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Neural correlates of interactions between cannabidiol and Δ(9) -tetrahydrocannabinol in mice: implications for medical cannabis.

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BPS (Pharm)

“It has been proposed that medicinal strains of cannabis and therapeutic preparations would be safer with a more balanced concentration ratio of Δ(9) -tetrahydrocannabinol (THC) to cannabidiol (CBD), as CBD reduces the adverse psychotropic effects of THC.

The aim of this study was to investigate whether CBD modulated the functional effects and c-Fos expression induced by THC, using a 1:1 dose ratio that approximates therapeutic strains of cannabis and nabiximols.

These data confirm that CBD modulated the pharmacological actions of THC and provide new information regarding brain regions involved in the interaction between CBD and THC.”

https://www.ncbi.nlm.nih.gov/pubmed/26377899

“A number of studies now support the view that cannabidiol (CBD) may reduce the negative psychotropic effects of THC while enhancing its positive therapeutic actions. Our results are consistent with the notion that cannabis plant strains that contain THC and CBD at 1:1 ratios may be preferable to street cannabis for medicinal applications because they maximize therapeutic efficacy while minimizing the adverse effects of THC.”  https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.13333

Effects of cannabidiol plus naltrexone on motivation and ethanol consumption.

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“The aim of this study was to explore if the administration of naltrexone (NTX) together with cannabidiol (CBD) may improve the efficacy in reducing alcohol consumption and motivation rather than any of the drugs given separately.

The administration of CBD + NTX significantly reduced motivation and ethanol intake in the oral self-administration procedure in a greater proportion than the drugs given alone. Only the combination of both drugs significantly reduced Oprm1, TH and 5-HT1A gene expressions in the NAc, VTA and DR, respectively. Interestingly, the administration of WAY100635 significantly blocked the actions of CBD + NTX but had no effects by itself.

CONCLUSION AND IMPLICATIONS:

The combination of low doses of CBD plus NTX resulted more effective to reduce ethanol consumption and motivation to drink. These effects, appears to be mediated, at least in part, by 5-HT1A receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/29859012

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14380

“Naltrexone belongs to a class of drugs known as opiate antagonists. It works in the brain to prevent opiate effects (e.g., feelings of well-being, pain relief). It also decreases the desire to take opiates. This medication is also used to treat alcohol abuse. It can help people drink less alcohol or stop drinking altogether. It also decreases the desire to drink alcohol when used with a treatment program that includes counseling, support, and lifestyle changes.” https://www.webmd.com/drugs/2/drug-7399/naltrexone-oral/details

“Cannabidiol reduces ethanol consumption, motivation and relapse in mice. Taken together, these results reveal that the administration of CBD reduced the reinforcing properties, motivation and relapse for ethanol. These findings strongly suggest that CBD may result useful for the treatment of alcohol use disorders.”   https://www.ncbi.nlm.nih.gov/pubmed/28194850

Marijuana use and fecundability in a North American preconception cohort study.

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“The influence of marijuana use on human fertility has not been well studied. We evaluated the association between female and male use of marijuana and fecundability in Pregnancy Study Online, a prospective cohort of North American couples.

RESULTS:

Men (14.2%) were more likely than women (11.6%) to be marijuana users. FRs for female marijuana use <1 and ≥1 time/week relative to non-use were 0.99 (95% CI 0.85 to 1.16) and 0.98 (95% CI 0.80 to 1.20), respectively. FRs for male marijuana use <1 and ≥1 time/week relative to non-use were 0.87 (95% CI 0.66 to 1.15) and 1.24 (95% CI 0.90 to 1.70), respectively. Associations for frequent marijuana use (≥1 time/week) were attenuated among non-smoking men (FR=1.21, 95% CI 0.84 to 1.74), but stronger among men reporting intercourse ≥4 times/week (FR=1.35, 95% CI 0.72 to 2.53).

CONCLUSIONS:

In this preconception cohort study, there was little overall association between female or male marijuana use and fecundability.”

https://www.ncbi.nlm.nih.gov/pubmed/29273628

http://jech.bmj.com/content/72/3/208

“BU: Marijuana use does not lower chances of getting pregnant”  https://www.eurekalert.org/pub_releases/2018-01/buso-bmu012218.php 

“New Study Says Marijuana Use Does Not Affect Fertility”  https://www.civilized.life/articles/marijuana-not-affect-fertility/

“New Study Says Marijuana Does Not Reduce Fertility In Men Or Women”  https://www.civilized.life/articles/new-study-says-marijuana-does-not-reduce-fertility-in-men-or-women/

Including cannabinoids in the treatment of painful schwannomatosis.

