THC vapor inhalation attenuates hyperalgesia in rats using a chronic inflammatory pain model

Posted on August 11, 2024 by David

“Humans use cannabinoid drugs to alleviate pain.

As cannabis and cannabinoids are legalized in the U.S. for medicinal and recreational use, it has become critical to determine the potential utilities and harms of cannabinoid drugs in individuals living with chronic pain.

Here, we tested the effects of repeated THC vapor inhalation on thermal nociception and mechanical sensitivity, in adult male and female Wistar rats using a chronic inflammatory pain model (i.e., treated with Complete Freund’s Adjuvant [CFA]).

We report that repeated THC vapor inhalation rescues thermal hyperalgesia in males and females treated with CFA, and also reduces mechanical hypersensitivity in CFA males but not females. Many of the anti-hyperalgesic effects of chronic THC vapor were still observable 24 hours after cessation of the last THC exposure.

We also report plasma levels of THC and its major metabolites, some of which are cannabinoid type-1 receptor (CB1) agonists, after the first and tenth days of THC vapor inhalation. Finally, we report that systemic administration of the CB1 inverse agonist AM251 (1mg/kg; i.p.) blocks the anti-hyperalgesic effects of THC vapor in males and females.

These data provide a foundation for future work that will explore the cells and circuits underlying the anti-hyperalgesic effects of THC vapor inhalation in individuals with chronic inflammatory pain.

PERSPECTIVE: Cannabinoids are thought to have potential utility in the treatment of chronic pain, but few animal studies have tested the effects of chronic THC or cannabis in animal models of chronic pain. We tested the effects of repeated THC vapor inhalation on chronic pain-related outcomes in male and female animals.”

https://pubmed.ncbi.nlm.nih.gov/39121915/

https://www.jpain.org/article/S1526-5900(24)00599-6/abstract

Clinical Benefits and Safety of Medical Cannabis Products: A Narrative Review on Natural Extracts

Posted on August 5, 2024 by David

“Interest in medical cannabis and cannabis-based medicinal products (CBMPs) has increased greatly in recent years. Two cannabinoids are of principal importance; delta-9-tetrahydrocannabinol (∆9-THC), the primary psychoactive component, and also cannabidiol (CBD), considered non-intoxicating. Each has distinct mechanisms of action and different therapeutic potentials. CBMPs differ in their ∆9-THC and CBD components; predominantly ∆9-THC, balanced formulations with equivalent ∆9-THC and CBD elements, and CBD-predominant products.

In this narrative review, we evaluate the published evidence for the clinical benefits of CBMPs and overall benefits in well-being. We also review the overall safety profile and discuss the potential for dependence with CBMPs. Evidence can be drawn from a wide range of randomized and other controlled studies and from observational real-world studies.

Most data from observational registry studies are supportive of ∆9-THC-based products (∆9-THC-predominant or balanced CBMPs) in the management of chronic neuropathic pain. Balanced products are also effective in reducing spasticity in multiple sclerosis. Most CBMPs show benefit in providing symptomatic benefits in reducing anxiety, nausea, and in improving sleep, but the place of specific products is more subtle, and choice guided by specific circumstances. Symptomatic improvements are accompanied by improved quality of life and well-being. Safety data indicate that CBMPs are generally well tolerated in most patients without specific contraindications. The majority of adverse effects are non-serious, and transient; most are principally associated with ∆9-THC and are dose-dependent. In contrast to recreational cannabis use, there is little evidence from clinical studies that CBMPs have any potential for dependence.”

https://pubmed.ncbi.nlm.nih.gov/39096481/

https://link.springer.com/article/10.1007/s40122-024-00643-0

Analgesic properties of next generation modulators of endocannabinoid signaling: leveraging modern tools for the development of novel therapeutics

Posted on August 2, 2024 by David

“Targeting the endocannabinoid (eCB) signaling system for pain relief is an important treatment option that is only now beginning to be mechanistically explored.

In this review, we focus on two recently appreciated cannabinoid-based targeting strategies, treatments with cannabidiol (CBD) and a/b-hydrolase domain containing 6 (ABHD6) inhibitors, which have the exciting potential to produce pain relief through distinct mechanisms of action (MOA) and without intoxication.

