The Pharmacology of Cannabinoids in Chronic Pain

Posted on March 6, 2025 by David

“Background: Our objective was to provide an overview of the currently available scientific and clinical data supporting the use of Cannabis and Cannabis-derived products for the treatment of chronic pain disorders. We also provide information for researchers, clinicians, and patients to be better informed and understand the approach behind the recommendation of Cannabis as a potential adjuvant in the treatment/control of chronic pain. Cannabis and its bioactive compounds have sparked interest in the field of pain treatment in spite of its controversial history and status as a controlled substance in many countries. With the increase in chronic pain, physicians and patients have started to look at alternative ways to treat pain aside from traditional treatments. One alternative is the use of cannabis to reduce/treat chronic pain disorders based on anecdotal accounts and the function of its phytocannabinoids. The two main cannabinoids in cannabis, tetrahydrocannabinol (THC) and cannabidiol, act on CB1 and CB2 receptors (in addition to several additional receptors). It is through these pleiotropic receptor interactions that these compounds elicit their biological function including the reduction of chronic pain. In this narrative review, we included the most recent evidence supporting the use of cannabis in the treatment of chronic pain disorders including chronic neuropathic pain, cancer-induced neuropathic pain, chronic musculoskeletal pain, and chronic headaches and migraines.

Summary: Evidence suggests that cannabis and cannabinoids have an analgesic effect that arises from a combination of compounds and various receptor systems. These effects may be maximized with the use of a combination of cannabinoids. At the same time, the combination of cannabinoids helps minimize the undesirable side effects of some cannabinoids such as the psychoactivity of THC. With these findings, further research is necessary to assess the analgesic properties of other cannabinoids like cannabichromene and cannabigerol and their contributions to the reduction of pain.”

https://pubmed.ncbi.nlm.nih.gov/40046175/

“Cannabis sativa L. has been used as a medicinal remedy for thousands of years. It has gone through multiple periods of acceptance, dismissal/rejection, reacceptance, illegality and, most recently, rediscovery of its potential to address chronic medical conditions. In the last few decades, its recreational use has received growing acceptance, while its medical use has been encouraged in multiple jurisdictions. Most modern research has focused on the phytocannabinoids produced by the plant which have been found to help minimize chronic neuropathic pain and mitigate other disorders including seizure conditions (e.g., Lennox-Gastaut and Dravet syndromes) and spasticity in MS. This review has provided scientific evidence supporting the use of cannabis as an adjuvant in the treatment of chronic pain which could also lead pain reduction to the point of minimizing other pharmacological treatments.”

https://karger.com/mca/article/8/1/31/920366/The-Pharmacology-of-Cannabinoids-in-Chronic-Pain

“Designer cannabinoids could be the key to pain relief without adverse effects”

https://www.nature.com/articles/d41586-025-00546-w

A systematic study of molecular targets of cannabidiol in Alzheimer’s disease

Posted on March 6, 2025 by David

“Background: Alzheimer’s disease (AD) is a prevalent, incurable, and chronic neurodegenerative condition characterized by the accumulation of amyloid-β protein (Aβ), disrupting various bodily systems. Despite the lack of a cure, phenolic compounds like cannabidiol (CBD), a non-psychoactive component of cannabis, have emerged as potential therapeutic agents for AD.

Objective: This systematic review explores the impact of different types of cannabidiol on AD, unveiling their neuroprotective mechanisms.

Methods: The research used PubMed, Scopus, and Web of Science databases with keywords like “Alzheimer’s disease” and “Cannabidiol.” Studies were evaluated based on title, abstract, and relevance to treating AD with CBD. No restrictions on research type or publication year. Excluded were hypothesis papers, reviews, books, unavailable articles, etc.

Results: Microsoft Excel identified 551 articles, with 92 included in the study, but only 22 were thoroughly evaluated. In-vivo and in-silico studies indicate that CBD may disrupt Aβ₄₂, reduce pro-inflammatory molecule release, prevent reactive oxygen species formation, inhibit lipid oxidation, and counteract Aβ-induced increases in intracellular calcium, thereby protecting neurons from apoptosis.

