Tag Archives: cannabinoid

Integrating endocannabinoid signaling in the regulation of anxiety and depression

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“Brain endogenous cannabinoid (eCB) signaling seems to harmonize appropriate behavioral responses, which are essential for the organism’s long-term viability and homeostasis. Dysregulation of eCB signaling contributes to negative emotional states and increased stress responses. An understanding of the underlying neural cell populations and neural circuit regulation will enable the development of therapeutic strategies to mitigate behavioral maladaptation and provide insight into the influence of eCB on the neural circuits involved in anxiety and depression. This review focuses on recent evidence that has added a new layer of complexity to the idea of targeting the eCB system for therapeutic benefits in neuropsychiatric disease and on the future research direction of neural circuit modulation.” 

https://www.nature.com/articles/s41401-018-0051-5

Effectiveness of Raw, Natural Medical Cannabis Flower for Treating Insomnia under Naturalistic Conditions.

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“Background: We use a mobile software application (app) to measure for the first time, which fundamental characteristics of raw, natural medical Cannabis flower are associated with changes in perceived insomnia under naturalistic conditions.

Methods: Four hundred and nine people with a specified condition of insomnia completed 1056 medical cannabis administration sessions using the Releaf AppTM educational software during which they recorded real-time ratings of self-perceived insomnia severity levels prior to and following consumption, experienced side effects, and product characteristics, including combustion method, cannabis subtypes, and/or major cannabinoid contents of cannabis consumed. Within-user effects of different flower characteristics were modeled using a fixed effects panel regression approach with standard errors clustered at the user level.

Results: Releaf AppTM users showed an average symptom severity reduction of -4.5 points on a 0⁻10 point visual analogue scale (SD = 2.7, d = 2.10, p < 0.001). Use of pipes and vaporizers was associated with greater symptom relief and more positive and context-specific side effects as compared to the use of joints, while vaporization was also associated with lower negative effects. Cannabidiol (CBD) was associated with greater statistically significant symptom relief than tetrahydrocannabinol (THC), but the cannabinoid levels generally were not associated with differential side effects. Flower from C. sativa plants was associated with more negative side effects than flower from C. indica or hybrid plant subtypes.

Conclusions: Consumption of medical Cannabis flower is associated with significant improvements in perceived insomnia with differential effectiveness and side effect profiles, depending on the product characteristics.”

https://www.ncbi.nlm.nih.gov/pubmed/29997343

http://www.mdpi.com/2305-6320/5/3/75

Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results.

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“Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded-access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016.

METHODS:

Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2-10 mg/kg/d, titrated to a maximum dose of 25-50 mg/kg/d. Patient visits were every 2-4 weeks through 16 weeks and every 2-12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation-carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit.

RESULTS:

Of 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%).

SIGNIFICANCE:

Results from this ongoing EAP support previous observational and clinical trial data showing that add-on CBD may be an efficacious long-term treatment option for TRE.”

https://www.ncbi.nlm.nih.gov/pubmed/29998598

https://onlinelibrary.wiley.com/doi/abs/10.1111/epi.14477

Development of a Cannabinoid-Based Photoaffinity Probe to Determine the Δ8/9-Tetrahydrocannabinol Protein Interaction Landscape in Neuroblastoma Cells.

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“Δ9-Tetrahydrocannabinol (THC), the principle psychoactive ingredient in Cannabis, is widely used for its therapeutic effects in a large variety of diseases, but it also has numerous neurological side effects. The cannabinoid receptors (CBRs) are responsible to a large extent for these, but not all biological responses are mediated via the CBRs.

Objectives: The identification of additional target proteins of THC to enable a better understanding of the (adverse) physiological effects of THC.

Methods: In this study, a chemical proteomics approach using a two-step photoaffinity probe is applied to identify potential proteins that may interact with THC.

Results: Photoaffinity probe 1, containing a diazirine as a photocrosslinker, and a terminal alkyne as a ligation handle, was synthesized in 14 steps. It demonstrated high affinity for both CBRs. Subsequently, two-step photoaffinity labeling in neuroblastoma cells led to identification of four potential novel protein targets of THC. The identification of these putative protein hits is a first step towards a better understanding of the protein interaction profile of THC, which could ultimately lead to the development of novel therapeutics based on THC.”

https://www.ncbi.nlm.nih.gov/pubmed/29992186

https://www.liebertpub.com/doi/10.1089/can.2018.0003

In Vitro Model of Neuroinflammation: Efficacy of Cannabigerol, a Non-Psychoactive Cannabinoid.

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“Inflammation and oxidative stress play main roles in neurodegeneration. Interestingly, different natural compounds may be able to exert neuroprotective actions against inflammation and oxidative stress, protecting from neuronal cell loss.

Among these natural sources, Cannabis sativa represents a reservoir of compounds exerting beneficial properties, including cannabigerol (CBG), whose antioxidant properties have already been demonstrated in macrophages.

Here, we aimed to evaluate the ability of CBG to protect NSC-34 motor neurons against the toxicity induced from the medium of LPS-stimulated RAW 264.7 macrophages.

