A Systematic Review of Minor Phytocannabinoids With Promising Neuroprotective Potential

British Journal of Pharmacology “Embase and Pubmed were systematically searched for articles addressing the neuroprotective properties of phytocannabinoids, aside from cannabidiol and Δ9 -tetrahydrocannabinol, including Δ9 -tetrahydrocannabinolic acid (Δ9 -THCA), Δ9 -tetrahydrocannabivarin (Δ9 -THCV), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabichromene (CBC), cannabichromenic acid (CBCA), cannabichromevarin (CBCV), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerivarin (CBGV), cannabigerovarinic acid (CBGVA), cannabichromevarinic acid (CBCVA) cannabidivarinic acid (CBDVA) and cannabinol (CBN).

CBG (range 5 mg.kg-1 to 20 mg.kg-1 ) and CBDV (range 0.2 mg.kg-1 to 400 mg.kg-1 ) displayed efficacy in models of Huntington’s disease and epilepsy.

CBC (10-75 mg.kg-1 ), Δ9 -THCA (20 mg.kg-1 ) and Δ9 -THCV (range 0.025-2.5 mg.kg-1 ) showed promise in models of seizure and hypomobility, Huntington’s and Parkinson’s disease.

Limited mechanistic data showed CBG, VCE.003, VCE.003.2 and Δ9 -THCA mediated some of their effects through PPARy, but no other receptors were probed. Further studies with these phytocannabinoids, and their combinations, are warranted across a range of neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/32608035/

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.15185

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The pharmacokinetics, efficacy, and safety of a novel selective‐dose cannabis inhaler in patients with chronic pain: A randomized, double‐blinded, placebo‐controlled trial

European Journal of Pain“Precise cannabis treatment dosing remains a major challenge, leading to physicians’ reluctance to prescribe medical cannabis.

Objective

To test the pharmacokinetics, analgesic effect, cognitive performance and safety effects of an innovative medical device that enables the delivery of inhaled therapeutic doses of Δ9‐Tetrahydrocannabinol (THC) in patients with chronic pain.

Methods

In a randomized, three‐arms, double‐blinded, placebo‐controlled, cross‐over trial, 27 patients received a single inhalation of Δ9‐THC: 0.5mg, 1mg, or a placebo.

Δ9‐THC plasma levels were measured at baseline and up to 150‐min post‐inhalation. Pain intensity and safety parameters were recorded on a 10‐cm visual analogue scale (VAS) at pre‐defined time points. The cognitive performance was evaluated using the selective sub‐tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB).

Results

Following inhalation of 0.5 mg or 1mg, Δ9‐THC plasma max ± SD were 14.3 ± 7.7 and 33.8 ± 25.7 ng/ml. max ± SD were 3.7 ± 1.4 and 4.4 ± 2.1 min, and AUC0 → infinity±SD were 300 ± 144 and 769 ± 331 ng*min/ml, respectively. Both doses, but not the placebo, demonstrated a significant reduction in pain intensity compared with baseline and remained stable for 150‐min. The 1‐mg dose showed a significant pain decrease compared to the placebo. Adverse events were mostly mild and resolved spontaneously. There was no evidence of consistent impairments in cognitive performance.

Conclusion

This feasibility trial demonstrated that a metered‐dose cannabis inhaler delivered precise and low THC doses, produced a dose‐dependent and safe analgesic effect in patients with neuropathic pain/ complex‐regional pain syndrome (CRPS). Thus, it enables individualization of medical cannabis regimens that can be evaluated pharmacokinetically and pharmacodynamically by accepted pharmaceutical models.

Significance

Evidence suggests that cannabis‐based medicines are an effective treatment for chronic pain in adults. The pharmacokinetics of THC varies as a function of its route of administration. Pulmonary assimilation of inhaled THC causes rapid onset of analgesia. However, currently used routes of cannabinoids delivery provide unknown doses, making it impossible to implement a pharmaceutical standard treatment plan. A novel selective‐dose cannabis inhaler delivers significantly low and precise doses of THC, thus allowing the administration of inhaled cannabis‐based medicines according to high pharmaceutical standards. These low doses of THC can produce safe and effective analgesia in patients with chronic pain.

