Tag Archives: therapeutic

Practical considerations in medical cannabis administration and dosing.

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European Journal of Internal Medicine

“Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised controlled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment.

With the advent of pharmaceutical cannabis-based medicines (Sativex/nabiximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable.

In this article, the authors endeavour to present concise data on cannabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance.

CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks.

Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities.”

https://www.ncbi.nlm.nih.gov/pubmed/29307505
http://www.ejinme.com/article/S0953-6205(18)30004-9/fulltext

Surprising outcomes in cannabinoid CB1/CB2 receptor double knockout mice in two models of ischemia.

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“Although the number of individuals suffering from stroke in the United States and worldwide will continue to grow, therapeutic intervention for treatment following stroke remains frustratingly limited.

Both the cannabinoid 1 receptor (CB1R) and the cannabinoid 2 receptor (CB2R) have been studied in relationship to stroke. Deletion of the CB2R has been shown to worsen outcome, while selective CB2R agonists have been demonstrated to be neuroprotective following stroke.

We tested the hypothesis that CB1/CB2 receptor double knockout would produce significant increases in infarct size and volume and significant worsening in clinical score, using two mouse models, one of permanent ischemia and one of ischemia/reperfusion.

The results surprisingly revealed that CB1/CB2 double knockout mice showed improved outcomes, with the most improvements in the mouse model of permanent ischemia.

Although initial studies of CB1R knockout mice demonstrated increased injury following stroke, indicating that activation of the CB1R was neuroprotective, later studies of selective antagonists of the CB1R also demonstrated a protective effect.

Surprisingly the double knockout animals had improved outcome.

Since the phenotype of the double knockout is not dramatically changed, significant changes in the contribution of other homeostatic pathways in compensation for the loss of these two important receptors may explain these apparently contradictory results.”

https://www.ncbi.nlm.nih.gov/pubmed/29288767

http://www.sciencedirect.com/science/article/pii/S002432051730677X

Expression of cannabinoid 1 and, 2 receptors and the effects of cannabinoid 1 and, 2 receptor agonists on detrusor overactivity associated with bladder outlet obstruction in rats.

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“This study investigated changes in the expression of cannabinoid (CB) receptors and the effects of CB1 and CB2 agonists on detrusor overactivity (DO) associated with bladder outlet obstruction (BOO) in rats.

CONCLUSIONS:

CB1 and CB2 receptors, especially CB1, play a role in the pathophysiology of BOO-associated DO, and could serve as therapeutic targets.”  https://www.ncbi.nlm.nih.gov/pubmed/29284441

“The results of this study suggest that CB1 and CB2 receptors in the bladder, particularly CB1 receptors, play a significant role in the pathophysiology of BOO-associated DO, and could serve as diagnostic biomarker and therapeutic targets in this disorder.”
https://bmcurol.biomedcentral.com/articles/10.1186/s12894-017-0313-4

From “Azalla” to Anandamide: Distilling the Therapeutic Potential of Cannabinoids

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Biological Psychiatry Home

“Cannabis has held a unique place in the hearts and minds of people since time immemorial: some have exalted its properties and considered it to be sacred; others have reviled it, considering it a root cause of social evil.

The Assyrians, who lived about 3000 years ago, documented the effects of cannabis on clay tablets. They referred to the plant according to its various uses: as “azalla,” when used as a medical agent; as hemp; and as “gan-zi-gun-nu”—“the drug that takes away the mind”   These seemingly contradictory properties—a substance that can be both a therapeutic agent and a corrupting psychoactive drug—have continued to puzzle us over the ensuing centuries.

As early as the 11th century, excessive cannabis use was suggested to be a cause of “moral degeneracy.”  On the other hand, the ostensible therapeutic value of cannabis was documented extensively in the early 19th century by Sir William B. O’Shaughnessy, an Irish physician working in Calcutta, India.

Given the critical role of the endocannabinoid system in modulating anxiety, it is clear that compounds that can modulate this system offer great promise as therapeutic agents for psychiatric disorders. It is therefore not surprising that the concept of medical marijuana is compelling to laypersons, clinicians, and researchers alike.

While there is not yet a robust body of literature supporting any specific psychiatric indication (despite the regulatory approval in some states of medical marijuana for specific psychiatric disorders), active lines of investigation of therapeutic targets within the endocannabinoid system offer hope for better treatment options.

The evidence at present suggests that the question of whether cannabinoids are good or bad is not dichotomous—it is likely both good and bad depending on the context of use, including dose, duration of exposure, and an individual’s genetic vulnerabilities. Therefore, the challenge that remains is to distill the good therapeutic effects of cannabinoids and thus weed out “gan-zi-gun-nu” from “azalla.””

http://www.biologicalpsychiatryjournal.com/article/S0006-3223(17)32207-2/fulltext

 

The endocannabinoid system in cardiovascular function: novel insights and clinical implications.