All together, these results indicated the neuroprotective effects of CBG, that may be a potential treatment against neuroinflammation and oxidative stress.”

https://www.ncbi.nlm.nih.gov/pubmed/29986533

http://www.mdpi.com/1422-0067/19/7/1992

The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study.

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“Initial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies.

With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available.

The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life.

DISCUSSION:

This paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/29981580

“Children with epileptic encephalopathies resistant to standard therapy are at considerable risk for long-term neurocognitive impairment and poor quality of life. CBD-enriched Cannabis based therapies have been shown in several studies to provide a reduction in seizure frequencies and improvements in sleep patterns, mood, and alertness.”  https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-018-1191-y

Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors.

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“We sought to understand why (-)-cannabidiol (CBD) and (-)-cannabidiol-dimethylheptyl (CBD-DMH) exhibit distinct pharmacology, despite near identical structures.

KEY RESULTS:

At CB1R, CBD was a negative allosteric modulator (NAM) and CBD-DMH was a mixed agonist/positive allosteric modulator. CBD and Org27569 shared multiple interacting residues in the antagonist-bound model of CB1R (5TGZ), but shared a binding site with CP55,940 in the agonist-bound model of CB1R (5XRA). The binding site for CBD-DMH in the CB1R models overlapped with CP55,940 and Org27569. At CB2R, CBD was a partial agonist, and CBD-DMH was a positive allosteric modulator of cAMP modulation, but a NAM of βarrestin1 recruitment. CBD, CP55,940, and SR144528 shared a binding site in the CB2R models that was separate from CBD-DMH.

CONCLUSION AND IMPLICATIONS:

The pharmacological activity of CBD and CBD-DMH in HEK293A cells and their modelled binding sites at CB1R and CB2R may explain their in vivo effects and illuminates the difficulties associated with the development of allosteric modulators for CB1R and CB2R.”

https://www.ncbi.nlm.nih.gov/pubmed/29981240

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14440

Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation.

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 Neuropharmacology

“Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects.

Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects.

Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy.

Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/29981335

https://www.sciencedirect.com/science/article/pii/S0028390818303575?via%3Dihub

Anti-Proliferative Properties and Proapoptotic Function of New CB2 Selective Cannabinoid Receptor Agonist in Jurkat Leukemia Cells.

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“Several studies demonstrated that cannabinoids reduce tumor growth, inhibit angiogenesis, and decrease cancer cell migration. As these molecules are well tolerated, it would be interesting to investigate the potential benefit of newly synthesized compounds, binding cannabinoid receptors (CBRs).

In this study, we describe the synthesis and biological effect of 2-oxo-1,8-naphthyridine-3-carboxamide derivative LV50, a new compound with high CB2 receptor (CB2R) affinity. We demonstrated that it decreases viability of Jurkat leukemia cells, evaluated by Trypan Blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), but mainly induces a proapoptotic effect. We observed an increase of a hypodiploid peak by propidium iodide staining and changes in nuclear morphology by Hoechst 33258. These data were confirmed by a significant increase of Annexin V staining, cleavage of the nuclear enzyme poly(ADP-ribose)-polymerase (PARP), and caspases activation. In addition, in order to exclude that LV50 non-specifically triggers death of all normal leukocytes, we tested the new compound on normal peripheral blood lymphocytes, excluding the idea of general cytotoxicity. To characterize the involvement of CB2R in the anti-proliferative and proapoptotic effect of LV50, cells were pretreated with a specific CB2R antagonist and the obtained data showed reverse results.

Thus, we suggest a link between inhibition of cell survival and proapoptotic activity of the new compound that elicits this effect as selective CB2R agonist.”

https://www.ncbi.nlm.nih.gov/pubmed/29973514

http://www.mdpi.com/1422-0067/19/7/1958

Hippocampal mammalian target of rapamycin is implicated in stress-coping behavior induced by cannabidiol in the forced swim test.

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“Cannabidiol is a non-psychotomimetic compound with antidepressant-like effects.

However, the mechanisms and brain regions involved in cannabidiol effects are not yet completely understood. Brain-derived neurotrophic factor/tropomyosin-receptor kinase B/mammalian target of rapamycin (BDNF-TrkB-mTOR) signaling, especially in limbic structures, seems to play a central role in mediating the effects of antidepressant drugs.

RESULTS:

Systemic cannabidiol administration induced antidepressant-like effects and increased BDNF levels in the dorsal hippocampus. Rapamycin, but not K252a, injection into the dorsal hippocampus prevented the antidepressant-like effect induced by systemic cannabidiol treatment (10 mg/kg). Differently, hippocampal administration of cannabidiol (10 nmol/0.2 µL) reduced immobility time, an effect that was blocked by both rapamycin and K252a local microinjection.

CONCLUSION:

Altogether, our data suggest that the hippocampal BDNF-TrkB-mTOR pathway is vital for cannabidiol-induced antidepressant-like effect when the drug is locally administered. However, other brain regions may also be involved in cannabidiol-induced antidepressant effect upon systemic administration.”

https://www.ncbi.nlm.nih.gov/pubmed/29968502

http://journals.sagepub.com/doi/abs/10.1177/0269881118784877?journalCode=jopa