The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No “Strain,” No Gain

Image result for frontiers in plant science

“The current wave of excitement in Cannabis commerce has translated into a flurry of research on alternative sources, particularly yeasts, and complex systems for laboratory production have emerged, but these presuppose that single compounds are a desirable goal. Rather, the case for Cannabis synergy via the “entourage effect” is currently sufficiently strong as to suggest that one molecule is unlikely to match the therapeutic and even industrial potential of Cannabis itself as a phytochemical factory.

These studies and others provide a firm foundation for Cannabis synergy, and support for botanical drug development vs. that of single components, or production via fermentation methods in yeast or other micro-organisms.

This article has briefly outlined recently technological attempts to “reinvent the phytocannabinoid wheel.” Cogent arguments would support that it can be done, but should it be done? The data supporting the existence of Cannabis synergy and the astounding plasticity of the Cannabis genome suggests a reality that obviates the need for alternative hosts, or even genetic engineering of Cannabis sativa, thus proving that, “The plant does it better.””
Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

∆9-Tetrahydrocannabinol, a major marijuana component, enhances the anesthetic effect of pentobarbital through the CB1 receptor.

 “∆9 Tetrahydrocannabinol (∆9-THC) and cannabidiol (CBD), major psychoactive constituents of marijuana, induce potentiation of pentobarbital-induced sleep in mice.

We have elucidated the mechanism of enhancement of the anesthetic effect of pentobarbital by cannabinoids.

These results suggest that binding of ∆9-THC to the CB1 receptor is involved in the synergism with pentobarbital, and that potentiating effect of CBD with pentobarbital may differ from that of ∆9-THC. We successfully demonstrated that ∆9-THC enhanced the anesthetic effect of pentobarbital through the CB1 receptor.”

https://www.ncbi.nlm.nih.gov/pubmed/30636988

“The pharmacological results indicate the effect of ∆9-THC co-administered with pentobarbital was a synergistic, but not additive, action in mice. Further evidence suggests the CB1 receptor plays an important role as a trigger in potentiating pentobarbital-induced sleep by ∆9-THC.”

https://link.springer.com/article/10.1007%2Fs11419-018-0457-2

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Epidiolex (Cannabidiol): A New Hope for Patients With Dravet or Lennox-Gastaut Syndromes.

 SAGE Journals

“OBJECTIVE: To review the efficacy, safety, pharmacology and pharmacokinetics of pure, plant-derived cannabidiol (CBD; Epidiolex) in the treatment of Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).

DATA SYNTHESIS: Pure, plant-based CBD is a pharmaceutical grade extract that exhibits clinically significant antiseizure properties, with a hypothesized multimodal mechanism of action. In the GWPCARE trial series, CBD displayed superior efficacy in reducing key seizure frequencies (convulsive seizures in DS; drop seizures in LGS) by 17% to 23% compared with placebo as adjunctive therapy to standard antiepileptic drugs in patients 2 years of age and older. Common adverse effects were somnolence, diarrhea, and elevated hepatic transaminases. Noteworthy drug-drug interactions included clobazam, valproates, and significant inducers/inhibitors of CYP2C19 and 3A4 enzymes.

Relevance to Patient Care and Clinical Practice: A discussion regarding CBD dosing, administration, adverse effects, monitoring parameters, and interactions is provided to guide clinicians. CBD offers patients with DS and LGS a new treatment option for refractory seizures.

CONCLUSION:

This is the first cannabis-derived medication with approval from the US Food and Drug Administration. This CBD formulation significantly reduces seizures as an adjunct to standard antiepileptic therapies in patients ≥2 years old with DS and LGS and is well tolerated.”

https://www.ncbi.nlm.nih.gov/pubmed/30616356

https://journals.sagepub.com/doi/abs/10.1177/1060028018822124?journalCode=aopd

“Why marijuana is headed for the mainstream. The credibility of cannabis as a source of a legitimate pharmaceutical ingredient in prescription medications took a major step forward in 2018 when the FDA approved Epidiolex (cannabidiol) for two types of severe seizures. Epidiolex was a stellar candidate for approval. It reduced convulsive seizures by about 40% and has a good safety profile.”  https://www.ncbi.nlm.nih.gov/pubmed/30620324

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Cortical surface morphology in long-term cannabis users: A multi-site MRI study.

 European Neuropsychopharmacology

“Cannabis exerts its psychoactive effect through cannabinoid receptors that are widely distributed across the cortical surface of the human brain. It is suggested that cannabis use may contribute to structural alterations across the cortical surface.

In a large, multisite dataset of 120 controls and 141 cannabis users, we examined whether differences in key characteristics of the cortical surface – including cortical thickness, surface area, and gyrification index were related to cannabis use characteristics, including (i) cannabis use vs. non-use, (ii) cannabis dependence vs. non-dependence vs. non-use, and (iii) early adolescent vs. late adolescent onset of cannabis use vs. non-use.

Our results revealed that cortical morphology was not associated with cannabis use, dependence, or onset age.

The lack of effect of regular cannabis use, including problematic use, on cortical structure in our study is contrary to previous evidence of cortical morphological alterations (particularly in relation to cannabis dependence and cannabis onset age) in cannabis users.