We review evidence on plant-derived cannabinoids for pain, with an emphasis on CBD and its multiple molecular targets expressed in pain pathways. We also discuss the function of eCB signaling in regulating pain responses and the therapeutic promises of inhibitors targeting ABHD6, a 2-arachidonoylglycerol (2-AG) hydrolyzing enzyme. Finally, we discuss how the novel cannabinoid biosensor, GRAB_eCB2.0, may be leveraged to enable the discovery of targets modulated by cannabinoids at a circuit-specific level.

Significance Statement Cannabis has been used by humans as an effective medicine for millennia, including for pain management. Recent evidence emphasizes the therapeutic potential of compounds that modulate endocannabinoid signaling. Specifically, cannabidiol and inhibitors of the enzyme ABHD6 represent promising strategies to achieve pain relief by modulating endocannabinoid signaling in pain pathways via distinct, non-intoxicating, mechanisms of action.”

https://pubmed.ncbi.nlm.nih.gov/39060165/

https://jpet.aspetjournals.org/content/early/2024/07/26/jpet.124.002119

Impact of Cannabidiol and Exercise on Clinical Outcomes and Gut Microbiota for Chemotherapy-Induced Peripheral Neuropathy in Cancer Survivors: A Case Report

Posted on July 29, 2024 by David

“Chemotherapy-induced peripheral neuropathy (CIPN) remains a clinical challenge for up to 80% of breast cancer survivors. In an open-label study, participants underwent three interventions: standard care (duloxetine) for 1 month (Phase 1), oral cannabidiol (CBD) for 2 months (Phase 2), and CBD plus multi-modal exercise (MME) for another 2 months (Phase 3). Clinical outcomes and gut microbiota composition were assessed at baseline and after each phase. We present the case of a 52-year-old female with a history of triple-negative breast cancer in remission for over five years presenting with CIPN. She showed decreased monocyte counts, c-reactive protein, and systemic inflammatory index after each phase. Duloxetine provided moderate benefits and intolerable side effects (hyperhidrosis). She experienced the best improvement and least side effects with the combined (CBD plus MME) phase. Noteworthy were clinically meaningful improvements in CIPN symptoms, quality of life (QoL), and perceived physical function, as well as improvements in pain, mobility, hand/finger dexterity, and upper and lower body strength. CBD and MME altered gut microbiota, showing enrichment of genera that produce short-chain fatty acids. CBD and MME may improve CIPN symptoms, QoL, and physical function through anti-inflammatory and neuroprotective effects in cancer survivors suffering from long-standing CIPN.”

https://pubmed.ncbi.nlm.nih.gov/39065685/

“This case report provides initial but holistic evidence supporting complementary approaches for addressing CIPN in cancer survivors. It suggests that clinically meaningful improvements in CIPN symptoms, quality of life, and functional status can be achieved through combining the oral administration of 300 mg/day of CBD with a multi-modal exercise program. The synergistic benefit of this combination may be explained through an increase in circulating endocannabinoids and beneficial changes in the gut microbiota. Both CBD and exercise were also found to be better tolerated than duloxetine.”

https://www.mdpi.com/1424-8247/17/7/834

Cannabidiol and Beta-Caryophyllene Combination Attenuates Diabetic Neuropathy by Inhibiting NLRP3 Inflammasome/NFκB through the AMPK/sirT3/Nrf2 Axis

Posted on July 28, 2024 by David

“Background: In this study, we investigated in detail the role of cannabidiol (CBD), beta-caryophyllene (BC), or their combinations in diabetic peripheral neuropathy (DN). The key factors that contribute to DN include mitochondrial dysfunction, inflammation, and oxidative stress.

Methods: Briefly, streptozotocin (STZ) (55 mg/kg) was injected intraperitoneally to induce DN in Sprague-Dawley rats, and we performed procedures involving Randall Sellito calipers, a Von Frey aesthesiometer, a hot plate, and cold plate methods to determine mechanical and thermal hyperalgesia in vivo. The blood flow to the nerves was assessed using a laser Doppler device. Schwann cells were exposed to high glucose (HG) at a dose of 30 mM to induce hyperglycemia and DCFDA, and JC1 and Mitosox staining were performed to determine mitochondrial membrane potential, reactive oxygen species, and mitochondrial superoxides in vitro. The rats were administered BC (30 mg/kg), CBD (15 mg/kg), or combination via i.p. injections, while Schwann cells were treated with 3.65 µM CBD, 75 µM BC, or combination to assess their role in DN amelioration.