To the best of our knowledge, it is the first time that the delivery of selective, significantly low, and precise therapeutic single doses of inhaled THC demonstrates an analgesic effect. It allows patients to reach the optimum balance between symptom relief and controlled side effects, enabling patients to regain their quality of life. In addition, this metered‐dose cannabis inhaler enables the individualization of medical cannabis regimens that can be evaluated pharmacokinetically and pharmacodynamically using accepted pharmaceutical models.”

https://onlinelibrary.wiley.com/doi/10.1002/ejp.1605

Study Finds Microdosing THC Reduces Pain Levels”  https://www.painnewsnetwork.org/stories/2020/7/1/study-finds-microdosing-thc-reduces-pain-levels

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Interactions Between Cannabidiol and Δ 9 -Tetrahydrocannabinol in Modulating Seizure Susceptibility and Survival in a Mousae Model of Dravet Syndrome

British Journal of Pharmacology “Extracts from the cannabis plant can dramatically improve the health of children suffering from refractory epilepsies such as Dravet syndrome.

These extracts typically contain cannabidiol (CBD), a phytocannabinoid with well-documented anticonvulsant effects, but may also contain Δ9 -tetrahydrocannabinol (Δ9 -THC). It is unclear whether the presence of Δ9 -THC modulates the anticonvulsant efficacy of CBD. Here we utilized the Scn1a+/- mouse model of Dravet syndrome to examine this question.

Key results: Administered alone, CBD (100 mg/kg i.p.) was anticonvulsant against hyperthermia-induced seizures as were low (0.1 and 0.3 mg/kg i.p.) but not higher doses of Δ9 -THC. A subthreshold dose of CBD (12 mg/kg) enhanced the anticonvulsant effects Δ9 -THC (0.1 mg/kg). Subchronic oral administration of Δ9 -THC or CBD alone did not affect spontaneous seizure frequency or mortality while, surprisingly, their co-administration increased the severity of spontaneous seizures and overall mortality.

Conclusion and implications: Low doses of Δ9 -THC are anticonvulsant against hyperthermia-induced seizures in Scn1a+/ mice, effects that are enhanced by a sub-anticonvulsant dose of CBD. However, proconvulsant effects and increased premature mortality are observed when CBD and Δ9 -THC are subchronically dosed in combination. The possible explanations and implications of this are discussed.”

https://pubmed.ncbi.nlm.nih.gov/32608111/

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.15181

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The Effectiveness of Cannabis Flower for Immediate Relief From Symptoms of Depression

 Logo of yjbm“Scientific research on how consumption of whole, natural Cannabis flower affects low mood and behavioral motivations more generally is largely nonexistent, and few studies to date have measured how common and commercially available Cannabis flower used in vivo may affect the experience of “depression” in real-time.

Results: On average, 95.8% of users experienced symptom relief following consumption with an average symptom intensity reduction of -3.76 points on a 0-10 visual analogue scale (SD = 2.64, d = 1.71, p <.001). Symptom relief did not differ by labeled plant phenotypes (“C. indica,” “C. sativa,” or “hybrid”) or combustion method. Across cannabinoid levels, tetrahydrocannabinol (THC) levels were the strongest independent predictors of symptom relief, while cannabidiol (CBD) levels, instead, were generally unrelated to real-time changes in symptom intensity levels. Cannabis use was associated with some negative side effects that correspond to increased depression (e.g. feeling unmotivated) in up to 20% of users, as well as positive side effects that correspond to decreased depression (e.g. feeling happy, optimistic, peaceful, or relaxed) in up to 64% of users.

Conclusions: The findings suggest that, at least in the short term, the vast majority of patients that use cannabis experience antidepressant effects, although the magnitude of the effect and extent of side effect experiences vary with chemotypic properties of the plant.”

https://pubmed.ncbi.nlm.nih.gov/32607086/

“In conclusion, almost all patients in our sample experienced symptom relief from using Cannabis to treat depression and with minimal evidence of serious side effects in the short run.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309674/

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Pharmacological Analysis of Cannabis Sativa: A Potent Herbal Plant

“Genus Cannabis belong to family Cannabaceae and is traditionally used as medicinal plant against many diseases notably asthma, malaria, treatment of skin diseases, diabetes and headache. The plant Cannabis sativa L. is flowering and an annual herbaceous plant located to eastern Asia but now of cosmopolitan distribution due to extensive cultivation.

Aim of the study: The aim of review is to provide a complete evaluation of the botanical, ethnological and chemical aspects of Cannabis sativa L., and its importance in pharmacological studies.