Conclusions: In summary, the study indicates that CBD and its analogs reduce the production of Aβ₄₂. Overall, these findings support the potential of CBD in alleviating the underlying pathology and symptoms associated with AD, underscoring the crucial need for further rigorous scientific investigation to elucidate the therapeutic applications and mechanisms of CBD in AD.”

https://pubmed.ncbi.nlm.nih.gov/40034365/

“In conclusion, the finding of this study indicates that cannabidiol/derivatives inhibit AD progression through various mechanisms and key hypotheses regarding AD pathology. Nave CBD can reduce Aβ, IL-6 expression in peripheral leukocytes, and retarded cognitive decline. Compare with other CBD derivatives, CBD carbamate derivatives notably reduced Aβ1–42 levels, restored cognitive function to a normal state, and exhibited superior behavioral performance when compared to donepezil. CBD decreases Caspase 9, Caspase 3, and cleaved PARP1 protein levels and shows Antiapoptotic effects during cognitive decline. It also shows anti-cholinergic activity by inhibiting AChE and BuChE. As a result, the expression of ChAT can be normalized. In terms of the neuroinflammatory process, the expression of proinflammatory miRNAs (miR-146a, miR-155, and miR-34a) associated with TLR and NF-κB signaling is reduce. Therefore, continued research efforts should focus on elucidating the precise mechanisms of action, exploring potential synergies with other AD medications, and optimizing CBD formulations and derivatization to maximize therapeutic benefits in AD patients. These observations underscore the significance of further research and exploration into the therapeutic applications of CBD in the context of AD.”

https://journals.sagepub.com/doi/10.1177/25424823241284464

Chronic exposure to a synthetic cannabinoid improves cognition and increases locomotor activity in Tg4-42 Alzheimer’s disease mice

Posted on March 6, 2025 by David

“Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline and behavior impairments. Despite recent approvals of anti-amyloid antibodies, there remains a need for disease modifying and easily accessible therapies. Emerging evidence suggests that targeting the endocannabinoid system may hold promise for AD therapy as it plays a crucial role in different physiological processes, including learning, memory and anxiety, as well as inflammatory and immune responses.

Objective: In this study, we investigated the therapeutic potential of the synthetic cannabinoid WIN 55,212-2 on memory deficits in Tg4-42 transgenic mice.

Methods: Tg4-42 mice were assigned to two treatment groups to investigate the preventive effects of WIN 55,212-2 after a prolonged washout period, as well as the therapeutic effects of WIN 55,212-2 on behavior. Furthermore, the effects of WIN 55,212-2 treatment on AD pathology, including inflammation, amyloid-β load, neurogenesis, and brain glucose metabolism, were evaluated.

Results: Therapeutic WIN 55,212-2 treatment rescued recognition memory and spatial reference deficits in Tg4-42 mice. Furthermore, therapeutic WIN 55,212-2 administration improved motor performance. In addition, preventative WIN 55,212-2 treatment rescued spatial learning and reference memory deficits. Importantly, WIN 55,212-2 treatment did not affect anxiety-like behavior. However, therapeutic and preventative WIN 55,212-2 treatment resulted in an increase locomotor activity and swimming speed in Tg4-42 mice. WIN-treatment reduced microgliosis in the hippocampus of preventively treated mice and rescued brain glucose metabolism in therapeutically treated Tg4-42 mice.

