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

Perspectives on marijuana use and effectiveness: A survey of NARCOMS participants.

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Home“Interest in and use of marijuana by persons with multiple sclerosis (MS) has increased. While potential benefits have been reported, so have concerns about potential risks. Few large studies have been conducted about the perceptions and current usage of marijuana and medical cannabinoids in persons with MS.

METHODS:

Participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry were surveyed in 2014 regarding legality and history of marijuana usage, both before and after diagnosis with MS.

RESULTS:

A total of 5,481 participants responded, with 78.2% female, 90% relapsing disease at onset, and a current mean age of 55.5 (10.2) years. Sixty-four percent had tried marijuana prior to their MS diagnosis, 47% have considered using for their MS, 26% have used for their MS, 20% have spoken with their physician about use, and 16% are currently using marijuana. Ninety-one percent think marijuana should be legal in some form. Men, those with higher disability, current and past nicotine smokers, and younger age were associated with a higher likelihood of current use.

CONCLUSIONS:

The majority of responders favor legalization and report high interest in the use of marijuana for treatment of MS symptoms, but may be reluctant to discuss this with health care providers. Health care providers should systematically inquire about use of marijuana.”

https://www.ncbi.nlm.nih.gov/pubmed/29185555

 http://cp.neurology.org/content/7/4/333

Antinociceptive effects of mixtures of mu opioid receptor agonists and cannabinoid receptor agonists in rats: impact of drug and fixed-dose ratio.

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“Pain is a significant clinical problem, and there is a need for effective pharmacotherapies with fewer adverse effects than currently available drugs (e.g., mu opioid receptor agonists).

Cannabinoid receptor agonists enhance the antinociceptive effects of mu opioid receptor agonists, but it remains unclear which drugs and in what proportion will yield the most effective and safest treatments.

The antinociceptive effects of the mu opioid receptor agonists etorphine and morphine alone and in combination with the cannabinoid receptor agonists Δ9-THC and CP55940 were studied in male Sprague-Dawley rats (n=16) using a warm water tail withdrawal procedure.

The ratio of opioid to cannabinoid (3:1, 1:1, and 1:3) varied for each mixture. Drugs administered alone or as pairwise mixtures of an opioid and a cannabinoid dose-dependently increased tail withdrawal latency. Mixtures with morphine produced supra-additive (CP55940) and additive (Δ9-THC) effects, whereas mixtures with etorphine and either cannabinoid were sub-additive. The interactions were not different among ratios for a particular mixture.

The nature of the interaction between opioids and cannabinoids with regard to antinociceptive effects varies with the particular drugs in the mixture, which can have implications for designing combination therapies for pain.”

https://www.ncbi.nlm.nih.gov/pubmed/29183835

http://www.sciencedirect.com/science/article/pii/S0014299917307719

Two FDA drug approvals for idiopathic pulmonary fibrosis (IPF)

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“Pulmonary fibrosis is a disease in which tissue deep inside the lungs becomes thick, stiff, and scarred, decreasing the lungs’ ability to expand to take in air, and making it difficult to breathe. This is a progressive disease in which scarring and lack of elasticity in the lungs continues to increase until the patient can no longer breathe enough to sustain life.

Until recently, patients in the U.S. suffering from idiopathic pulmonary fibrosis (IPF), a form of pulmonary fibrosis in which the cause is unknown, had no drug treatment  approved by FDA for this debilitating, incurable, and terminal condition. However, this month, FDA approved Ofev (nintedanib) and Esbriet (pirfenidone), two important new therapies for the treatment of patients with IPF. Both drugs are “first-in-class” products that offer new hope for patients in the U.S. with IPF.

Researchers don’t understand exactly how Ofev and Esbriet work in the body against IPF, but the drugs seem to inhibit important pathways that help to prevent scarring. Neither drug is a cure. IPF may still progress after patients use these drugs. However, each drug has been shown to significantly slow the progression of the disease.”  https://blogs.fda.gov/fdavoice/index.php/2014/10/two-fda-drug-approvals-for-idiopathic-pulmonary-fibrosis-ipf/

https://blogs.fda.gov/fdavoice/index.php/2014/10/two-fda-drug-approvals-for-idiopathic-pulmonary-fibrosis-ipf/

http://www.thctotalhealthcare.com/category/pulmonary-fibrosis/

Δ9-Tetrahydrocannabinol Prevents Cardiovascular Dysfunction in STZ-Diabetic Wistar-Kyoto Rats.

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“The aim of this study was to determine if chronic, low-dose administration of a nonspecific cannabinoid receptor agonist could provide cardioprotective effects in a model of type I diabetes mellitus.

Δ9-Tetrahydrocannabinol administration to diabetic animals significantly reduced blood glucose concentrations and attenuated pathological changes in serum markers of oxidative stress and lipid peroxidation. Positive changes to biochemical indices in diabetic animals conferred improvements in myocardial and vascular function.

