“Background: Cannabis, more commonly known as marijuana or hemp, has been used for centuries to treat various conditions. Cannabis contains two main components cannabidiol (CBD) and tetrahydrocannabinol (THC). CBD, unlike THC, is devoid of psychoactive effects and is well tolerated by the human body but has no direct effect on the receptors of the endocannabid system, despite the lack of action on the receptors of the endocannabid system.
Objectives and methods: We have prepared a literature review based on the latest available literature regarding the analgesic effects of CBD. CBD has a wide range of effects on the human body. In this study, we will present the potential mechanisms responsible for the analgesic effect of CBD. To the best of our knowledge, this is the first review to explore the analgesic mechanisms of CBD.
Results and conclusion: The analgesic effect of CBD is complex and still being researched. CBD models the perception of pain by acting on G protein-coupled receptors. Another group of receptors that CBD acts on are serotonergic receptors. The effect of CBD on an enzyme of potential importance in the production of inflammatory factors such as cyclooxygenases and lipoxygenases has also been confirmed. The presented potential mechanisms of CBD’s analgesic effect are currently being extensively studied.”
“Background: Accumulating evidence has indicated that cannabis substitution is often used as a harm reduction strategy among people who use unregulated opioids (PWUO) and people living with chronic pain. We sought to investigate the association between cannabis use to manage opioid cravings and self-reported changes in opioid use among structurally marginalized PWUO.
Methods: The data were collected from a cross-sectional questionnaire administered to PWUO in Vancouver, Canada. Binary logistic regression was used to analyze the association between cannabis use to manage opioid cravings and self-reported changes in unregulated opioid use.
Results: A total of 205 people who use cannabis and opioids were enrolled in the present study from December 2019 to November 2021. Cannabis use to manage opioid cravings was reported by 118 (57.6%) participants. In the multivariable analysis, cannabis use to manage opioid cravings (adjusted Odds Ratio [aOR] = 2.13, 95% confidence interval [CI]: 1.07, 4.27) was significantly associated with self-reported reductions in opioid use. In the sub-analyses of pain, cannabis use to manage opioid cravings was only associated with self-assessed reductions in opioid use among people living with moderate to severe pain (aOR = 4.44, 95% CI: 1.52, 12.97). In the sub-analyses of males and females, cannabis use to manage opioid cravings was only associated with self-assessed reductions in opioid use among females (aOR = 8.19, 95% CI: 1.20, 55.81).
Conclusions: These findings indicate that cannabis use to manage opioid cravings is a prevalent motivation for cannabis use among PWUO and is associated with self-assessed reductions in opioid use during periods of cannabis use. Increasing the accessibility of cannabis products for therapeutic use may be a useful supplementary strategy to mitigate exposure to unregulated opioids and associated harm during the ongoing drug toxicity crisis.”
“Background: Chronic pain (CP) is experienced by as many as 50 million Americans and can negatively impact physical and mental health. Prescribing opioids is the most common approach to address moderate to severe CP though these potent analgesics are associated with a significant number of side effects. One alternative some Americans are turning to for CP management is cannabis. In addition to serving as an alternative, many individuals with CP use cannabis in addition to using prescription opioids. This study examined individuals with CP who enrolled in the state of Illinois’ opioid diversion program, the Opioid Alternative Pilot Program (OAPP), which offers individuals aged 21 and older a separate pathway to access medical cannabis if they have or could receive a prescription for opioids as certified by a licensed physician.
Methods: Cross-sectional survey data were collected from 450 participants. We described participants and compared those who use only cannabis with those who use cannabis and opioids.
Results: While 16% of the respondents were cannabis-only users, 84% of the respondents were co-users of opioids and cannabis. Both groups considered opioid use risky (100% cannabis-only, 89% co-users,). The majority (73%) of respondents sought to completely stop or never start using opioids for CP. Cannabis-only users reported lower levels of pain compared to co-users. Co-users (85%) were more likely to have their routine provider as a cannabis certifying physician than cannabis-only users (69%).
Conclusion: With increasing clinical evidence, legalization and acceptance, researchers should continue to examine how cannabis may be a viable alternative to reduce the risk of prescription opioid side effects, misuse, or dependence. Our findings also inform health care providers and state policymakers who increasingly are being asked to consider how cannabis may reduce the potential for harmful outcomes among persons with CP who use prescription opioids.”
“Objectives: Patient-reported outcomes are critical to evaluate the effectiveness of medical cannabis as an alternative treatment for chronic pain. This study examined the perceived effectiveness of medical cannabis for chronic pain management among middle-aged and older adults newly initiating medical cannabis.
