SELECTED CANNABIS TERPENES SYNERGIZE WITH THC TO PRODUCE INCREASED CB1 RECEPTOR ACTIVATION

Biochemical Pharmacology

“The cannabis plant exerts its pharmaceutical activity primarily by the binding of cannabinoids to two G protein-coupled cannabinoid receptors, CB1 and CB2. The role that cannabis terpenes play in this activation has been considered and debated repeatedly, based on only limited experimental results. In the current study we used a controlled in-vitro heterologous expression system to quantify the activation of CB1 receptors by sixteen cannabis terpenes individually, by tetrahydrocannabinol (THC) alone and by THC-terpenes mixtures. The results demonstrate that all terpenes, when tested individually, activate CB1 receptors, at about 10-50% of the activation by THC alone. The combination of some of these terpenes with THC significantly increases the activity of the CB1 receptor, compared to THC alone. In some cases, several fold. Importantly, this amplification is evident at terpene to THC ratios similar to those in the cannabis plant, which reflect very low terpene concentrations. For some terpenes, the activation obtained by THC- terpene mixtures is notably greater than the sum of the activations by the individual components, suggesting a synergistic effect. Our results strongly support a modulatory effect of some of the terpenes on the interaction between THC and the CB1 receptor. As the most effective terpenes are not necessarily the most abundant ones in the cannabis plant, reaching “whole plant” or “full spectrum” composition is not necessarily an advantage. For enhanced therapeutic effects, desired compositions are attainable by enriching extracts with selected terpenes. These compositions adjust the treatment for various desired medicinal and personal needs.”

https://pubmed.ncbi.nlm.nih.gov/37084981/

https://www.sciencedirect.com/science/article/pii/S0006295223001399?via%3Dihub

Activation of CB1R alleviates central sensitization by regulating HCN2-pNR2B signaling in a chronic migraine rat model

The Journal of Headache and Pain

“Background: Central sensitization has been widely accepted as an underlying pathophysiological mechanism of chronic migraine (CM), activation of cannabinoid type-1 receptor (CB1R) exerts antinociceptive effects by relieving central sensitization in many pain models. However, the role of CB1R in the central sensitization of CM is still unclear.

Methods: A CM model was established by infusing inflammatory soup (IS) into the dura of male Wistar rats for 7 days, and hyperalgesia was assessed by the mechanical and thermal thresholds. In the periaqueductal gray (PAG), the mRNA and protein levels of CB1R and hyperpolarization-activated cyclic nucleotide-gated cation channel 2 (HCN2) were measured by qRT-PCR and western blotting. After intraventricular injection of Noladin ether (NE) (a CB1R agonist), ZD 7288 (an HCN2 blocker), and AM 251 (a CB1R antagonist), the expression of tyrosine phosphorylation of N-methyl-D-aspartate receptor subtype 2B (pNR2B), calcium-calmodulin-dependent kinase II (CaMKII), and phosphorylated cAMP-responsive element binding protein (pCREB) was detected, and central sensitization was evaluated by the expression of calcitonin gene-related peptide (CGRP), c-Fos, and substance P (SP). Synaptic-associated protein (postsynaptic density protein 95 (PSD95) and synaptophysin (Syp)) and synaptic ultrastructure were detected to explore synaptic plasticity in central sensitization.

Results: We observed that the mRNA and protein levels of CB1R and HCN2 were both significantly increased in the PAG of CM rats. The application of NE or ZD 7288 ameliorated IS-induced hyperalgesia; repressed the pNR2B/CaMKII/pCREB pathway; reduced CGRP, c-Fos, SP, PSD95, and Syp expression; and inhibited synaptic transmission. Strikingly, the application of ZD 7288 relieved AM 251-evoked elevation of pNR2B, CGRP, and c-Fos expression.

Conclusions: These data reveal that activation of CB1R alleviates central sensitization by regulating HCN2-pNR2B signaling in CM rats. The activation of CB1R might have a positive influence on the prevention of CM by mitigating central sensitization.”

https://pubmed.ncbi.nlm.nih.gov/37085778/

https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-023-01580-7

A Retrospective Medical Record Review of Adults with Non-Cancer Diagnoses Prescribed Medicinal Cannabis

Logo of jclinmed

“Research describing patients using medicinal cannabis and its effectiveness is lacking. We aimed to describe adults with non-cancer diagnoses who are prescribed medicinal cannabis via a retrospective medical record review and assess its effectiveness and safety. From 157 Australian records, most were female (63.7%; mean age 63.0 years). Most patients had neurological (58.0%) or musculoskeletal (24.8%) conditions. Medicinal cannabis was perceived beneficial by 53.5% of patients.