This study demonstrates that chronic, low-dose administration of Δ9-tetrahydrocannabinol can elicit antihyperglycaemic and antioxidant effects in diabetic animals, leading to improvements in end organ function of the cardiovascular system. Implications from this study suggest that cannabinoid receptors may be a potential new target for the treatment of diabetes-induced cardiovascular disease.”   https://www.ncbi.nlm.nih.gov/pubmed/29181404

“The aim of this study was to determine if a nonspecific cannabinoid receptor agonist could provide cardioprotective effects in a model of type I diabetes mellitus. Outcomes from this study indicate that THC administration to STZ improved functional parameters of cardiovascular health by reducing oxidative stress, lipid peroxidation, and blood glucose levels. These results indicate that activation of cannabinoid receptors may be a viable experimental target for the prevention of oxidative stress-induced complications in type I diabetes mellitus.”  https://www.hindawi.com/journals/bmri/2017/7974149/

Analysis of cannabinoids in commercial hemp seed oil and decarboxylation kinetics studies of cannabidiolic acid (CBDA).

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Journal of Pharmaceutical and Biomedical Analysis

“Hemp seed oil from Cannabis sativa L. is a very rich natural source of important nutrients, not only polyunsaturated fatty acids and proteins, but also terpenes and cannabinoids, which contribute to the overall beneficial effects of the oil.

Hence, it is important to have an analytical method for the determination of these components in commercial samples. At the same time, it is also important to assess the safety of the product in terms of amount of any psychoactive cannabinoid present therein.

This work presents the development and validation of a highly sensitive, selective and rapid HPLC-UV method for the qualitative and quantitative determination of the main cannabinoids, namely cannabidiolic acid (CBDA), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), tetrahydrocannabinol (THC), cannabinol (CBN), cannabigerol (CBG) and cannabidivarin (CBDV), present in 13 commercial hemp seed oils.

Moreover, since decomposition of cannabinoid acids generally occurs with light, air and heat, decarboxylation studies of the most abundant acid (CBDA) were carried out in both open and closed reactor and the kinetics parameters were evaluated at different temperatures in order to evaluate the stability of hemp seed oil in different storage conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/29182999
http://www.sciencedirect.com/science/article/pii/S0731708517322367?via%3Dihub

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

Adolescent ethanol intake alters cannabinoid type-1 receptor localization in astrocytes of the adult mouse hippocampus.

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Addiction Biology

“Cannabinoid type-1 (CB1 ) receptors are widely distributed in the brain and play important roles in astrocyte function and the modulation of neuronal synaptic transmission and plasticity. However, it is currently unknown how CB1 receptor expression in astrocytes is affected by long-term exposure to stressors.

Here we examined CB1 receptors in astrocytes of ethanol (EtOH)-exposed adolescent mice to determine its effect on CB1 receptor localization and density in adult brain.

Our results revealed a significant reduction in CB1 receptor immunoparticles in astrocytic processes of EtOH-exposed mice when compared with controls (positive astrocyte elements: 21.50 ± 2.80 percent versus 37.22 ± 3.12 percent, respectively), as well as a reduction in particle density (0.24 ± 0.02 versus 0.35 ± 0.02 particles/μm).

Altogether, the decrease in the CB1 receptor expression in hippocampal astrocytes of adult mice exposed to EtOH during adolescence reveals a long lasting effect of EtOH on astrocytic CB1 receptors. This deficiency may also have negative consequences for synaptic function.”

https://www.ncbi.nlm.nih.gov/pubmed/29168269

http://onlinelibrary.wiley.com/doi/10.1111/adb.12585/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+

Acetaminophen Relieves Inflammatory Pain Through CB1 Cannabinoid Receptors in the Rostral Ventromedial Medulla.

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Journal of Neuroscience

“Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug with only incompletely understood mechanisms of action.

Previous work, using models of acute nociceptive pain, indicated that analgesia by acetaminophen involves an indirect activation of CB1 receptors by the acetaminophen metabolite and endocannabinoid re-uptake inhibitor AM 404.  However, the contribution of the cannabinoid system to anti-hyperalgesia against inflammatory pain, the main indication of acetaminophen, and the precise site of the relevant CB1 receptors have remained elusive.

Here, we analyzed acetaminophen analgesia in mice of either sex with inflammatory pain and found that acetaminophen exerted a dose-dependent anti-hyperalgesic action, which was mimicked by intrathecally injected AM 404. Both compounds lost their anti-hyperalgesic activity in CB1-/- mice confirming the involvement of the cannabinoid system.

Our results indicate that the cannabinoid system contributes not only to acetaminophen analgesia against acute pain but also against inflammatory pain, and suggest that the relevant CB1 receptors reside in the RVM.

SIGNIFICANCE STATEMENT: Acetaminophen is a widely used analgesic drug with multiple but only incompletely understood mechanisms of action including a facilitation of endogenous cannabinoid signaling via one of its metabolites. Our present data indicate that enhanced cannabinoid signaling is also responsible for the analgesic effects of acetaminophen against inflammatory pain. Local injections of the acetaminophen metabolite AM 404 and of cannabinoid receptor antagonists as well as data from tissue specific CB1 receptor deficient mice suggest the rostral ventromedial medulla as an important site of the cannabinoid-mediated analgesia by acetaminophen.”

https://www.ncbi.nlm.nih.gov/pubmed/29167401

http://www.jneurosci.org/content/early/2017/11/22/JNEUROSCI.1945-17.2017