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Clinical Autonomic Research

“Cardiovascular disease is now recognized as the number one cause of death in the world, and the size of the population at risk continues to increase rapidly. The dysregulation of the endocannabinoid (eCB) system plays a central role in a wide variety of conditions including cardiovascular disorders. Cannabinoid receptors, their endogenous ligands, as well as enzymes conferring their synthesis and degradation, exhibit overlapping distributions in the cardiovascular system. Furthermore, the pharmacological manipulation of the eCB system has effects on blood pressure, cardiac contractility, and endothelial vasomotor control. Growing evidence from animal studies supports the significance of the eCB system in cardiovascular disorders.

RESULTS:

Drugs targeting CB1R, CB2R, TRPV1 and PPARs are proven effective in animal models mimicking cardiovascular disorders such as hypertension, atherosclerosis and myocardial infarction. Despite the setback of two clinical trials that exhibited unexpected harmful side-effects, preclinical studies are accelerating the development of more selective drugs with promising results devoid of adverse effects.

CONCLUSION:

Over the last years, increasing evidence from basic and clinical research supports the role of the eCB system in cardiovascular function. Whereas new discoveries are paving the way for the identification of novel drugs and therapeutic targets, the close cooperation of researchers, clinicians and pharmaceutical companies is needed to achieve successful outcomes.”

https://www.ncbi.nlm.nih.gov/pubmed/29222605

https://link.springer.com/article/10.1007%2Fs10286-017-0488-5

Therapeutic Value of Medical Marijuana in New Jersey Patients: A Community Partnership Research Endeavor.

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“The Public Health Program at Stockton University partnered with the Compassionate Care Foundation to ascertain the impact of medical marijuana on patients in New Jersey.

Results provide insight into the diagnoses for which patients used medical marijuana.

Results indicate increased mood, general overall condition, and energy as the highest consequences; level of pain in the middle range; and most frequent usage as 3 to 4 times a day. Repeated measures done after visit 2 showed eight statistically significant differences for patients after using medical marijuana: an increase in general quality of life, mobility, and mood, with a decrease in inflammation, intraocular pressure, spasms, seizures, and pain.

Results after visit 3 indicated seven significant differences compared to visit 1: decreased seizures, intraocular pressure, spasms, nausea, and pain, along with increased energy and mobility. No differences were found by patient diagnosis or age, but sex-related differences occurred in inflammation, mood, and energy.

Results support positive therapeutic benefits of medical marijuana, and despite methodological limitations, our study contributes to the growing body of literature.”

https://www.ncbi.nlm.nih.gov/pubmed/29202158

 

Therapeutic use of Δ9-THC and cannabidiol: evaluation of a new extraction procedure for the preparation of cannabis-based olive oil.

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“Since 2013 Cannabis-based preparations, containing the two main cannabinoids of interest, Δ9-tetrahydrocannabinol (THC), and cannabidiol (CBD), can be used for therapeutic purposes, such as palliative care, neurodegenerative disorder treatment and other therapies.

The preparations may consist of a drug partition in sachets, capsules or through the extraction in certified olive oil.

OBJECTIVE:

the aims of the study were: a) to develop and validate a new liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for the identification and quantification of THC and CBD in olive oil; b) to evaluate the extraction efficiency and reproducibility of a new commercial extractor on the market.

METHODS:

the olive oil was simply diluted three consecutive times, using organic solvents with increasing polarity index (n-hexane → isopropanol → methanol). The sample was then direct injected into LC-MS/MS system, operating in Multiple Reaction Monitoring Mode, in positive polarization. The method was then fully validated.

RESULTS:

The method assessed to be linear over the range 0.1-10 ng/µL for both THC and CBD. Imprecision and accuracy were within 12.2% and 16.9% respectively; matrix effects proved to be negligible; THC concentration in oil is stable up to two months at room temperature, whenever kept in the dark. CBD provided a degradation of 30% within ten weeks. The method was then applied to olive oil after sample preparation, in order to evaluate the efficiency of extraction of a new generation instrument. Temperature of extraction is the most relevant factor to be optimized. Indeed, a difference of 2 °C (from 94.5°C to 96.5°C, the highest temperature reached in the experiments) of the heating phase, increases the percentage of extraction from 54.2% to 64.0% for THC and from 58.2% to 67.0% for CBD. The amount of THC acid and CBD acid that are decarboxylated during the procedure must be check out in the future.