Methods: Interview data from participants in a three-month pilot study were analyzed to assess the perceived effectiveness of medical cannabis on chronic pain and related outcomes. The interview was conducted after approximately one month of usage and responses were analyzed using the RADaR (Rigorous and Accelerated Data Reduction) technique.
Results: 51 adults initiating medical cannabis for chronic pain were interviewed (24 women, 27 men, mean age 54.4, SD = 12.0), with the majority (n=41) identifying as Non-Hispanic White followed by Non-Hispanic Black (n=7), Multi-racial (2), Hispanic White (1). Most study participants (62.7%) reported MC being overall effective. Common benefits included reduced pain intensity, anxiety, and dependency on pain and psychiatric medications. Improvements in physical functioning, sleep quality, and mood were reported. Common challenges included difficulty finding a suitable product or dose, experiencing side effects such as ‘undesired high’, ‘stomach issues’, and a limited ‘threshold of pain’ treatable by the product.
Discussion: Findings suggest most participants perceived medical cannabis to be overall effective for chronic pain management. Participants reported improved physical and mental functioning and reduced use of pain and psychiatric medications. Future research systematically assessing side effects, dosage and mode of consumption is needed to further evaluate the outcomes among adults initiating medical cannabis.”
“Microglia is a heterogeneous population that mediates neuroinflammation in the central nervous system (CNS) and plays a crucial role in developing neuropathic pain. FKBP5 facilitates the assembly of the IκB kinase (IKK) complex for the activation of NF-κB, which arises as a novel target for treating neuropathic pain. In this study, cannabidiol (CBD), a main active component of Cannabis, was identified as an antagonist of FKBP5. In vitro protein intrinsic fluorescence titration showed that CBD directly bound to FKBP5. Cellular thermal shift assay (CETSA) indicated that CBD binding increased the FKBP5 stability, which implies that FKBP5 is the endogenous target of CBD. CBD was found to inhibit the assembly of the IKK complex and the activation of NF-κB, therefore blocking LPS-induced NF-κB downstream pro-inflammatory factors NO, IL-1β, IL-6 and TNF-α. Stern-Volmer analysis and protein thermal shift assay revealed that tyrosine 113 (Y113) of FKBP5 was critical for FKBP5 interacting with CBD, which is consistent with in silico molecular docking simulation. FKBP5 Y113 mutation (Y113A) alleviated the effect of CBD inhibiting LPS-induced pro-inflammatory factors overproduction. Furthermore, systemic administration of CBD inhibited chronic constriction injury (CCI)-induced microglia activation and FKBP5 overexpression in lumbar spinal cord dorsal horn. These data imply that FKBP5 is an endogenous target of CBD.”
“Cannabidiol (CBD) is the main active component of cannabis with good BBB permeability (Calapai et al., 2020) and has been gaining great attention for its safety, non-psychoactive effect and several beneficial pharmacological activities (Devinsky et al., 2016, Lucas et al., 2018, Pisanti et al., 2017). CBD has a good anti-neuroinflammatory effect (Atalay et al., 2019) and is used to treat neurological diseases caused by neuroinflammation, such as major depression (Florensa-Zanuy et al., 2021) and Parkinson’s disease (Giuliano et al., 2021) in animal models as well as autism spectrum disorder (Carbone et al., 2021) and multiple sclerosis (Nielsen et al., 2018) in clinical trials. As CBD has a low affinity for cannabinoid receptors (Rosenthaler et al., 2014), it would be worthy to explore the molecular target, which mediates the anti-inflammatory activity of CBD. Herein, FKBP5 was found as an endogenous target of CBD. CBD inhibited the assembly of the IKK complex and the activation of NF-κB, therefore suppressing LPS-induced pro-inflammatory factors. The FKBP5 tyrosine 113 (Y113) mutation abolished FKBP5 interacting with CBD, therefore ameliorating the effect of CBD inhibiting LPS-induced pro-inflammatory factors. Moreover, oral CBD attenuated peripheral nerve injury-induced overexpression of FKBP5 in activated microglia of lumbar spinal cord dorsal horn in vivo. These data implicate that FKBP5 is a direct binding target of CBD.”
“Bacterial infections are often accompanied by fever and generalized muscle pain. However, the treatment of pain with an infectious etiology has been overlooked. Thus, we investigated the impact of cannabidiol (CBD) in bacterial lipopolysaccharide (LPS)-induced nociception.