Mixed-effects modelling and post hoc multiple comparisons analysis showed significant changes overtime for pain, bowel problems, fatigue, difficulty sleeping, mood, quality of life (all p < 0.0001), breathing problems (p = 0.0035), and appetite (p = 0.0465) Symptom Assessment Scale scores. For the conditions, neuropathic pain/peripheral neuropathy had the highest rate of perceived benefit (66.6%), followed by Parkinson’s disease (60.9%), multiple sclerosis (60.0%), migraine (43.8%), chronic pain syndrome (42.1%), and spondylosis (40.0%). For the indications, medicinal cannabis had the greatest perceived effect on sleep (80.0%), followed by pain (51.5%), and muscle spasm (50%). Oral oil preparations of balanced delta-9-tetrahydrocannabinol/cannabidiol (average post-titration dose of 16.9 mg and 34.8 mg per day, respectively) were mainly prescribed. Somnolence was the most frequently reported side effect (21%).

This study supports medicinal cannabis’ potential to safely treat non-cancer chronic conditions and indications.”

“Cannabis (Cannabaceae) has been used medicinally since 400 AD for its analgesic, appetite enhancement, and myorelaxant properties. Emerging evidence suggests that people with chronic conditions may benefit from using medicinal cannabis for treating chronic pain, multiple sclerosis-related spasticity, epilepsy, Parkinson’s disease, insomnia, and anxiety.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9965412/

UK medical cannabis registry: assessment of clinical outcomes in patients with headache disorders

Publication Cover

“Objectives: Headache disorders are a common cause of disability and reduced health-related quality of life globally. Growing evidence supports the use of cannabis-based medicinal products (CBMPs) for chronic pain; however, a paucity of research specifically focuses on CBMPs’ efficacy and safety in headache disorders. This study aims to assess changes in validated patient-reported outcome measures (PROMs) in patients with headaches prescribed CBMPs and investigate the clinical safety in this population.

Methods: A case series of the UK Medical Cannabis Registry was conducted. Primary outcomes were changes from baseline in PROMs (Headache Impact Test-6 (HIT-6), Migraine Disability Assessment (MIDAS), EQ-5D-5L, Generalized Anxiety Disorder-7 (GAD-7) questionnaire and Single-Item Sleep Quality Scale (SQS)) at 1-, 3-, and 6-months follow-up. P-values <0.050 were deemed statistically significant.

Results: Ninety-seven patients were identified for inclusion. Improvements in HIT-6, MIDAS, EQ-5D-5L and SQS were observed at 1-, 3-, and 6-months (p < 0.005) follow-up. GAD-7 improved at 1- and 3-months (p < 0.050). Seventeen (17.5%) patients experienced a total of 113 (116.5%) adverse events.

Conclusion: Improvements in headache/migraine-specific PROMs and general health-related quality of life were associated with the initiation of CBMPs in patients with headache disorders. Cautious interpretation of results is necessary, and randomized control trials are required to ascertain causality.”

https://pubmed.ncbi.nlm.nih.gov/36722292/

https://www.tandfonline.com/doi/full/10.1080/14737175.2023.2174017

Efficacy and Safety of Medical Marijuana in Migraine Headache: A Systematic Review

“Medical marijuana treatment for migraine is becoming more common, although the legality and societal acceptance of marijuana for medical purposes in the United States have been challenged by the stigma attached to it as a recreational drug.

These substances function to reduce nociception and decrease the frequency of migraine by having an impact on the endocannabinoid system.

Our study reviewed the clinical response, dosing, and side effects of marijuana in migraine management. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a literature search in PubMed, Google Scholar, and Science Direct, and nine studies were included in the systematic review.