Results and discussions: This article briefly reviews the botany, traditional knowledge, pharmacological and therapeutic application of the plant C. sativa. This is an attempt to compile and document information about the chemical constituent, pharmacological and therapeutic effects of C. sativa as important herbal drug due to its safety and effectiveness. Studies have revealed its use as anti-bacterial, anti-fungal, anti-cancer, anti-inflammatory and improving testicular function in rats. Consumption of C. sativa is greater in all over the world among all other drugs of abuse in its various forms such as marijuana, hashish and cannabis oil. The study of herbal medicine spans the knowledge of biology, history, source, physical and chemical nature, and mechanism of action, traditional, medicinal and therapeutic use of drug. This article also provide knowledge about macroscopically and microscopically characters of Cannabis sativa with geographical sources. The wellknown cannabinoids are Tetrahydrocannabinol (THC), Cannabidiol (CBD) and Cannabichromene (CBC) and their pharmacological properties and importance have been extensively studied. Hence, efforts are required to establish and validate evidence regarding safety and practices of Ayurveda medicines.

Conclusion: Thes studies will help in expanding the current therapeutic potential of C. sativa and it also provide a strong support to its future clinical use as herbal medicines having safe in use with no side effects.”

https://pubmed.ncbi.nlm.nih.gov/32600228/

https://www.eurekaselect.com/183226/article

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Use of Cannabis for Agitation in Patients With Dementia

 logo“Studies have reported changes in the endocannabinoid system in the brain of patients with Alzheimer’s disease (AD), playing a role in the pathophysiology of AD. Cannabinoids have been shown to have neuroprotective properties, reduce neuroinflammation, and enhance neurogenesis. Evidence suggests that the utilization of marijuana products containing both tetrahydrocannabinol (THC) and cannabidiol (CBD) or CBD alone have been effective and safe for use in older people with agitation associated with dementia.

A review in 2017 summarized positive findings for therapeutic benefits of cannabinoids in agitation of AD and dementia, but there was no definitive conclusion because of varying cannabinoid products. Cannabinoids were shown to be well tolerated, with few short-term side effects. This differs from first-line medications utilized for dementia behaviors, which can have unwanted side effects. Further research regarding the safety, efficacy, and variability of these products in older people is needed.”

https://pubmed.ncbi.nlm.nih.gov/32600509/

https://www.ingentaconnect.com/content/ascp/tscp/2020/00000035/00000007/art00006;jsessionid=1ivcuvrvy4g1s.x-ic-live-03

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Antioxidants Help Favorably Regulate the Kinetics of Lipid Peroxidation, Polyunsaturated Fatty Acids Degradation and Acidic Cannabinoids Decarboxylation in Hempseed Oil

 Scientific Reports“The seed of the hemp plant (Cannabis sativa L.) has been revered as a nutritional resource in Old World Cultures. This has been confirmed by contemporary science wherein hempseed oil (HSO) was found to exhibit a desirable ratio of omega-6 and omega-3 polyunsaturated fatty acids (PUFAs) considered optimal for human nutrition. HSO also contains gamma-linoleic acid (GLA) and non-psychoactive cannabinoids, which further contribute to its’ potential bioactive properties. Herein, we present the kinetics of the thermal stability of these nutraceutical compounds in HSO, in the presence of various antioxidants (e.g. butylated hydroxytoluene, alpha-tocopherol, and ascorbyl palmitate). We focussed on oxidative changes in fatty acid profile and acidic cannabinoid stability when HSO was heated at different temperatures (25 °C to 85 °C) for upto 24 h. The fatty acid composition was evaluated using both GC/MS and 1H-NMR, and the cannabinoids profile of HSO was obtained using both HPLC-UV and HPLC/MS methods. The predicted half-life (DT50) for omega-6 and omega-3 PUFAs in HSO at 25 °C was about 3 and 5 days, respectively; while that at 85 °C was about 7 and 5 hours respectively, with respective activation energies (Ea) being 54.78 ± 2.36 and 45.02 ± 2.87 kJ/mol. Analysis of the conjugated diene hydroperoxides (CDH) and p-Anisidine value (p-AV) revealed that the addition of antioxidants significantly (p < 0.05) limited lipid peroxidation of HSO in samples incubated at 25-85 °C for 24 h. Antioxidants reduced the degradation constant (k) of PUFAs in HSO by upto 79%. This corresponded to a significant (p < 0.05) increase in color stability and pigment retention (chlorophyll a, chlorophyll b and carotenoids) of heated HSO. Regarding the decarboxylation kinetics of cannabidiolic acid (CBDA) in HSO, at both 70 °C and 85 °C, CBDA decarboxylation led to predominantly cannabidiol (CBD) production. The half-life of CBDA decarboxylation (originally 4 days) could be increased to about 17 days using tocopherol as an antioxidant. We propose that determining acidic cannabinoids decarboxylation kinetics is a useful marker to measure the shelf-life of HSO. The results from the study will be useful for researchers looking into the thermal treatment of hempseed oil as a functional food product, and those interested in the decarboxylation kinetics of the acidic cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/32601363/