Results: Our results revealed that exposure to BC and CBD diminished HG-induced hyperglycemia in Schwann cells, in part by reducing mitochondrial membrane potential, reactive oxygen species, and mitochondrial superoxides. Furthermore, the BC and CBD combination treatment in vivo could prevent the deterioration of the mitochondrial quality control system by promoting autophagy and mitochondrial biogenesis while improving blood flow. CBD and BC treatments also reduced pain hypersensitivity to hyperalgesia and allodynia, with increased antioxidant and anti-inflammatory action in diabetic rats. These in vivo effects were attributed to significant upregulation of AMPK, sirT3, Nrf2, PINK1, PARKIN, LC3B, Beclin1, and TFAM functions, while downregulation of NLRP3 inflammasome, NFκB, COX2, and p62 activity was noted using Western blotting.

Conclusions: the present study demonstrated that STZ and HG-induced oxidative and nitrosative stress play a crucial role in the pathogenesis of diabetic neuropathy. We find, for the first time, that a CBD and BC combination ameliorates DN by modulating the mitochondrial quality control system.”

https://www.mdpi.com/2227-9059/12/7/1442

“In summary, the present studies demonstrated that STZ- and HG-induced oxidative and nitrosative stress play a crucial role in the pathogenesis of diabetic neuropathy. The functional, behavioral, and molecular deficits were due to oxidant-induced damage, neuroinflammation, and bioenergetic deficits. These pathological consequences of nerve injury have been attenuated by the combination of CBD and BC in vitro and in vivo.

Our findings suggest that the enhanced neuroprotective effects of combination therapy may be attributable to simultaneous inhibition of oxidative stress, neuroinflammation, and NLRP3, as well as activation of Nrf2. Hence, the combination therapy could be suggested as a potential strategy that can be further pursued for the management of STZ- and HG-induced diabetic neuropathy.”

https://pubmed.ncbi.nlm.nih.gov/39062016/

Cannabidiol and pain

Posted on July 20, 2024 by David

“Chronic pain presents significant personal, psychological, and socioeconomic hurdles, impacting over 30% of adults worldwide and substantially contributing to disability. Unfortunately, current pharmacotherapy often proves inadequate, leaving fewer than 70% of patients with relief. This shortfall has sparked a drive to seek alternative treatments offering superior safety and efficacy profiles.

Cannabinoid-based pharmaceuticals, notably cannabidiol (CBD), hold promise in pain management, driven by their natural origins, versatility, and reduced risk of addiction. As we navigate the opioid crisis, ongoing research plunges into CBD’s therapeutic potential, buoyed by animal studies revealing its pain-relieving prowess through various system tweaks. However, the efficacy of cannabis in chronic pain management remains a contentious and stigmatized issue.

The International Association for the Study of Pain (IASP) presently refrains from endorsing cannabinoid use for pain relief. Nevertheless, evidence indicates their potential in alleviating cancer-related, neuropathic, arthritis, and musculoskeletal pain, necessitating further investigation. Crucially, our comprehension of CBD’s role in pain management is a journey still unfolding, with animal studies illustrating its analgesic effects through interactions with the endocannabinoid, inflammatory, and nociceptive systems.

As the plot thickens, it’s clear: the saga of chronic pain and CBD’s potential offers a compelling narrative ripe for further exploration and understanding.”

https://pubmed.ncbi.nlm.nih.gov/39029988/

https://www.sciencedirect.com/science/article/abs/pii/S0074774224000680?via%3Dihub

Potential analgesic effect of a novel cannabidiol nanocrystals powder for the treatment of neuropathic pain

Posted on July 11, 2024 by David

“Background: The current analgesics often prevent patients from getting effective treatment due to their adverse effects. Cannabidiol (CBD) is well tolerated, has few side effects and has been extensively investigated in analgesia. However, its oral bioavailability is extremely low. In order to solve this problem, we developed the cannabidiol nanocrystals (CBD-NC) in the earlier stage.