Male Swiss mice received intrathecal (i.t.) LPS injection, and the nociceptive threshold was measured by the von Frey filaments test. Spinal involvement of the cannabinoid CB2 receptor, toll-like receptor 4 (TLR4), microglia and astrocytes were evaluated by i.t. administration of their respectively antagonists or inhibitors. Western blot, immunofluorescence, ELISA and liquid chromatography-mass spectrometry were used to assess Cannabinoid CB2 receptors and TLR4 spinal expression, proinflammatory cytokines and endocannabinoid levels. CBD was administered intraperitoneally at 10 mg/kg.
The pharmacological assay demonstrated TLR4 participation in LPS-induced nociception. In addition, spinal TLR4 expression and proinflammatory cytokine levels were increased in this process.
CBD treatment prevented LPS-induced nociception and TLR4 expression.
AM630 reversed antinociception and reduced CBD-induced endocannabinoids upregulation. Increased spinal expression of the cannabinoid CB2 receptor was also found in animals receiving LPS, which was accompanied by reduced TLR4 expression in CBD-treated mice.
Taken together, our findings indicated that CBD is a potential treatment strategy to control LPS-induced pain by attenuating TLR4 activation via the endocannabinoid system.”
“The most frequently reported use of medical marijuana is for pain relief. However, its psychoactive component Δ9-tetrahydrocannabinol (THC) causes significant side effects. Cannabidiol (CBD) and β-caryophyllene (BCP), two other cannabis constituents, possess more benign side effect profiles and are also reported to reduce neuropathic and inflammatory pain. We evaluated the analgesic potential of CBD and BCP individually and in combination in a rat spinal cord injury (SCI) clip compression chronic pain model. Individually, both phytocannabinoids produced dose-dependent reduction in tactile and cold hypersensitivity in male and female rats with SCI. When co-administered at fixed ratios based on individual A50s, CBD and BCP produced enhanced dose-dependent reduction in allodynic responses with synergistic effects observed for cold hypersensitivity in both sexes and additive effects for tactile hypersensitivity in males. Antinociceptive effects of both individual and combined treatment were generally less robust in females than males. CBD:BCP co-administration also partially reduced morphine-seeking behavior in a conditioned place preference (CPP) test. Minimal cannabinoidergic side effects were observed with high doses of the combination. The antinociceptive effects of the CBD:BCP co-administration were not altered by either CB2 or μ-opioid receptor antagonist pretreatment but, were nearly completely blocked by CB1 antagonist AM251. Since neither CBD or BCP are thought to mediate antinociception via CB1 activity, these findings suggest a novel CB1 interactive mechanism between these two phytocannabinoids in the SCI pain state. Together, these findings suggest that CBD:BCP co-administration may provide a safe and effective treatment option for the management of chronic SCI pain.”
“In conclusion, the current findings indicate that the combination of readily accessible non-psychoactive cannabis components CBD oil and BCP may be particularly effective in reducing neuropathic pain resulting from spinal cord injury. In addition, cannabinoid-like side effects were minimal using this combination. Further, the observed decrease in opioid-seeking behavior suggest that this treatment may be useful as a supplemental therapeutic to reduce opioid needed for effective pain management. Together, these findings are supportive of the beneficial effects of combining cannabis components in the armamentarium for chronic pain management.”
“Cannabis has been used for centuries to treat pain.
The antinociceptive activity of tetrahydrocannabinol (THC) or cannabidiol (CBD) has been widely studied. However, the antinociceptive effects of other cannabis components, such as cannabichromene (CBC) and cannabigerol (CBG), have rarely been revealed. The antinociceptive mechanism of CBG is not yet clear, so we investigated the antinociceptive effect of CBG on different pain models, and explored the mechanism of action of CBG to exert antinociceptive effects.
In the current study, we compared the antinociceptive effects of CBC, CBD, and CBG on the carrageenan-induced inflammatory pain model in mice, and the results showed that CBG had a better antinociceptive effects through intraplantar administration. On this basis, we further investigated the antinociceptive effect of CBG on CIA-induced arthritis pain model and nerve pain model in mice, and found that CBG also relieved on both types of pain. Then, we explored the antinociceptive mechanism of CBG, which revealed that CBG can activate TRPV1 and desensitize it to block the transmission of pain signals. In addition, CBG can further activate CB2R, but not CB1R, to stimulate the release of β-endorphin, which greatly promotes the antinociceptive effect.
Finally, the safety test results showed that CBG had no irritating effect on the rabbits’ skin, and it did not induce significant biochemical and hematological changes in mice. Transdermal delivery results also indicated that CBG has certain transdermal properties. Overall, this study indicates that CBG is promising for developing a transdermal dosage for pain management.”
