Effects of cannabidiol, with and without ∆9-tetrahydrocannabinol, on anxiety-like behavior following alcohol withdrawal in mice.

Introduction: Alcohol use disorder (AUD) is commonly associated with anxiety disorders and enhanced stress-sensitivity; symptoms that can worsen during withdrawal to perpetuate continued alcohol use. Alcohol increases neuroimmune activity in the brain. Our recent evidence indicates that alcohol directly modulates neuroimmune function in the central amygdala (CeA), a key brain region regulating anxiety and alcohol intake, to alter neurotransmitter signaling. We hypothesized that cannabinoids, such as cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC), which are thought to reduce neuroinflammation and anxiety, may have potential utility to alleviate alcohol withdrawal-induced stress-sensitivity and anxiety-like behaviors via modulation of CeA neuroimmune function. Methods: We tested the effects of CBD and CBD:THC (3:1 ratio) on anxiety-like behaviors and neuroimmune function in the CeA of mice undergoing acute (4-h) and short-term (24-h) withdrawal from chronic intermittent alcohol vapor exposure (CIE). We further examined the impact of CBD and CBD:THC on alcohol withdrawal behaviors in the presence of an additional stressor. Results: We found that CBD and 3:1 CBD:THC increased anxiety-like behaviors at 4-h withdrawal. At 24-h withdrawal, CBD alone reduced anxiety-like behaviors while CBD:THC had mixed effects, showing increased center time indicating reduced anxiety-like behaviors, but increased immobility time that may indicate increased anxiety-like behaviors. These mixed effects may be due to altered metabolism of CBD and THC during alcohol withdrawal. Immunohistochemical analysis showed decreased S100ß and Iba1 cell counts in the CeA at 4-h withdrawal, but not at 24-h withdrawal, with CBD and CBD:THC reversing alcohol withdrawal effects.. Discussion: These results suggest that the use of cannabinoids during alcohol withdrawal may lead to exacerbated anxiety depending on timing of use, which may be related to neuroimmune cell function in the CeA.

Systematic review of drug-drug interactions of delta-9-tetrahydrocannabinol, cannabidiol, and Cannabis.

Background: The recent exponential increase in legalized medical and recreational cannabis, development of medical cannabis programs, and production of unregulated over-the-counter products (e.g., cannabidiol (CBD) oil, and delta-8-tetrahydrocannabinol (delta-8-THC)), has the potential to create unintended health consequences. The major cannabinoids (delta-9-tetrahydrocannabinol and cannabidiol) are metabolized by the same cytochrome P450 (CYP) enzymes that metabolize most prescription medications and xenobiotics (CYP3A4, CYP2C9, CYP2C19). As a result, we predict that there will be instances of drug-drug interactions and the potential for adverse outcomes, especially for prescription medications with a narrow therapeutic index. Methods: We conducted a systematic review of all years to 2023 to identify real world reports of documented cannabinoid interactions with prescription medications. We limited our search to a set list of medications with predicted narrow therapeutic indices that may produce unintended adverse drug reactions (ADRs). Our team screened 4,600 reports and selected 151 full-text articles to assess for inclusion and exclusion criteria. Results: Our investigation revealed 31 reports for which cannabinoids altered pharmacokinetics and/or produced adverse events. These reports involved 16 different Narrow Therapeutic Index (NTI) medications, under six drug classes, 889 individual subjects and 603 cannabis/cannabinoid users. Interactions between cannabis/cannabinoids and warfarin, valproate, tacrolimus, and sirolimus were the most widely reported and may pose the greatest risk to patients. Common ADRs included bleeding risk, altered mental status, difficulty inducing anesthesia, and gastrointestinal distress. Additionally, we identified 18 instances (58%) in which clinicians uncovered an unexpected serum level of the prescribed drug. The quality of pharmacokinetic evidence for each report was assessed using an internally developed ten-point scale. Conclusion: Drug-drug interactions with cannabinoids are likely amongst prescription medications that use common CYP450 systems. Our findings highlight the need for healthcare providers and patients/care-givers to openly communicate about cannabis/cannabinoid use to prevent unintended adverse events. To that end, we have developed a free online tool (www.CANN-DIR.psu.edu) to help identify potential cannabinoid drug-drug interactions with prescription medications.

The Potential of Cannabichromene (CBC) as a Therapeutic Agent.

There is a growing interest in the use of medicinal plants to treat a variety of diseases, and one of the most commonly used medicinal plants globally is Cannabis sativa The two most abundant cannabinoids (Δ9-tetrahydrocannabinol and cannabidiol) have been governmentally approved to treat selected medical conditions; however, the plant produces over 100 cannabinoids, including cannabichromene (CBC). While the cannabinoids share a common precursor molecule, cannabigerol, they are structurally and pharmacologically unique. These differences may engender differing therapeutic potentials. In this review, we will examine what is currently known about CBC with regards to pharmacodynamics, pharmacokinetics, and receptor profile. We will also discuss the therapeutic areas that have been examined for this cannabinoid, notably antinociceptive, antibacterial, and anti-seizure activities. Finally, we will discuss areas where new research is needed and potential novel medicinal applications for CBC. Significance Statement Cannabichromene (CBC) has been suggested to have disparate therapeutic benefits such as anti-inflammatory, anticonvulsant, antibacterial, and antinociceptive effects. Most of the focus on the medical benefits of cannabinoids has been focused on THC and CBD. The preliminary studies on CBC indicate that this phytocannabinoid may have unique therapeutic potential that warrants further investigation. Following easier access to hemp, CBC products are commercially available over-the-counter and are being widely utilized with little or no evidence of their safety or efficacy.