Methods: In this study, we evaluated the nociceptive behaviours associated with neuropathic pain (NP) induced by the spared nerve injury (SNI) model. Assessment of pain threshold was evaluated by paw withdraw threshold (PWT) and paw withdrawal latency (PWL). The improving effect on the motor dysfunction was determined by rota-rod testing. To assess the neuroprotective effect, nerve demyelination and expression of peripheral myelin protein PMP22 were measured with myelin sheath staining and western blotting. Protein expressions in microglia of spinal cord were tested by western blot to explore the underlying mechanism.

Results: Compared with the CBD oil solution, CBD-NC significantly reduced mechanical allodynia and thermal hyperalgesia in rats. CBD-NC could improve motor dysfunction induced by SNI in rats, significantly reverse the demyelination and increase the expression of the marker protein of peripheral myelin. Underlying spinal analgesic mechanism of microglia and related factors were preliminarily confirmed.

Conclusions: CBD-NC administration is an effective treatment for NP associated with SNI, and the analgesic effect of CBD-NC was significantly better than that of CBD oil sol. By contrast, CBD-NC has a fast-acting and long-term effect in the treatment of NP. Our study further supports the potential therapeutic effect of CBD-NC on NP.

Significance: The absolute bioavailability of the CBD-NC intramuscular injection formulation can reach 203.31%, which can solve the problem of low oral bioavailability. This research evaluated the therapeutic effect of CBD-NC on NP associated with the SNI model for the first time. All available date showed that whatever the analgesic or neuroprotective effect of CBD-NC, it was significantly better than that of CBD oil sol., which was consistent with the results of the pharmacokinetic. This research supports the initiation of more trials testing the efficacy of CBD-NC for treating NP.”

https://pubmed.ncbi.nlm.nih.gov/38982797/

https://onlinelibrary.wiley.com/doi/10.1002/ejp.2300

The potential neuroprotective effects of cannabinoids against paclitaxel-induced peripheral neuropathy: in vitro study on neurite outgrowth

Posted on June 27, 2024 by David

“Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a shared burden for 68.1% of oncological patients undergoing chemotherapy with Paclitaxel (PTX). The symptoms are intense and troublesome, patients reporting paresthesia, loss of sensation, and dysesthetic pain. While current medications focus on decreasing the symptom intensity, often ineffective, no medication is yet recommended by the guidelines for the prevention of CIPN. Cannabinoids are an attractive option, as their neuroprotective features have already been demonstrated in neuropathies with other etiologies, by offering the peripheral neurons protection against toxic effects, which promotes analgesia.

Methods: We aim to screen several new cannabinoids for their potential use as neuroprotective agents for CIPN by investigating the cellular toxicity profile and by assessing the potential neuroprotective features against PTX using a primary dorsal root ganglion neuronal culture.

Results: Our study showed that synthetic cannabinoids JWH-007, AM-694 and MAB-CHMINACA and phytocannabinoids Cannabixir^® Medium dried flowers (NC1) and Cannabixir^® THC full extract (NC2) preserve the viability of fibroblasts and primary cultured neurons, in most of the tested dosages and time-points. The combination between the cannabinoids and PTX conducted to a cell viability of 70%-89% compared to 40% when PTX was administered alone for 48 h. When assessing the efficacy for neuroprotection, the combination between cannabinoids and PTX led to better preservation of neurite length at all tested time-points compared to controls, highly drug and exposure-time dependent. By comparison, the combination of the cannabinoids and PTX administered for 24 h conducted to axonal shortening between 23% and 44%, as opposed to PTX only, which shortened the axons by 63% compared to their baseline values.

Discussion and Conclusion: Cannabinoids could be potential new candidates for the treatment of paclitaxel-induced peripheral neuropathy; however, our findings need to be followed by additional tests to understand the exact mechanism of action, which would support the translation of the cannabinoids in the oncological clinical practice.”

https://pubmed.ncbi.nlm.nih.gov/38933665/

“Our study paves the way for the benefits of either synthetic cannabinoids or phytocannabinoids for the palliation of chemotherapy-induced peripheral neuropathy.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1395951/full

Select Minor Cannabinoids from Cannabis sativa are Cannabimimetic and Antinociceptive in a Mouse Model of Chronic Neuropathic Pain

Posted on June 5, 2024 by David

“Chronic pain conditions affect nearly 20% of the population in the United States. Current medical interventions, such as opioid drugs, are effective at relieving pain but are accompanied by many undesirable side effects. This is one reason increased numbers of chronic pain patients have been turning to Cannabis for pain management.