Conclusions: Our findings emphasize the therapeutic promise of the synthetic cannabinoid WIN 55,212-2 in alleviating behavioral and cognitive deficits linked to AD.”

https://pubmed.ncbi.nlm.nih.gov/40034517/

https://journals.sagepub.com/doi/10.1177/25424823241306770

“WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC)”

Value of cannabidiol as adjunctive treatment for Lennox Gastaut syndrome: cost-effectiveness and budget impact analysis

Posted on March 6, 2025 by David

“Background: Lennox-Gastaut syndrome (LGS) is a severe encephalopathic disease that leads to a decrease in the quality of life, physical injury, psychosocial impairment, and a significant increase in treatment costs. Cannabidiol (CBD) is approved for the adjunctive treatment of tonic-colonic seizures in LGS. This study aimed to determine the cost-effectiveness of CBD compared to the usual treatment in patients with LGS syndrome.

Methods: We developed a lifetime-horizon Markov model to compare the cost-effectiveness of adjunctive CBD versus usual care. Additionally, we performed a budget impact analysis over a 5-year time horizon. The findings were presented as the incremental cost-effectiveness ratio (ICER) for CEA, with a willingness to pay threshold of $18,261 per QALY gained, and as the difference in the overall budget ($) between the scenarios with and without CBD for budget impact assessment.

Results: In the base case scenario, CBD was cost-effective compared with usual care $6573 per QALY. Sensitivity analyses substantiated these results. From a healthcare perspective, there is a 77% probability that CBD is cost-effective at a willingness to pay of $18,261 per quality-adjusted life-year (QALY). Overall, the market access of CBD was associated to an increased budget of about $3,459,846 (+ 33%) in the next 5 years simulated.

Conclusions: Compared to usual care, CBD seems to be cost-effective in LGS patients and sustainable, with less than 34% overall budget increased in the next 5 years. Future studies need to confirm our results in the real word setting and in other countries.”

https://pubmed.ncbi.nlm.nih.gov/40038638/

“Our study demonstrates that CBD is valuable as an add-on therapy for patients with LGS in Iran. At current list prices in Iran and assuming a WTP threshold of $18,261/QALY, CBD is cost-effective for the treatment of LGS. So CBD has a more advantage of efficacy compared with usual care and its incremental BI for health system is relatively acceptable. The present study also provides a reference for stakeholders to judge the value of cannabidiol.”

https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-025-03972-9

A within-subject, double-blind, placebo-controlled randomized evaluation of the combined effects of cannabidiol and hydromorphone in a human laboratory pain model

Posted on March 6, 2025 by David

“Preclinical and epidemiological evidence supports that cannabinoids may have opioid-sparing properties and could be one strategy to decrease opioid use and associated harms like overdose and extramedical use.

The objective of this within subjects, double-blind, double-dummy, randomized human laboratory trial was to examine whether cannabidiol (CBD) increases opioid analgesic effects and whether there are corresponding increases in other opioid mediated effects.

Healthy participants (N = 31) attended 5 outpatient sessions where they received the following drug conditions: (1) placebo + placebo, (2) 4 mg hydromorphone + placebo, (3) 4 mg hydromorphone + 50 mg CBD, (4) 4 mg hydromorphone + 100 mg CBD, and (5) 4 mg hydromorphone + 200 mg CBD. Before and at multiple time points after drug administration, participants completed (1) quantitative sensory testing, which induced and assessed acute and chronic laboratory models of pain; (2) standard assessments, which queried acute subjective drug effects; and (3) tasks, which assessed psychomotor performance.

When combined with a dose of hydromorphone that did not reliably produce analgesic effects on its own, CBD increased the analgesic effects for some laboratory acute pain outcomes but none of the laboratory chronic pain outcomes. At the highest dose of CBD (200 mg), there were concurrent increases in self-report Bad Effects and adverse effects that were not observed at lower doses of CBD (50 mg). Cannabidiol mitigated psychomotor impairment observed with hydromorphone alone.

These findings suggest that lower doses of CBD (50 mg) may have utility for enhancing acute analgesic properties of opioids without having corresponding increases in bad effects.”

https://pubmed.ncbi.nlm.nih.gov/40035623/

https://journals.lww.com/pain/abstract/9900/a_within_subject,_double_blind,_placebo_controlled.840.aspx