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“A 47‐year‐old man, affected by Schwannomatosis, presented a very severe pain (10/10, NRS) with paroxysmal shooting episodes, allodynia, paresthesia, and dysesthesia; in parallel, the patient had lost weight (from 70 to 49 kg) and experienced fatigue and deep depression. The previous pain prescription, including opioids and antineutopathic drugs, was fully ineffective. We progressively substituted this therapy with 15 drops, 3 times/daily, of THC/CBD in a concentration ratio 5:1, equal to 15 mg of active substance each time, reaching improvement in pain intensity (6/10) and in several other aspects as mood and quality of life”

https://www.ncbi.nlm.nih.gov/pubmed/29845778  

https://onlinelibrary.wiley.com/doi/abs/10.1002/brb3.1011

“Schwannomatosis is a rare genetic disorder that results in tumors (called schwannomas) that grow on the peripheral nerves throughout the body. It is recognized most often in people over the age of 30. Schwannomatosis can cause severe, debilitating pain and neurological dysfunction.”  https://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/neurofibromatosis/schwannomatosis/index.html

The effect of hemp seed and linseed addition on the quality of liver pâtés.

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“Liver p&acirc;t&eacute;s are popular all over the world, but they usually contain high amounts of animal fats. It may be beneficial to improve their dietetic value by decreasing the saturated fatty acid content, while maintaining their sensory quality. One way to do this is to add ingredients which are rich in polyunsaturated fatty acids, such as hemp seed or linseed. Hemp seeds are valuable because of their fat and protein content and linseed is known for its high &alpha;-linolenic fatty acid (ALA) content. Both are good sources of fiber.

RESULTS:

The addition of hemp and linseed increased the fat content. The fatty acid profile improved signifi- cantly. There were more polyunsaturated fatty acids and the n-6 to n-3 ratio was reduced in both products containing oil seeds compared to the control sample, which is important from the health point of view. The color parameters were not changed. The hardness, chewiness and adhesiveness increased in products contain- ing oil seeds. Those products received higher scores in sensory analysis.

CONCLUSIONS:

The quality of the p&acirc;t&eacute;s with added oil seed is comparable to or better than the traditional ones. The products with both hemp and linseed can be treated as a good source of n-3 fatty acids. The amount of ALA is high enough to label the product as a source of n-3 fatty acids.”

 https://www.ncbi.nlm.nih.gov/pubmed/29803219

The Pharmacological Inhibition of Fatty Acid Amide Hydrolase Prevents Excitotoxic Damage in the Rat Striatum: Possible Involvement of CB1 Receptors Regulation.

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Molecular Neurobiology

“The endocannabinoid system (ECS) actively participates in several physiological processes within the central nervous system.

Among such, its involvement in the downregulation of the N-methyl-D-aspartate receptor (NMDAr) through a modulatory input at the cannabinoid receptors (CBr) has been established. After its production via the kynurenine pathway (KP), quinolinic acid (QUIN) can act as an excitotoxin through the selective overactivation of NMDAr, thus participating in the onset and development of neurological disorders.

In this work, we evaluated whether the pharmacological inhibition of fatty acid amide hydrolase (FAAH) by URB597, and the consequent increase in the endogenous levels of anandamide, can prevent the excitotoxic damage induced by QUIN. URB597 (0.3 mg/kg/day × 7 days, administered before, during and after the striatal lesion) exerted protective effects on the QUIN-induced motor (asymmetric behavior) and biochemical (lipid peroxidation and protein carbonylation) alterations in rats.

URB597 also preserved the structural integrity of the striatum and prevented the neuronal loss (assessed as microtubule-associated protein-2 and glutamate decarboxylase localization) induced by QUIN (1 μL intrastriatal, 240 nmol/μL), while modified the early localization patterns of CBr1 (CB1) and NMDAr subunit 1 (NR1).

Altogether, these findings support the concept that the pharmacological manipulation of the endocannabinoid system plays a neuroprotective role against excitotoxic insults in the central nervous system.”

 https://www.ncbi.nlm.nih.gov/pubmed/29802570
https://link.springer.com/article/10.1007%2Fs12035-018-1129-2

Computational investigation on the binding modes of Rimonabant analogues with CB1 and CB2.

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“The human cannabinoid G protein coupled receptor 1 (CB1) is highly expressed in central nervous system. CB1-selective antagonists show therapeutic promise in a wide range of disorders, such as obesity-related metabolic disorders, dyslipidemia, drug abuse and type 2 diabetes.

Rimonabant (SR141716A), MJ08 and MJ15 are selective CB1 antagonists with selectivity >1000 folds over CB2 despite of 42% sequence identity between CB1 and CB2. The integration of homology modeling, automated molecular docking and molecular dynamics simulation were used to investigate the binding modes of these selective inverse agonists/antagonists with CB1 and CB2 and their selectivity.

Our analyses showed that the hydrophobic interactions between ligands and hydrophobic pockets of CB1 account for the main binding affinity. In addition, instead of interacting with ligands directly as previously reported, the Lys1923.28in CB1 was engaged in indirect interactions with ligands to keep inactive-state CB1 stable by forming the salt bridge with Asp1762.63 . Lastly, our analyses indicated that the selectivity of these antagonists came from the difference in geometry shapes of binding pockets of CB1 and CB2.

The present study could guide future experimental works on these receptors and has the guiding significance for the design of functionally selective drugs targeting CB1 or CB2 receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/29797785

https://onlinelibrary.wiley.com/doi/abs/10.1111/cbdd.13337

Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort.