CONCLUSION:

the developed method was simple and fast. The extraction procedure proved to be highly reproducible and applicable routinely to cannabis preparations.”

https://www.ncbi.nlm.nih.gov/pubmed/29189144

http://www.eurekaselect.com/157854/article

“Extraction Method and Analysis of Cannabinoids in Cannabis Olive Oil Preparations.”  https://www.ncbi.nlm.nih.gov/pubmed/29202510

Selective cannabinoid 2 receptor stimulation reduces tubular epithelial cell damage following renal ischemia-reperfusion injury.

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Journal of Pharmacology and Experimental Therapeutics “Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), which is an increasing problem in the clinic and has been associated with increased rates of mortality. Currently, therapies to treat AKI are not available, so identification of new targets which, upon diagnosis of AKI, can be modulated to ameliorate renal damage is essential.

In this study, a novel cannabinoid receptor 2 (CB2) agonist, SMM-295, was designed, synthesized, and tested in vitro and in silico.

These data suggests that selective CB2 receptor activation could be a potential therapeutic target in the treatment for AKI.”

https://www.ncbi.nlm.nih.gov/pubmed/29187590

http://jpet.aspetjournals.org/content/early/2017/11/29/jpet.117.245522

Targeting Cannabinoid Signaling in the Immune System: “High”-ly Exciting Questions, Possibilities, and Challenges.

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“It is well known that certain active ingredients of the plants of Cannabis genus, i.e., the “phytocannabinoids” [pCBs; e.g., (-)-trans-Δ9-tetrahydrocannabinol (THC), (-)-cannabidiol, etc.] can influence a wide array of biological processes, and the human body is able to produce endogenous analogs of these substances [“endocannabinoids” (eCB), e.g., arachidonoylethanolamine (anandamide, AEA), 2-arachidonoylglycerol (2-AG), etc.].

These ligands, together with multiple receptors (e.g., CB1 and CB2 cannabinoid receptors, etc.), and a complex enzyme and transporter apparatus involved in the synthesis and degradation of the ligands constitute the endocannabinoid system (ECS), a recently emerging regulator of several physiological processes.

The ECS is widely expressed in the human body, including several members of the innate and adaptive immune system, where eCBs, as well as several pCBs were shown to deeply influence immune functions thereby regulating inflammation, autoimmunity, antitumor, as well as antipathogen immune responses, etc.

Based on this knowledge, many in vitro and in vivo studies aimed at exploiting the putative therapeutic potential of cannabinoid signaling in inflammation-accompanied diseases (e.g., multiple sclerosis) or in organ transplantation, and to dissect the complex immunological effects of medical and “recreational” marijuana consumption.

Thus, the objective of the current article is (i) to summarize the most recent findings of the field; (ii) to highlight the putative therapeutic potential of targeting cannabinoid signaling; (iii) to identify open questions and key challenges; and (iv) to suggest promising future directions for cannabinoid-based drug development.”   https://www.ncbi.nlm.nih.gov/pubmed/29176975

“Although, many open questions await to be answered, pharmacological modulation of the (endo)cannabinoid signaling, and restoration of the homeostatic eCB tone of the tissues augur to be very promising future directions in the management of several pathological inflammation-accompanied diseases.”   https://www.frontiersin.org/articles/10.3389/fimmu.2017.01487/full

Inhibition of monoacylglycerol lipase terminates diazepam-resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet.

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Epilepsia

“Status epilepticus (SE) is a life-threatening and commonly drug-refractory condition. Novel therapies are needed to rapidly terminate seizures to prevent mortality and morbidity.

Monoacylglycerol lipase (MAGL) is the key enzyme responsible for the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) and a major contributor to the brain pool of arachidonic acid (AA). Inhibiting of monoacylglycerol lipase modulates synaptic activity and neuroinflammation, 2 mediators of excessive neuronal activation underlying seizures.

We studied the effect of a potent and selective irreversible MAGL inhibitor, CPD-4645, on SE that was refractory to diazepam, its neuropathologic sequelae, and the mechanism underlying the drug’s effects.

SIGNIFICANCE:

MAGL represents a novel therapeutic target for treating status epilepticus and improving its sequelae. CPD-4645 therapeutic effects appear to be predominantly mediated by modulation of neuroinflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/29171003

http://onlinelibrary.wiley.com/doi/10.1111/epi.13950/abstract?systemMessage=Wiley+Online+Library+usage+report+download+page+will+be+unavailable+on+Friday+24th+November+2017+at+21%3A00+EST+%2F+02.00+GMT+%2F+10%3A00+SGT+%28Saturday+25th+Nov+for+SGT+