https://www.nature.com/articles/s41598-020-67267-0

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Cannabis, the Endocannabinoid System and Immunity-the Journey From the Bedside to the Bench and Back

ijms-logo“The Cannabis plant contains numerous components, including cannabinoids and other active molecules. The phyto-cannabinoid activity is mediated by the endocannabinoid system. Cannabinoids affect the nervous system and play significant roles in the regulation of the immune system.

While Cannabis is not yet registered as a drug, the potential of cannabinoid-based medicines for the treatment of various conditions has led many countries to authorize their clinical use. However, the data from basic and medical research dedicated to medical Cannabis is currently limited.

A variety of pathological conditions involve dysregulation of the immune system. For example, in cancer, immune surveillance and cancer immuno-editing result in immune tolerance. On the other hand, in autoimmune diseases increased immune activity causes tissue damage.

Immuno-modulating therapies can regulate the immune system and therefore the immune-regulatory properties of cannabinoids, suggest their use in the therapy of immune related disorders.

In this contemporary review, we discuss the roles of the endocannabinoid system in immunity and explore the emerging data about the effects of cannabinoids on the immune response in different pathologies. In addition, we discuss the complexities of using cannabinoid-based treatments in each of these conditions.”

https://pubmed.ncbi.nlm.nih.gov/32585801/

https://www.mdpi.com/1422-0067/21/12/4448

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Cannabis Constituents Reduce Seizure Behavior in Chemically-Induced and scn1a-mutant Zebrafish

Epilepsy and Behavior Journal | Epilepsy Foundation“Current antiepileptic drugs (AEDs) are undesirable for many reasons including the inability to reduce seizures in certain types of epilepsy, such as Dravet syndrome (DS) where in one-third of patients does not respond to current AEDs, and severe adverse effects that are frequently experienced by patients.

Epidiolex, a cannabidiol (CBD)-based drug, was recently approved for treatment of DS. While Epidiolex shows great promise in reducing seizures in patients with DS, it is used in conjunction with other AEDs and can cause liver toxicity. To investigate whether other cannabis-derived compounds could also reduce seizures, the antiepileptic effects of CBD, Δ9-tetrahydrocannabinol (THC), cannabidivarin (CBDV), cannabinol (CBN), and linalool (LN) were compared in both a chemically-induced (pentylenetetrazole, PTZ) and a DS (scn1Lab-/-) seizure models.

Cannabidiol (0.6 and 1 μM) and THC (1 and 4 μM) significantly reduced PTZ-induced total distance moved. At the highest THC concentration, the significant reduction in PTZ-induced behavior was likely the result of sedation as opposed to antiseizure activity.

In the DS model, CBD (0.6 μM), THC (1 μM), CBN (0.6 and 1 μM), and LN (4 μM) significantly reduced total distance traveled. Cannabinol was the most effective at reducing total distance relative to controls. In addition to CBD, other cannabis-derived compounds showed promise in reducing seizure-like activity in zebrafish.

Specifically, four of the five compounds were effective in the DS model, whereas in the PTZ model, only CBD and THC were, suggesting a divergence in the mode of action among the cannabis constituents.”

https://pubmed.ncbi.nlm.nih.gov/32585475/

“In the DS model, CBD, THC, CBN, and LN caused significant reduction in seizure behavior, while THC and CBD were effective in both models.”

https://linkinghub.elsevier.com/retrieve/pii/S1525505020303310

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Recent Cannabis Use in HIV Is Associated With Reduced Inflammatory Markers in CSF and Blood

 Home“Objective: To determine whether cannabis may reduce HIV-related persistent inflammation, we evaluated the relationship of cannabis use in people with HIV (PWH) to inflammatory cytokines in CSF and blood plasma.

Conclusions: Recent cannabis use was associated with lower levels of inflammatory biomarkers, both in CSF and blood, but in different patterns. These results are consistent with compartmentalization of immune effects of cannabis. The principal active components of cannabis are highly lipid soluble and sequestered in brain tissue; thus, our findings are consistent with specific anti-neuroinflammatory effects that may benefit HIV neurologic dysfunction.”

https://pubmed.ncbi.nlm.nih.gov/32554630/

https://nn.neurology.org/content/7/5/e809

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