Monthly Archives: May 2018

Ventilatory-depressant effects of opioids alone and in combination with cannabinoids in rhesus monkeys.

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“Pain is a serious health problem that is commonly treated with opioids, although the doses of opioids needed to treat pain are often similar to those that decrease respiration. Combining opioids with drugs that relieve pain through non-opioid mechanisms can decrease the doses of opioids needed for analgesia, resulting in an improved therapeutic window, but only if the doses of opioids that decrease respiration are not similarly decreased. Using small doses of opioids to treat pain has the potential to reduce the number of overdoses and deaths.

This study investigated whether the cannabinoid receptor agonists Δ9-tetrahydrocannabinol (Δ9-THC) and CP 55,940 modify the ventilatory-depressant effects of morphine and fentanyl in three monkeys.

In summary, cannabinoid receptor agonists, which increase the potency of opioids to produce antinociception, did not increase their potency to depress ventilation. Thus, the therapeutic window is greater for opioids when they are combined with cannabinoid receptor agonists, indicating a possible advantage for these drug mixtures in treating pain.”

https://www.ncbi.nlm.nih.gov/pubmed/29807027

https://www.sciencedirect.com/science/article/pii/S0014299918303108

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

Endocannabinoid CB1 receptors are involved in antiepileptogenic effect of low frequency electrical stimulation during perforant path kindling in rats.

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Epilepsy Research

“Administration of low-frequency electrical stimulation (LFS) at the kindling site has an antiepileptogenic effect. In the present study, we investigated the role of cannabinoid receptors type 1 (CB1) in mediating the inhibitory effects of LFS on the development of perforant path kindled seizures.

RESULTS:

Application of LFS had inhibitory effect on development of kindled seizures (kindling rate). Microinjection of AM281 (0.5 μg/μl) immediately after the last kindling stimulation (before LFS application) reduced the inhibitory effect of LFS on the kindling rate and suppressed the effects of LFS on potentiation (increasing the magnitude) of both population spike amplitude and population excitatory postsynaptic potential slope during kindling acquisition. AM281 pretreatment also prevented the effects of LFS on kindling-induced increase in early and late paired pulse depression. The higher dose of AM281 (2 μg/μl) failed to exert the effects observed with its lower dose (0.5 μg/μl). In addition, there was a decreased CB1 receptors immunostaining in kindled animals compared to control. However, application of LFS following kindling stimulations led to overexpression of CB1 receptors in the dentate gyrus.

CONCLUSION:

Obtained results showed that activation of overexpressed cannabinoid CB1 receptors by endogenous cannabinoids may have a role in mediating the inhibitory effect of LFS on perforant path kindled seizures.”

https://www.ncbi.nlm.nih.gov/pubmed/29800824

https://www.sciencedirect.com/science/article/pii/S0920121117304291?via%3Dihub

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

Cannabinoid CB2 receptors in the mouse brain: relevance for Alzheimer’s disease.

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“Because of their low levels of expression and the inadequacy of current research tools, CB2 cannabinoid receptors (CB2R) have been difficult to study, particularly in the brain. This receptor is especially relevant in the context of neuroinflammation, so novel tools are needed to unveil its pathophysiological role(s).

METHODS:

We have generated a transgenic mouse model in which the expression of enhanced green fluorescent protein (EGFP) is under the control of the cnr2 gene promoter through the insertion of an Internal Ribosomal Entry Site followed by the EGFP coding region immediately 3′ of the cnr2 gene and crossed these mice with mice expressing five familial Alzheimer’s disease (AD) mutations (5xFAD).

RESULTS:

Expression of EGFP in control mice was below the level of detection in all regions of the central nervous system (CNS) that we examined. CB2R-dependent-EGFP expression was detected in the CNS of 3-month-old AD mice in areas of intense inflammation and amyloid deposition; expression was coincident with the appearance of plaques in the cortex, hippocampus, brain stem, and thalamus. The expression of EGFP increased as a function of plaque formation and subsequent microgliosis and was restricted to microglial cells located in close proximity to neuritic plaques. AD mice with CB2R deletion exhibited decreased neuritic plaques with no changes in IL1β expression.

CONCLUSIONS:

Using a novel reporter mouse line, we found no evidence for CB2R expression in the healthy CNS but clear up-regulation in the context of amyloid-triggered neuroinflammation. Data from CB2R null mice indicate that they play a complex role in the response to plaque formation.”

 https://www.ncbi.nlm.nih.gov/pubmed/29793509
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-018-1174-9

An overview of the cannabinoid type 2 receptor system and its therapeutic potential.