Careful reevaluation of the evidence on cannabis-related harm will be necessary to address concerns surrounding the long-term effects of cannabis use and inform policies in a changing cannabis regulation climate.”

https://www.ncbi.nlm.nih.gov/pubmed/30558823

https://www.sciencedirect.com/science/article/pii/S0924977X18319874?via%3Dihub

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Cannabinoid CB1 Receptor Antagonist Rimonabant Decreases Levels of Markers of Organ Dysfunction and Alters Vascular Reactivity in Aortic Vessels in Late Sepsis in Rats.

“Sepsis is a life-threatening condition with high mortality rates that is caused by dysregulation of the host response to infection. We previously showed that treatment with the cannabinoid CB1 receptor antagonist rimonabant reduced mortality rates in animals with sepsis that was induced by cecal ligation and puncture (CLP). This improvement in the survival rate appeared to be related to an increase in arginine vasopressin (AVP) levels 12 h after CLP.

The present study investigated the effects of rimonabant on organ dysfunction, hematologic parameters, and vascular reactivity in male Wistar rats with sepsis induced by CLP. Intraperitoneal treatment with rimonabant (10 mg/kg, 4 h after CLP) abolished the increase in the plasma levels of lactate, lactate dehydrogenase, glucose, and creatinine kinase MB without altering hematological parameters (i.e., leukopenia and a reduction of platelet counts). CLP increased plasma levels of nitrate/nitrite (NOx) and induced vasoconstriction in the tail artery. The treatment of CLP rats with rimonabant did not alter NOx production but reduced the vasoconstriction. Rimonabant also attenuated the hyperreactivity to AVP induced by CLP without affecting hyporesponsiveness to phenylephrine in aortic rings.

These results suggest that rimonabant reduces organ dysfunction during sepsis, and this effect may be related to AVP signaling in blood vessels. This effect may have contributed to the higher survival rate in rimonabant-treated septic animals.”

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Cannabis-based products for pediatric epilepsy: A systematic review.

Epilepsia banner

“Evidence from high-quality randomized controlled trials (RCTs) suggests that cannabidiol probably reduces seizures among children with drug-resistant epilepsy (moderate certainty).”

https://www.ncbi.nlm.nih.gov/pubmed/30515765 

https://onlinelibrary.wiley.com/doi/abs/10.1111/epi.14608

“Phytocannabinoids produce anticonvulsant effects through the endocannabinoid system, with few adverse effects.” https://www.ncbi.nlm.nih.gov/pubmed/25475762

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Peripubertal cannabidiol treatment rescued behavioral and neurochemical abnormalities in MAM model of schizophrenia.

 Neuropharmacology

“In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression which might be due to a reduction in DNA methylation at gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult.”

https://www.ncbi.nlm.nih.gov/pubmed/30496751

https://www.sciencedirect.com/science/article/pii/S0028390818308761?via%3Dihub

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Novel inverse agonists for the orphan G protein-coupled receptor 6.

Image result for Heliyon.

“The orphan G protein-coupled receptor 6 (GPR6) displays unique promise as a therapeutic target for the treatment of neuropsychiatric disorders due to its high expression in the striatopallidal neurons of the basal ganglia.

GPR6, along with closely related orphan receptors GPR3 and GPR12, are phylogenetically related to CB1 and CB2 cannabinoid receptors.

In the current study, we performed concentration-response studies on the effects of three different classes of cannabinoids: endogenous, phyto-, and synthetic, on both GPR6-mediated cAMP accumulation and β-arrestin2 recruitment. In addition, structure-activity relationship studies were conducted on cannabidiol (CBD), a recently discovered inverse agonist for GPR6.

We have identified four additional cannabinoids, cannabidavarin (CBDV), WIN55212-2, SR141716A and SR144528, that exert inverse agonism on GPR6. Furthermore, we have discovered that these cannabinoids exhibit functional selectivity toward the β-arrestin2 recruitment pathway.

These novel, functionally selective inverse agonists for GPR6 can be used as research tools and potentially developed into therapeutic agents.”

https://www.ncbi.nlm.nih.gov/pubmed/30480157

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Inhibition of Cannabinoid Receptor 1 Can Influence the Lipid Metabolism in Mice with Diet-Induced Obesity.

“A growing number of evidences accumulated about critical metabolic role of cannabinoid type 1 receptor (CB1), carnitine palmitoyltransferase-1 (CPT1) and peroxisome proliferator-activated receptors (PPARs) in some peripheral tissues, including adipose tissue, liver, skeletal muscle and heart.

Taken together, these data indicate that the inhibition of CB1 could ameliorate lipid metabolism via the stimulation of the CPT1A and CPT1B expression in vivo. Simultaneously, the PPARα and PPARγ expression levels significantly differed compared to that of PPARβ in obesity and lipid metabolism-related disorders under blockade of CB1.

Both the mechanism of the influence of CB1 inhibition on lipid metabolism in the examined tissues and the specific mechanism of PPARα, PPARγ and PPARβ involvement in lipid exchange under these conditions remain to be further elucidated.”

https://www.ncbi.nlm.nih.gov/pubmed/30472964

https://link.springer.com/article/10.1134%2FS0006297918100127

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous