Category Archives: THC (Delta-9-Tetrahydrocannabinol)

Cannabinoid modulation of corticolimbic activation during extinction learning and fear renewal in adults with posttraumatic stress disorder

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Neurobiology of Learning and Memory

“Failure to successfully extinguish fear is a hallmark of trauma-related disorders, like posttraumatic stress disorder (PTSD). PTSD is also characterized by dysfunctional corticolimbic activation and connectivity.

The endocannabinoid system is a putative system to target for rescuing these behavioral and neural deficits. In healthy adults, acute, low-dose delta-9-tetrahydrocannabinol (THC) facilitates fear extinction and increases cortico-limbic activation and connectivity in response to threat.

The present study determines the effect of acute, low-dose THC on fear-related brain activation and connectivity during fear extinction in trauma-exposed adults with (PTSD = 19) and without PTSD [trauma-exposed controls (TEC) = 26] and non-trauma-exposed [healthy controls (HC) = 26]. We used a Pavlovian fear conditioning and extinction paradigm, where we measured concurrent functional magnetic resonance imaging (fMRI) and behavioral responses (i.e., skin conductance responding and expectancy ratings). Using a randomized, double-blind, placebo-controlled design, N = 71 subjects were randomized to receive placebo (PBO, n = 37) or THC (n = 34) prior to fear extinction learning.

During early extinction learning, individuals with PTSD given THC had greater vmPFC activation than their TEC counterparts. During a test of the return of fear (i.e., renewal), HC and individuals with PTSD given THC had greater vmPFC activation compared to TEC. Individuals with PTSD given THC also had greater amygdala activation compared to those given PBO. We found no effects of trauma group or THC on behavioral fear indices during extinction learning, recall, and fear renewal.

These data suggest that low dose, oral THC can affect neural indices of fear learning and memory in adults with trauma-exposure; this may be beneficial for future therapeutic interventions seeking to improve fear extinction learning and memory.”

https://pubmed.ncbi.nlm.nih.gov/37088409/

https://www.sciencedirect.com/science/article/abs/pii/S1074742723000394?via%3Dihub

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

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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

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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

Endocannabinoid System: Chemical Characteristics and Biological Activity

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“The endocannabinoid system (eCB) has been studied to identify the molecular structures present in Cannabis sativa. eCB consists of cannabinoid receptors, endogenous ligands, and the associated enzymatic apparatus responsible for maintaining energy homeostasis and cognitive processes.

Several physiological effects of cannabinoids are exerted through interactions with various receptors, such as CB1 and CB2 receptors, vanilloid receptors, and the recently discovered G-protein-coupled receptors (GPR55, GPR3, GPR6, GPR12, and GPR19). Anandamide (AEA) and 2-arachidoylglycerol (2-AG), two small lipids derived from arachidonic acid, showed high-affinity binding to both CB1 and CB2 receptors.

eCB plays a critical role in chronic pain and mood disorders and has been extensively studied because of its wide therapeutic potential and because it is a promising target for the development of new drugs. Phytocannabinoids and synthetic cannabinoids have shown varied affinities for eCB and are relevant to the treatment of several neurological diseases.

This review provides a description of eCB components and discusses how phytocannabinoids and other exogenous compounds may regulate the eCB balance. Furthermore, we show the hypo- or hyperfunctionality of eCB in the body and how eCB is related to chronic pain and mood disorders, even with integrative and complementary health practices (ICHP) harmonizing the eCB.”

https://pubmed.ncbi.nlm.nih.gov/37017445/

“The roles of cannabinoid receptors and their agonists in multiple conditions have been addressed in this review. Since research with derivatives of Cannabis has started and the biological functions of isolated compounds in experimental and human diseases have shown promising outcomes, it is evident that selective ligands of specific Cannabis receptors could induce beneficial outcomes, depending on the clinical condition. More research on the biological function of each Cannabis derivative should be encouraged.”

https://www.mdpi.com/1424-8247/16/2/148

Medicinal cannabis for Australian patients with chronic refractory pain including arthritis

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“Objectives: To examine the tolerability and effectiveness of medicinal cannabis prescribed to patients for chronic, refractory pain, with a subset analysis on arthritis.

Methods: This was an interim analysis of the CA Clinics Observational Study investigating self-reported adverse events (AEs) and changes in health-related quality of life (HRQoL) outcomes over time after commencing medicinal cannabis. Patients were prescribed medicinal cannabis by a medical practitioner, containing various ratios of Δ9-tetrahydrocannabinol (THC) and/or cannabidiol (CBD).