The studies demonstrated that medical marijuana has a significant clinical response by reducing the length and frequency of migraines. No severe adverse effects were noted. Due to its effectiveness and convenience, medical marijuana therapy may be helpful for patients suffering from migraines. However, additional clinical trials and observational studies with longer follow-ups are required to study the efficacy and safety of the drug.”

https://pubmed.ncbi.nlm.nih.gov/36660507/

“The main objective of this article is to assess the efficacy and safety of medical marijuana for the treatment of migraine headaches. All the studies showed encouraging findings on the therapeutic effects of medicinal marijuana in migraine treatment. Additionally, medical marijuana is well-tolerated with fewer side effects and is safe to use in migraine patients.”

https://www.cureus.com/articles/118190-efficacy-and-safety-of-medical-marijuana-in-migraine-headache-a-systematic-review

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

ijms-logo“The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems.

In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development.

The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development.

The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases.

This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.”

https://pubmed.ncbi.nlm.nih.gov/34502379/

https://www.mdpi.com/1422-0067/22/17/9472

 

“Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830475/

Alleviative effects of Cannabis flower on migraine and headache

 Journal of Integrative Medicine“Few studies to date have measured the real-time effects of consumption of common and commercially available Cannabis products for the treatment of headache and migraine under naturalistic conditions. This study examines, for the first time, the effectiveness of using dried Cannabis flower, the most widely used type of Cannabis product in the United States, in actual time for treatment of headache- and migraine-related pain and the associations between different product characteristics and changes in symptom intensity following Cannabis use.

Results

Ninety-four percent of users experienced symptom relief within a two-hour observation window. The average symptom intensity reduction was 3.3 points on a 0−10 scale (standard deviation = 2.28, Cohen’s d = 1.58), with males experiencing greater relief than females (P < 0.001) and a trend that younger users (< 35 years) experience greater relief than older users (P = 0.08). Mixed effects regression models showed that, among the known (i.e., labeled) product characteristics, tetrahydrocannabinol levels 10% and higher are the strongest independent predictors of symptom relief, and this effect is particularly prominent in headache rather than migraine sufferers (P < 0.05), females (P < 0.05) and younger users (P < 0.001). Females and younger users also appear to gain greater symptom relief from flower labeled as “C. indica” rather than “C. sativa” or other hybrid strains.

Conclusion

These results suggest that whole dried Cannabis flower may be an effective medication for treatment of migraine- and headache-related pain, but the effectiveness differs according to characteristics of the Cannabis plant, the combustion methods, and the age and gender of the patient.”

https://www.sciencedirect.com/science/article/abs/pii/S2095496420300741

Receptor Mechanisms Mediating the Anti-Neuroinflammatory Effects of Endocannabinoid System Modulation in a Rat Model of Migraine

European Jnl of Neuroscience – Applications sur Google Play

“Calcitonin gene-related peptide (CGRP), substance-P and dural mast cells are main contributors in neurogenic inflammation underlying migraine pathophysiology.

Modulation of endocannabinoid system attenuates migraine pain, but its mechanisms of action remains unclear.

We investigated receptor mechanisms mediating anti-neuroinflammatory effects of endocannabinoid system modulation in in-vivo migraine model and ex-vivo hemiskull preparations in rats.

Selective ligands targeting CB1 and CB2 receptors may provide novel and effective treatment strategies against migraine.”

https://pubmed.ncbi.nlm.nih.gov/32639078/

https://onlinelibrary.wiley.com/doi/abs/10.1111/ejn.14897

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

Migraine Frequency Decrease Following Prolonged Medical Cannabis Treatment: A Cross-Sectional Study

brainsci-logo“Medical cannabis (MC) treatment for migraine is practically emerging, although sufficient clinical data are not available for this indication. This cross-sectional questionnaire-based study aimed to investigate the associations between phytocannabinoid treatment and migraine frequency.

Compared to non-responders, responders (n = 89, 61%) reported lower current migraine disability and lower negative impact, and lower rates of opioid and triptan consumption. Subgroup analysis demonstrated that responders consumed higher doses of the phytocannabinoid ms_373_15c and lower doses of the phytocannabinoid ms_331_18d (3.40 95% CI (1.10 to 12.00); p < 0.01 and 0.22 95% CI (0.05-0.72); p < 0.05, respectively).

Conclusions: These findings indicate that MC results in long-term reduction of migraine frequency in >60% of treated patients and is associated with less disability and lower antimigraine medication intake. They also point to the MC composition, which may be potentially efficacious in migraine patients.”

https://pubmed.ncbi.nlm.nih.gov/32526965/

https://www.mdpi.com/2076-3425/10/6/360