Cannabis contains many bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids in Cannabis lacks uniformity between experimental groups and/or excludes female mice from investigation. This makes it challenging to draw conclusions between experiments done with different minor cannabinoid compounds between labs or parse out potential sex differences that could be present.

We chose five minor cannabinoids found in lower quantities within Cannabis: cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), Δ8-tetrahydrocannabinol (Δ8-THC), and Δ9-tetrahydrocannabivarin (THCV). These compounds were then tested for their cannabimimetic and pain-relieving behaviors in a cannabinoid tetrad assay and a chemotherapy-induced peripheral neuropathy (CIPN) pain model in male and female CD-1 mice.

We found that the minor cannabinoids we tested differed in the cannabimimetic behaviors evoked, as well as the extent. We found that CBN, CBG, and high dose Δ8-THC evoked some tetrad behaviors in both sexes, while THCV and low dose Δ8-THC exhibited cannabimimetic tetrad behaviors only in females. Only CBN efficaciously relieved CIPN pain, which contrasts with reports from other researchers. Together these findings provide further clarity to the pharmacology of minor cannabinoids and suggest further investigation into their mechanism and therapeutic potential.

Significance Statement Minor cannabinoids are poorly studied ligands present in lower levels in Cannabis than cannabinoids like THC. In this study we evaluated 5 minor cannabinoids (CBN, CBDV, CBG, THCV, and Δ8-THC) for their cannabimimetic and analgesic effects in mice. We found that 4 of the 5 minor cannabinoids showed cannabimimetic activity, while one was efficacious in relieving chronic neuropathic pain. This work is important in further evaluating the activity of these drugs, which are seeing wider public use with marijuana legalization.”

https://pubmed.ncbi.nlm.nih.gov/38834356/

https://jpet.aspetjournals.org/content/early/2024/06/04/jpet.124.002212

Cannabidiol in the dorsal hippocampus attenuates emotional and cognitive impairments related to neuropathic pain: Role of prelimbic neocortex-hippocampal connections

Posted on May 30, 2024 by David

“Background and purpose: Chronic neuropathic pain (NP) is commonly associated with cognitive and emotional impairments. Cannabidiol (CBD) presents a broad spectrum of action with a potential analgesic effect. This work investigates the CBD effect on comorbidity between chronic NP, depression, and memory impairment.

Experimental approach: The connection between the neocortex and the hippocampus was investigated with biotinylated dextran amine (BDA) deposits in the prelimbic cortex (PrL). Wistar rats were submitted to chronic constriction injury (CCI) of the sciatic nerve and CA1 treatment with CBD (15, 30, 60 nmol).

Key results: BDA-labeled were found in CA₁ and dentate gyrus. CCI-induced mechanical and cold allodynia increased c-Fos protein expression in the PrL and CA₁. The number of astrocytes in PrL and CA₁ increased, and the number of neuroblasts decreased in CA₁. The CCI animals showed increasing depressive-like behaviors, such as memory impairment. CBD (60 nmol) treatment decreased mechanical and cold allodynia, attenuated depressive-associated behaviors, and improved memory performance. Cobalt chloride (CoCl₂: 1 nM), WAY-100635 (0.37 nmol), and AM251 (100 nmol) intra-PrL reversed the CBD (60 nmol) effect intra-CA₁, both in nociceptive, cognitive, and depressive behaviors.

Conclusion: CBD represents a promising therapeutic perspective in the pharmacological treatment of chronic NP and associated comorbidities such as depression and memory impairments. The CBD effects possibly recruit the CA₁-PrL pathway, inducing neuroplasticity. CBD acute treatment into the CA₁ produces functional and molecular morphological improvements.”

https://pubmed.ncbi.nlm.nih.gov/38797491/

“Cannabidiol (CBD), in turn, is an essential tool for treating symptoms associated with pain and comorbidities with emotional and cognitive changes.”

https://www.sciencedirect.com/science/article/abs/pii/S0278584624001076?via%3Dihub

www.thctotalhealthcare.com

Category Archives: Neuropathic Pain