Results: The overall chronic pain cohort, and specifically the balanced CBD:THC products, were associated with significantly reduced pain intensity scores (p = 0.003, p = 0.025), with 22% of patients reporting a clinically meaningful reduction in pain intensity. Patients in the arthritis subset (n = 199) reported significantly reduced pain intensity scores (p = 0.005) overall, and specifically for those taking CBD-only (p = 0.018) and balanced products (p = 0.005). Other HRQoL outcomes, including pain interference and pain impact scores were significantly improved depending on the CBD:THC ratio. Products that contained a balanced ratio of CBD:THC were associated with improvements in the most number of PROMIS-29 domains. Approximately half (n = 364; 51%) of the chronic pain cohort experienced at least one AE, the most common being dry mouth (24%), somnolence (19%) or fatigue (12%). These findings were similar in the arthritis subset.

Discussion: Medicinal cannabis was observed to improve pain intensity scores and HRQoL outcomes in patients with chronic, refractory pain, providing real-world insights into medicinal cannabis’ therapeutic potential.”

https://pubmed.ncbi.nlm.nih.gov/37057257/

https://journals.sagepub.com/doi/10.1177/20494637221147115

Effectiveness and Safety of Cannabinoids as an Add-On Therapy in the Treatment of Resistant Spasticity in Multiple Sclerosis: A Systematic Review

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“Background: Spasticity continues to be a very prevalent, highly invalidating, and difficult-to-manage symptom in patients with multiple sclerosis (MS). The aim of this systematic review is to evaluate the effectiveness of the use of cannabis and cannabinoids in these patients, evaluating its use as an additional therapy. 

Methods: We performed a systematic review of the literature searching in the major scientific databases (PubMed, Scopus, EMBASE, WOS, and Cochrane Library) for articles from January 2017 to May 2022 containing information about the effectiveness of cannabis and cannabinoids in patients with insufficient response to first-line oral antispastic treatment. 

Results: A total of five medium high-quality articles were selected to be part of the study and all evaluated the effectiveness of the tetrahydrocannabinol (THC) and cannabidiol (CBD) spray. The effectiveness of this drug and the significant improvements are produced on the patient-related spasticity assessment scales, obtaining improvement up to 45%; and on quality of life, producing a decrease in the appearance of symptoms related to spasticity, as well as an increase in the development of basic activities of daily living. The average dose is 5-7 sprays/day. The discontinuation rate for these treatments is around 40% due to lack of effectiveness and adverse events. All reported adverse effects are mild to moderate in severity and their incidence is ∼17%, although this figure tends to decrease with drug use. 

Conclusions: Adding the THC:CBD sprays have been shown to be more effective in treating MS spasticity than optimizing the dose of first-line antispastic drugs in selected responders patients. The safety and tolerability profiles remain in line with those obtained in other trials. More patients would benefit from treatment if the initial response search period was extended.”

https://pubmed.ncbi.nlm.nih.gov/37057959/

https://www.liebertpub.com/doi/10.1089/can.2022.0254

Medical Cannabis in the Treatment of Parkinson’s Disease

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Clinical Neuropharmacology

“Objectives: Medical cannabis (MC) has recently garnered interest as a potential treatment for neurologic diseases, including Parkinson’s disease (PD). A retrospective chart review was conducted to explore the impact of MC on the symptomatic treatment of patients with PD.

Methods: Patients with PD treated with MC in the normal course of clinical practice were included (n = 69). Data collected from patient charts included MC ratio/formulation changes, PD symptom changes after initiation of MC, and adverse events (AEs) from MC use. Information regarding changes in concomitant medications after MC initiation, including opioids, benzodiazepines, muscle relaxants, and PD medications, was also collected.

Results: Most patients were initially certified for a 1:1 (∆9-tetrahydrocannabinol:cannabidiol) tincture. Eight-seven percent of patients (n = 60) were noted to exhibit an improvement in any PD symptom after starting MC. Symptoms with the highest incidence of improvement included cramping/dystonia, pain, spasticity, lack of appetite, dyskinesia, and tremor. After starting MC, 56% of opioid users (n = 14) were able to decrease or discontinue opioid use with an average daily morphine milligram equivalent change from 31 at baseline to 22 at the last follow-up visit. The MC was well-tolerated with no severe AEs reported and low rate of MC discontinuation due to AEs (n = 4).

Conclusions: The MC may improve motor and nonmotor symptoms in patients with PD and may allow for reduction of concomitant opioid medication use. Large, placebo-controlled, randomized studies of MC use in patients with PD are required.”

https://pubmed.ncbi.nlm.nih.gov/37071411/

https://journals.lww.com/clinicalneuropharm/Abstract/9900/Medical_Cannabis_in_the_Treatment_of_Parkinson_s.48.aspx

Δ8-THC Protects against Amyloid Beta Toxicity Modulating ER Stress In Vitro: A Transcriptomic Analysis

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“Alzheimer’s disease (AD) represents the most common form of dementia, characterized by amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs). It is characterized by neuroinflammation, the accumulation of misfolded protein, ER stress and neuronal apoptosis. It is of main importance to find new therapeutic strategies because AD prevalence is increasing worldwide.

