and Pharmacokinetics

“Although the application of medical marijuana and cannabinoid drugs is controversial, it is a part of modern-day medicine.

The list of diseases in which cannabinoids are promoted as a treatment is constantly expanding. Cases of significant improvement in patients with a very poor prognosis of glioma or epilepsy have already been described. However, the occurrence of side effects is still difficult to estimate, and the current knowledge of the therapeutic effects of cannabinoids is still insufficient.

In our opinion, the answers to many questions and concerns regarding the medical use of cannabis can be provided by pharmacogenetics. Knowledge based on proteins and molecules involved in the transport, action, and metabolism of cannabinoids in the human organism leads us to predict candidate genes which variations are responsible for the presence of the therapeutic and side effects of medical marijuana and cannabinoid-based drugs.

We can divide them into: receptor genes-CNR1, CNR2, TRPV1, and GPR55, transporters-ABCB1, ABCG2, SLC6A, biotransformation, biosynthesis, and bioactivation proteins encoded by CYP3A4, CYP2C19, CYP2C9, CYP2A6, CYP1A1, COMT, FAAH, COX2, ABHD6, ABHD12 genes, and also MAPK14. This review organizes the current knowledge in the context of cannabinoids pharmacogenetics according to individualized medicine and cannabinoid drugs therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/28534260

“There is a feeling that the next milestone, after legal acceptance of medical marijuana, will be intensive pharmacogenetic-oriented study of individual populations, which hopefully explain the previous contradictory results and identify in the future genetic markers to personalize cannabinoids treatment.” https://link.springer.com/article/10.1007%2Fs13318-017-0416-z

Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome

Posted on May 25, 2017 by David

“BACKGROUND

The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome.

METHODS

In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period.

RESULTS

The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence interval [CI], −41.1 to −5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.

CONCLUSIONS

Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375.)”

http://www.nejm.org/doi/10.1056/NEJMoa1611618

“Cannabinoids for Epilepsy — Real Data, at Last” http://www.nejm.org/doi/full/10.1056/NEJMe1702205

“Cannabidiol (CBD) Significantly Reduces Convulsive Seizure Frequency in Dravet Syndrome (DS): Results of a Multi-center, Randomized, Double-blind, Placebo-controlled Trial (GWPCARE1)” http://files.shareholder.com/downloads/AMDA-1TW341/201889199x0x919787/73B57FA6-CD45-4ABB-8C89-87EFEA36B4ED/1332B_AES_Poster_Dravet_Part_B_.pdf

“EPILEPSY AND MARIJUANA: CANNABIS DRUG REDUCES DRAVET SYNDROME SEIZURES IN LARGE-SCALE CLINICAL TRIAL” http://www.newsweek.com/cannabis-marijuana-dravet-syndrome-epilepsy-clinical-trial-614982

“Study proves medicinal cannabis can help children with severe epilepsy, researchers say” http://www.abc.net.au/news/2017-05-25/scientific-study-medicinal-cannabis-helps-children-with-epilepsy/8556180

“Cannabis Drug Reduces Seizures in Severe Epilepsy Cases” http://www.nbcnews.com/health/health-news/cannabis-drug-reduces-seizures-severe-epilepsy-cases-n764381

“Marijuana Extract Cuts Seizures In Uncommon Epilepsy” http://www.scienceworldreport.com/articles/59637/20170525/marijuana-extract-cuts-seizures-severe-epilepsy.htm

“Time to say ‘I told you so’: cannabis can treat seizures” https://www.theverge.com/2017/5/24/15684556/cannabis-marijuana-cannabidiol-health-epilepsy-dravet-seizure-epidiolex-drugs

Evaluation of Cannabidiol in Animal Seizure Models by the Epilepsy Therapy Screening Program (ETSP).

Posted on May 10, 2017 by David

Neurochemical Research

“Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy.

Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs). Initial studies appear to demonstrate that CBD preparations may be a useful treatment for pharmacoresistant epilepsy.

The National Institute of Neurological Disorders and Stroke (NINDS) funded Epilepsy Therapy Screening Program (ETSP) investigated CBD in a battery of seizure models using a refocused screening protocol aimed at identifying pharmacotherapies to address the unmet need in pharmacoresistant epilepsy. Applying this new screening workflow, CBD was investigated in mouse 6 Hz 44 mA, maximal electroshock (MES), corneal kindling models and rat MES and lamotrigine-resistant amygdala kindling models.

Following intraperitoneal (i.p.) pretreatment, CBD produced dose-dependent protection in the acute seizure models; mouse 6 Hz 44 mA (ED₅₀ 164 mg/kg), mouse MES (ED₅₀ 83.5 mg/kg) and rat MES (ED₅₀ 88.9 mg/kg). In chronic models, CBD produced dose-dependent protection in the corneal kindled mouse (ED₅₀ 119 mg/kg) but CBD (up to 300 mg/kg) was not protective in the lamotrigine-resistant amygdala kindled rat. Motor impairment assessed in conjunction with the acute seizure models showed that CBD exerted seizure protection at non-impairing doses.

The ETSP investigation demonstrates that CBD exhibits anti-seizure properties in acute seizure models and the corneal kindled mouse. However, further preclinical and clinical studies are needed to determine the potential for CBD to address the unmet needs in pharmacoresistant epilepsy.” https://www.ncbi.nlm.nih.gov/pubmed/28478594

https://link.springer.com/article/10.1007%2Fs11064-017-2287-8

Cannabidiol administration reduces sublesional cancellous bone loss in rats with severe spinal cord injury.

Posted on May 10, 2017 by David

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“Patients with spinal cord injury (SCI) undergo severe loss of bone mineral below the level of lesion, and data on available treatment options after SCI is scarce.

The aim of this work was to investigate the therapeutic effect of cannabidiol (CBD), a non-psychoactive cannabis, on sublesional bone loss in a rat model of SCI.

In conclusion, CBD administration attenuated SCI-induced sublesional cancellous bone loss.”

https://www.ncbi.nlm.nih.gov/pubmed/28479140

http://www.sciencedirect.com/science/article/pii/S0014299917303230

Compound found in cannabis helps ‘shrink’ four-year-old’s brain tumour

Posted on May 2, 2017 by David

Four-year-old William Frost from Newark

“The family of a four-year-old boy from Nottinghamshire are backing new research into whether a non-psychoactive compound found in cannabis can reduce paediatric brain cancer cells.

Experts from Nottingham’s Children’s Brain Tumour Research Centre, at The University of Nottingham, will test Cannabidiol (CBD) for its effects on paediatric brain tumours in youngsters. This research will form part of the pre-clinical phase of the evaluation of the potential use of cannabidiol in paediatric brain tumours” http://www.nottinghampost.com/compound-found-in-cannabis-helps-shrink-four-year-old-s-brain-tumour/story-30307458-detail/story.html

“Scientists plan study after Nottinghamshire boy’s tumour shrinks during cannabis compound treatment” https://nottstv.com/notts-scientists-treating-brain-tumours-with-cannabis-backed-by-four-year-old-boy-with-the-condition/

“Study looks at cannabis ingredient’s ability to help children’s tumours. UK research into cannabidiol (CBD) comes after surge in parents administering it to children without medical advice” https://www.theguardian.com/society/2017/may/02/study-cannabis-cannabidiol-cbd-ability-to-help-children-brain-tumours