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“Medicinal cannabis registries typically report pain as the most common reason for use. It would be clinically useful to identify patterns of cannabis treatment in migraine and headache, as compared to arthritis and chronic pain, and to analyze preferred cannabis strains, biochemical profiles, and prescription medication substitutions with cannabis.

RESULTS:

Of 2032 patients, 21 illnesses were treated with cannabis. Pain syndromes accounted for 42.4% (n = 861) overall; chronic pain 29.4% (n = 598;), arthritis 9.3% (n = 188), and headache 3.7% (n = 75;). Across all 21 illnesses, headache was a symptom treated with cannabis in 24.9% (n = 505). These patients were given the ID Migraine™ questionnaire, with 68% (n = 343) giving 3 “Yes” responses, 20% (n = 102) giving 2 “Yes” responses (97% and 93% probability of migraine, respectively). Therefore, 88% (n = 445) of headache patients were treating probable migraine with cannabis. Hybrid strains were most preferred across all pain subtypes, with “OG Shark” the most preferred strain in the ID Migraine™ and headache groups. Many pain patients substituted prescription medications with cannabis (41.2-59.5%), most commonly opiates/opioids (40.5-72.8%). Prescription substitution in headache patients included opiates/opioids (43.4%), anti-depressant/anti-anxiety (39%), NSAIDs (21%), triptans (8.1%), anti-convulsants (7.7%), muscle relaxers (7%), ergots (0.4%).

CONCLUSIONS:

Chronic pain was the most common reason for cannabis use, consistent with most registries. The majority of headache patients treating with cannabis were positive for migraine. Hybrid strains were preferred in ID Migraine™, headache, and most pain groups, with “OG Shark”, a high THC (Δ9-tetrahydrocannabinol)/THCA (tetrahydrocannabinolic acid), low CBD (cannabidiol)/CBDA (cannabidiolic acid), strain with predominant terpenes β-caryophyllene and β-myrcene, most preferred in the headache and ID Migraine™ groups. This could reflect the potent analgesic, anti-inflammatory, and anti-emetic properties of THC, with anti-inflammatory and analgesic properties of β-caryophyllene and β-myrcene. Opiates/opioids were most commonly substituted with cannabis. Prospective studies are needed, but results may provide early insight into optimizing crossbred cannabis strains, synergistic biochemical profiles, dosing, and patterns of use in the treatment of headache, migraine, and chronic pain syndromes.”

 https://www.ncbi.nlm.nih.gov/pubmed/29797104
https://thejournalofheadacheandpain.springeropen.com/articles/10.1186/s10194-018-0862-2

Synthesis of 13 C6 -labeled, dual-target inhibitor of Cannabinoid-1 receptor (CB1 R) and inducible nitric oxide synthase (iNOS).

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“Cannabinoid-1 receptor (CB1 R) antagonists/inverse agonists have great potential in the treatment of metabolic disorders like dyslipidemia, type 2 diabetes and non-alcoholic steatohepatitis (NASH).

CB1 R inverse agonists have also been reported to be effective in mitigating fibrotic disorders in murine models.

Inducible nitric oxide synthase is another promising target implicated in fibrotic and inflammatory disorders.

We have disclosed MRI-1867 as a potent and selective, peripherally acting dual-target inhibitor of the cannabinoid receptor (CB1 R) and inducible nitric oxide synthase (iNOS).

Herein, we report the synthesis of [13 C6 ]-MRI-1867 as a racemate from commercially available chlorobenzene-13 C6 as the starting, stable-isotope label reagent. The racemic [13 C6 ]-MRI-1867 was further processed to the stable-isotope labeled enantiopure compounds utilizing chiral chromatography. Both racemic [13 C6]-MRI-1867 and S-13 C6 -MRI-1867 will be used to quantitate unlabeled S-MRI-1867 during clinical DMPK studies and will be used as an LC-MS/MS bioanalytical standard.”

https://www.ncbi.nlm.nih.gov/pubmed/29790591

https://onlinelibrary.wiley.com/doi/abs/10.1002/jlcr.3639

Self-initiated use of topical cannabidiol oil for epidermolysis bullosa.

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“Epidermolysis bullosa is a rare blistering skin disorder that is challenging to manage because skin fragility and repeated wound healing cause itching, pain, limited mobility, and recurrent infections.

Cannabidiol, an active cannabinoid found in cannabis, is postulated to have antiinflammatory and analgesic effects.

We report 3 cases of self-initiated topical cannabidiol use in patients with epidermolysis bullosa in an observational study.

One patient was weaned completely off oral opioid analgesics. All 3 reported faster wound healing, less blistering, and amelioration of pain with cannabidiol use.

Although these results demonstrate promise, further randomized, double-blind clinical trials are necessary to provide scientific evidence of our observed benefits of cannabidiol for the treatment of epidermolysis bullosa.”

https://www.ncbi.nlm.nih.gov/pubmed/29786144

https://onlinelibrary.wiley.com/doi/abs/10.1111/pde.13545