Cannabinoids are arising as promising neuroprotective phytocompounds. In this study, we evaluated the neuroprotective potential of Δ8-THC pretreatment in an in vitro model of AD through transcriptomic analysis.

We found that Δ8-THC pretreatment restored the loss of cell viability in retinoic acid-differentiated neuroblastoma SH-SY5Y cells treated with Aβ1-42. Moreover, the transcriptomic analysis provided evidence that the enriched biological processes of gene ontology were related to ER functions and proteostasis. In particular, Aβ1-42 upregulated genes involved in ER stress and unfolded protein response, leading to apoptosis as demonstrated by the increase in Bax and the decrease in Bcl-2 both at gene and protein expression levels. Moreover, genes involved in protein folding and degradation were also deregulated. On the contrary, Δ8-THC pretreatment reduced ER stress and, as a consequence, neuronal apoptosis.

Then, the results demonstrated that Δ8-THC might represent a new neuroprotective agent in AD.”

https://pubmed.ncbi.nlm.nih.gov/37047608/

“The results suggested that Δ8-THC may represent a novel neuroprotective agent in AD but also in other neurodegenerative diseases characterized by the accumulation of misfolded proteins.”

https://www.mdpi.com/1422-0067/24/7/6598

The impact of cannabinoids on inflammasome signaling in HIV-1 infection

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NeuroImmune Pharmacology and Therapeutics

“Human immunodeficiency virus type 1 (HIV-1) is a chronic disease that afflicts over 38 million people worldwide without a known cure. The advent of effective antiretroviral therapies (ART) has significantly decreased the morbidity and mortality associated with HIV-1 infection in people living with HIV-1 (PWH), thanks to durable virologic suppression. Despite this, people with HIV-1 experience chronic inflammation associated with co-morbidities. While no single known mechanism accounts for chronic inflammation, there is significant evidence to support the role of the NLRP3 inflammasome as a key driver.

Numerous studies have demonstrated therapeutic impact of cannabinoids, including exerting modulatory effects on the NLRP3 inflammasome. Given the high rates of cannabinoid use in PWH, it is of great interest to understand the intersecting biology of the role of cannabinoids in HIV-1-associated inflammasome signaling. Here we describe the literature of chronic inflammation in people with HIV, the therapeutic impact of cannabinoids in PWH, endocannabinoids in inflammation, and HIV-1-associated inflammation. We describe a key interaction between cannabinoids, the NLRP3 inflammasome, and HIV-1 viral infection, which supports further investigation of the critical role of cannabinoids in HIV-1 infection and inflammasome signaling.”

https://pubmed.ncbi.nlm.nih.gov/37027347/

“It is evident from the literature that cannabinoids show protective effects against inflammation associated with HIV-1. In both human and animal studies, THC/cannabis treatment has been shown to reduce inflammatory markers, including NLRP3-associated cytokine signaling and T-cell activation and proliferation. Studies also implicate a neuroprotective effect against NO-mediated cytotoxicity and BBB breakdown in rodents. Taken together, these findings suggest a role for cannabinoid receptor activation in reducing chronic inflammation and associated pathologies in PWH.”

https://www.degruyter.com/document/doi/10.1515/nipt-2023-0002/html

Risk of Motor Vehicle Collisions and Culpability among Older Drivers Using Cannabis: A Meta-Analysis

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brainsci-logo

“Limited studies have investigated the effects of cannabis use on driving among older adults, who represent the fastest growing segment of drivers globally. We conducted a systematic review and meta-analysis to evaluate the effects of delta-9-tetrahydrocannabinol (THC) exposure on risks of (1) motor vehicle collisions (MVC) and (2) culpability for MVCs among adults 50 years and older. Three reviewers screened 7022 studies identified through MEDLINE, EMBASE, CENTRAL, and PsycINFO. Odds Ratios (OR) were calculated using the Mantel-Haenszel method in Review Manager 5.4.1. Heterogeneity was assessed using I2. The National Heart, Lung, and Blood Institute tool was used to assess the quality of each study. Seven cross-sectional studies were included. Three studies evaluated culpability while four evaluated MVC.

The pooled risk of MVC was not significantly different between THC-positive and THC-negative older drivers (OR, 95% CI 1.15 [0.40, 3.31]; I2 = 72%). In culpability studies, THC exposure was not significantly associated with an increased risk of being culpable for MVC among adults over the age of 50 (OR, 95% CI 1.24 [0.95, 1.61]; I2 = 0%). Inspection of funnel plots did not indicate publication bias.

Our review found that THC exposure was not associated with MVC involvement nor with culpability for MVCs.”

https://pubmed.ncbi.nlm.nih.gov/36979231/

https://www.mdpi.com/2076-3425/13/3/421