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“This narrative review summarizes recent insights into the role of the cannabinoid type 2 (CB2) receptor as potential therapeutic target in neuropathic pain and neurodegenerative conditions.

RECENT FINDINGS:

The cannabinoid system continues to receive attention as a therapeutic target. The CB2 receptor is primarily expressed on glial cells only when there is active inflammation and appears to be devoid of undesired psychotropic effects or addiction liability. The CB2 receptor has been shown to have potential as a therapeutic target in models of diseases with limited or no currently approved therapies, such as neuropathic pain and neurodegenerative conditions such as Alzheimer’s disease.

SUMMARY:

The functional involvement of CB2 receptor in neuropathic pain and other neuroinflammatory diseases highlights the potential therapeutic role of drugs acting at the CB2 receptor.”

https://www.ncbi.nlm.nih.gov/pubmed/29794855

https://insights.ovid.com/crossref?an=00001503-900000000-98981

Randomised Controlled Trial (RCT) of cannabinoid replacement therapy (Nabiximols) for the management of treatment-resistant cannabis dependent patients: a study protocol.

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“The cannabis extract nabiximols (Sativex®) effectively supresses withdrawal symptoms and cravings in treatment resistant cannabis dependent individuals, who have high relapse rates following conventional withdrawal treatments.

This study examines the efficacy, safety and cost-effectiveness of longer-term nabiximols treatment for outpatient cannabis dependent patients who have not responded to previous conventional treatment approaches.

This is the first outpatient community-based randomised controlled study of nabiximols as an agonist replacement medication for treating cannabis dependence, targeting individuals who have not previously responded to conventional treatment approaches. The study and treatment design is modelled upon an earlier study with this population and more generally on other agonist replacement treatments (e.g. nicotine, opioids).”

https://www.ncbi.nlm.nih.gov/pubmed/29776349

“There is a need for more effective treatment approaches for cannabis dependent patients who are unable to discontinue their illicit use through psychosocial interventions alone. Longer-term agonist replacement treatment approaches rather than acute withdrawal management are likely to be more effective, with the combination of THC:CBD nabiximols preparation being potentially advantageous over synthetic THC analogues. This is the first large-scale outpatient RCT of nabiximols for this population, and has required the development of clinical and research methods specific to agonist treatment with a plant-derived cannabinoid formulation, building upon clinical research models previously used in opioid agonist treatment approaches.”

https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-018-1682-2

Effects of exercise on experimentally manipulated craving for cannabis: A preliminary study.

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Cover image for Experimental and Clinical Psychopharmacology

“Cannabis is the most commonly used illicit drug in the United States, and craving for cannabis is related to cannabis use.

Exercise has been demonstrated to reduce craving for substances.

The findings suggest that moderate exercise may be useful for reducing craving, particularly among those who use larger quantities of cannabis.”

 https://www.ncbi.nlm.nih.gov/pubmed/29792472

http://psycnet.apa.org/doiLanding?doi=10.1037%2Fpha0000200

“Exercise activates the endocannabinoid system.”  https://www.ncbi.nlm.nih.gov/pubmed/14625449

“Aerobic exercise training reduces cannabis craving and use in non-treatment seeking cannabis-dependent adults.”  https://www.ncbi.nlm.nih.gov/pubmed/21408154

Sativex® as Add-on therapy Vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-blind, placebo-controlled randomised clinical trial.

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“Purpose/aim: To evaluate the efficacy of tetrahydrocannabinol [THC]:cannabidiol [CBD] oromucosal spray (Sativex®) as add-on therapy to optimized standard antispasticity treatment in patients with moderate to severe multiple sclerosis (MS) spasticity.

RESULTS:

Of 191 patients who entered Phase A, 106 were randomised in Phase B to receive add-on THC:CBD spray (n = 53) or placebo (n = 53). The proportion of clinically-relevant responders after 12 weeks (≥ 30% NRS improvement; primary efficacy endpoint) was significantly greater with THC:CBD spray than placebo (77.4 vs 32.1%; P < 0.0001). Compared with placebo, THC:CBD spray also significantly improved key secondary endpoints: changes in mean spasticity NRS (P < 0.0001), mean pain NRS (P = 0.0013), and mean modified Ashworth’s scale (P = 0.0007) scores from Phase B baseline to week 12. Adverse events, when present, were mild/moderate and without new safety concerns.

CONCLUSIONS:

Add-on THC:CBD oromucosal spray provided better and clinically relevant improvement of resistant MS spasticity compared with adjusting first-line antispasticity medication alone.”

https://www.ncbi.nlm.nih.gov/pubmed/29792372

https://www.tandfonline.com/doi/abs/10.1080/00207454.2018.1481066