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

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“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

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“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

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“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

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“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

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“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

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“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

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“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

The Potential Antinociceptive Effect and Mechanism of Cannabis sativa L. Extract on Paclitaxel-Induced Neuropathic Pain in Rats Uncovered by Multi-Omics Analysis

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“Cannabis sativa L. (hemp) is a herbaceous plant rich in cannabinoids with a long history of use in pain treatment.

The most well-characterized cannabinoids, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC), garnered much attention in chemotherapy-induced peripheral neuropathy (CIPN) treatment. However, few studies have investigated the biological benefits and mechanism of hemp extract on CIPN.

In the present study, hemp extract (JG) rich in cannabinoids was extracted by supercritical fluid carbon dioxide extraction (SFCE). The antinociceptive efficacy was evaluated using a paclitaxel-induced peripheral neuropathy (PIPN) rat model based on behavioral tests. Further omics-based approaches were applied to explore the potential mechanisms.

The results showed that JG decreased mechanical allodynia, thermal hyperalgesia, and inflammatory cytokines in PIPN rats significantly. Transcriptome analysis identified seven key genes significantly regulated by JG in PIPN model rats, mainly related to the neuroactive ligand-receptor interaction pathway, PPAR signaling pathway, and cAMP signaling pathway. In metabolomic analysis, a total of 39 significantly altered metabolites were identified, mainly correlated with pentose and glucuronate interconversions and the glycerophospholipid metabolism pathway.

Gut microbiota analysis suggested that increased community Lachnoclostridium and Lachnospiraceae_UCG-006 in PIPN rats can be reversed significantly by JG.

In conclusion, hemp extract exhibited antinociceptive effects on PIPN. The analgesic mechanism was probably related to the regulation of inflammation, neuroactive ligand-receptor interaction pathway, sphingolipid metabolism, etc. This study provides novel insights into the functional interactions of Cannabis sativa L. extract on PIPN.”

https://pubmed.ncbi.nlm.nih.gov/38731449/

“In conclusion, the antinociceptive effects and mechanism of Cannabis sativa L. extract rich in cannabinoids in PIPN rats were evaluated by using pharmacological methods integrated with transcriptomic analysis, metabolomic analysis, and gut microbiota analysis. 

Cannabis sativa L. extract effectively alleviated neuropathic pain induced by PTX, mainly by the identified 7 key genes, 39 metabolic biomarkers, and 2 bacterial genera.

Related pathways may be involved in the inflammatory response, regulating neuroactive ligand–receptor interaction pathway, PPAR signaling pathway, inflammatory mediator regulation of TRP channels, glycerophospholipid metabolism, pentose and glucuronate interconversions, etc.

Our study provides novel insights into the functional interactions of Cannabis sativa L. extract on PIPN, which offers key information for new strategies in PIPN treatment and provides a reference for the medicinal development of hemp.”

https://www.mdpi.com/1420-3049/29/9/1958

Terpenes from Cannabis sativa induce antinociception in a mouse model of chronic neuropathic pain via activation of adenosine A2A receptors

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“Terpenes are small hydrocarbon compounds that impart aroma and taste to many plants, including Cannabis sativa.

A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action.

In our previous work, we showed that the terpenes geraniol, linalool, β-pinene, α-humulene, and β-caryophyllene produced cannabimimetic behavioral effects via multiple receptor targets. We thus expanded this work to explore the potential antinociception and mechanism of these Cannabis terpenes in a mouse model of chronic pain.

We first tested for antinociception by injecting terpenes (200 mg/kg, IP) into male and female CD-1 mice with mouse models of chemotherapy-induced peripheral neuropathy (CIPN) or lipopolysaccharide-induced inflammatory pain, finding that the terpenes produced roughly equal antinociception to 10 mg/kg morphine or 3.2 mg/kg WIN55,212. We further found that none of the terpenes produced reward as measured by conditioned place preference, while low doses of terpene (100 mg/kg) combined with morphine (3.2 mg/kg) produced enhanced antinociception vs either alone. We then used the adenosine A2A receptor (A2AR) selective antagonist istradefylline (3.2 mg/kg, IP) and spinal cord-specific CRISPR knockdown of the A2AR to identify this receptor as the mechanism for terpene antinociception in CIPN. In vitro cAMP and binding studies and in silico modeling studies further suggested that the terpenes act as A2AR agonists.

Together these studies identify Cannabis terpenes as potential therapeutics for chronic neuropathic pain and identify a receptor mechanism for this activity.”

https://pubmed.ncbi.nlm.nih.gov/38709489/

https://journals.lww.com/pain/abstract/9900/terpenes_from_cannabis_sativa_induce.589.aspx

Cannabidiol induces systemic analgesia through activation of the PI3Kγ/nNOS/NO/KATP signaling pathway in neuropathic mice. A KATP channel S-nitrosylation-dependent mechanism

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“Background: Cannabidiol (CBD) is the second most abundant pharmacologically active component present in Cannabis sp. Unlike Δ-9-tetrahydrocannabinol (THC), it has no psychotomimetic effects and has recently received significant interest from the scientific community due to its potential to treat anxiety and epilepsy. CBD has excellent anti-inflammatory potential and can be used to treat some types of inflammatory and neuropathic pain. In this context, the present study aimed to evaluate the analgesic mechanism of cannabidiol administered systemically for the treatment of neuropathic pain and determine the endogenous mechanisms involved with this analgesia.

Methods: Neuropathic pain was induced by sciatic nerve constriction surgery, and the nociceptive threshold was measured using the paw compression test in mice.

Results: CBD produced dose-dependent antinociception after intraperitoneal injection. Selective inhibition of PI3Kγ dose-dependently reversed CBD-induced antinociception. Selective inhibition of nNOS enzymes reversed the antinociception induced by CBD, while selective inhibition of iNOS and eNOS did not alter this antinociception. However, the inhibition of cGMP production by guanylyl cyclase did not alter CBD-mediated antinociception, but selective blockade of ATP-sensitive K+ channels dose-dependently reversed CBD-induced antinociception. Inhibition of S-nitrosylation dose-dependently and completely reversed CBD-mediated antinociception.

Conclusion: Cannabidiol has an antinociceptive effect when administered systemically and this effect is mediated by the activation of PI3Kγ as well as by nitric oxide and subsequent direct S-nitrosylation of KATP channels on peripheral nociceptors.”

https://pubmed.ncbi.nlm.nih.gov/38428514/

“Canabidiol (CBD) induces significant analgesia at 20 mg/kg in neuropathic mice.”

https://www.sciencedirect.com/science/article/abs/pii/S1089860324000284?via%3Dihub