“Purpose of review: Cannabis has been used since ancient times for medical and recreational research. This review article will document the validity of how medical cannabis can be utilized for chronic nonmalignant pain management.
Recent findings: Current cannabis research has shown that medical cannabis is indicated for symptom management for many conditions not limited to cancer, chronic pain, headaches, migraines, and psychological disorders (anxiety and post-traumatic stress disorder). Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are active ingredients in cannabis that modulate a patient’s symptoms. These compounds work to decrease nociception and symptom frequency via the endocannabinoid system. Research regarding pain management is limited within the USA as the Drug Enforcement Agency (DEA) classifies it as a schedule one drug. Few studies have found a limited relationship between chronic pain and medical cannabis use. A total of 77 articles were selected after a thorough screening process using PubMed and Google Scholar. This paper demonstrates that medical cannabis use provides adequate pain management. Patients suffering from chronic nonmalignant pain may benefit from medical cannabis due to its convenience and efficacy.”
“Patients often seek medical consultations most commonly because of having intolerable chronic pain. Medications such as NSAIDs or opioids are being used to relieve such pain. However, long-term use of these medications can also cause adverse effects on health. Several studies have been done regarding cannabis as an alternative for chronic pain. Some patients were reported to get relief from cannabis consumption through various routes, and the use of it has been legalized, too, in some states in the USA and countries like Germany. Italy, the Netherlands, UK, Australia, Uruguay, Brazil, Colombia, Chile, Thailand, and Jamaica. Compared with opioids, studies show that cannabis use has lesser adverse effects, and it could even lessen opioid dependence.”
“Importance: Patients with chronic pain often receive long-term opioid therapy (LOT), which places them at risk of opioid use disorder and overdose. This presents the need for alternative or companion treatments; however, few studies on the association of medical cannabis (MC) with reducing opioid dosages exist.
Objective: To assess changes in opioid dosages among patients receiving MC for longer duration compared with shorter duration.
Design, setting, and participants: This cohort study of New York State Prescription Monitoring Program data from 2017 to 2019 included patients receiving MC for chronic pain while also receiving opioid treatment. Of these, patients receiving LOT prior to receiving MC were selected. Individuals were studied for 8 months after starting MC. Data were analyzed from November 2021 to February 2022.
Exposures: Selected patients were divided into 2 groups based on the duration of receiving MC: the nonexposure group received MC for 30 days or fewer, and the exposure group received MC for more than 30 days.
Main outcomes and measures: The main outcome was opioid dosage, measured by mean daily morphine milligram equivalent (MME). Analyses were conducted for 3 strata by opioid dosage prior to receiving MC: MME less than 50, MME of 50 to less than 90, and MME of 90 or greater.
Results: A total of 8165 patients were included, with 4041 (median [IQR] age, 57 [47-65] years; 2376 [58.8%] female) in the exposure group and 4124 (median [IQR] age, 54 (44-62) years; 2370 [57.5%] female) in the nonexposure group. Median (IQR) baseline MMEs for the exposure vs nonexposure groups were 30.0 (20.0-40.0) vs 30.0 (20.0-40.0) in the lowest stratum, 60.0 (60.0-70.0) vs 60.0 (60.0-90.0) in the middle stratum, and 150.0 (100.0-216.2) vs 135.0 (100.0-218.0) in the highest stratum. During follow-up, significantly greater reductions in opioid dosage were observed among the exposure group. A dose-response association of patients’ opioid dosage at baseline was observed with the differences in the monthly MME reductions between exposure and nonexposure groups, with a difference of -1.52 (95% CI, -1.67 to -1.37) MME for the lowest stratum, -3.24 (95% CI, -3.61 to -2.87) MME for the middle stratum, and -9.33 (95% CI, -9.89 to -8.77) MME for the highest stratum. The daily MME for the last month of the follow-up period among patients receiving longer MC was reduced by 48% in the lowest stratum, 47% in the middle stratum, and 51% in the highest stratum compared with the baseline dosages. Among individuals in the nonexposure group, daily MME was reduced by only 4% in the lowest stratum, 9% in the middle stratum, and 14% in the highest stratum.
Conclusions and relevance: In this cohort study of patients receiving LOT, receiving MC for a longer duration was associated with reductions in opioid dosages, which may lower their risk of opioid-related morbidity and mortality.”
“This cohort study found that receiving MC for longer was associated with opioid dosage reductions. The reductions were larger among individuals who were prescribed higher dosages of opioids at baseline. These findings contribute robust evidence for clinicians regarding the potential benefits of MC in reducing the opioid burden for patients receiving LOT and possibly reduce their risk for overdose.”