Library Screening and Preliminary Characterization of Synthetic Cannabinoids Against Prostate and Pancreatic Cancer Cell Lines.

Background: Our previous screening efforts with colorectal cancer cell lines suggested potential cannabinoid therapeutic leads for other solid cancers. Objectives: The aim of this study was to identify cannabinoid lead compounds that have cytostatic and cytocidal activities against prostate and pancreatic cancer cell lines and profile cellular responses and molecular pathways of select leads. Materials and Methods: A library of 369 synthetic cannabinoids was screened against 4 prostate and 2 pancreatic cancer cell lines with 48 h of exposure at 10 µM in medium with 10% fetal bovine serum using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) viability assay. Concentration titration of the top 6 hits was carried out to identify their concentration-response patterns and calculate IC50 values. Three select leads were examined for cell cycle, apoptosis, and autophagy responses. The role of cannabinoid receptors (CB1 and CB2) and noncanonical receptors in apoptosis signaling was examined with selective antagonists. Results: Two independent screening experiments in each cell line detected growth inhibitory activities against all six or a majority of cancer cell lines for HU-331 (a known cannabinoid topoisomerase II inhibitor), (±)5-epi-CP55,940, and PTI-2, each previously identified in our colorectal cancer study. 5-Fluoro NPB-22, FUB-NPB-22, and LY2183240 were novel hits. Morphologically and biochemically, (±)5-epi-CP55,940 elicited caspase-mediated apoptosis of PC-3-luc2 (a PC-3 subline with luciferase) prostate cancer and Panc-1 pancreatic cancer cell lines, each the most aggressive of the respective organ site. The apoptosis induced by (±)5-epi-CP55,940 was abolished by the CB2 antagonist, SR144528, but not modulated by the CB1 antagonist, rimonabant, and GPR55 antagonist, ML-193, nor TRPV1 antagonist, SB-705498. In contrast, 5-fluoro NPB-22 and FUB-NPB-22 did not cause substantial apoptosis in either cell line, but resulted in cytosolic vacuoles and increased LC3-II formation (suggestive of autophagy) and S and G2/M cell cycle arrests. Combining each fluoro compound with an autophagy inhibitor, hydroxychloroquine, enhanced the apoptosis. Conclusions: 5-Fluoro NPB-22, FUB-NPB-22, and LY2183240 represent new leads against prostate and pancreatic cancer cells in addition to the previously reported compounds, HU-331, (±)5-epi-CP55,940, and PTI-2. Mechanistically, the two fluoro compounds and (±)5-epi-CP55,940 differed regarding their structures, CB receptor involvement, and death/fate responses and signaling. Safety and antitumor efficacy studies in animal models are warranted to guide further R&D.

Chronic Cannabigerol as an Effective Therapeutic for Cisplatin-Induced Neuropathic Pain.

Cannabigerol (CBG), derived from the cannabis plant, acts as an acute analgesic in a model of cisplatin-induced peripheral neuropathy (CIPN) in mice. There are no curative, long-lasting treatments for CIPN available to humans. We investigated the ability of chronic CBG to alleviate mechanical hypersensitivity due to CIPN in mice by measuring responses to 7 and 14 days of daily CBG. We found that CBG treatment (i.p.) for 7 and 14 consecutive days significantly reduced mechanical hypersensitivity in male and female mice with CIPN and reduced pain sensitivity up to 60-70% of baseline levels (p < 0.001 for all), 24 h after the last injection. Additionally, we found that daily treatment with CBG did not evoke tolerance and did not incur significant weight change or adverse events. The efficacy of CBG was independent of the estrous cycle phase. Therefore, chronic CBG administration can provide at least 24 h of antinociceptive effect in mice. These findings support the study of CBG as a long-lasting neuropathic pain therapy, which acts without tolerance in both males and females.

Cannabidiol and Cannabigerol, Nonpsychotropic Cannabinoids, as Analgesics that Effectively Manage Bone Fracture Pain and Promote Healing in Mice.

Bone fractures are among the most prevalent musculoskeletal injuries, and pain management is an essential part of fracture treatment. Fractures heal through an early inflammatory phase, followed by repair and remodeling. Nonsteroidal anti-inflammatory drugs (NSAIDs) are not recommended for fracture pain control as they potently inhibit the inflammatory phase and, thus, impair the healing. Opioids do not provide a better alternative for several reasons, including abuse potential. Accordingly, there is an unmet clinical need for analgesics that effectively ameliorate postfracture pain without impeding the healing. Here, we investigated the analgesic efficacy of two nonpsychotropic cannabinoids, cannabidiol (CBD) and cannabigerol (CBG), in a mouse model for tibial fracture. Mice with fractured tibiae exhibited increased sensitivity to mechanical, cold, and hot stimuli. Both CBD and CBG normalized pain sensitivity to all tested stimuli, and their analgesic effects were comparable to those of the NSAIDs. Interestingly, CBD and CBG promoted bone healing via multiple mechanisms during the early and late phases. During the early inflammatory phase, both cannabinoids increased the abundance of periosteal bone progenitors in the healing hematoma and promoted the osteogenic commitment of these progenitors. During the later phases of healing, CBD and CBG accelerated the fibrocartilaginous callus mineralization and enhanced the viability and proliferation of bone and bone-marrow cells. These effects culminated in higher bone volume fraction, higher bone mineral density, and improved mechanical quality of the newly formed bone. Together, our data suggest CBD and CBG as therapeutic agents that can replace NSAIDs in managing postfracture pain as both cannabinoids exert potent analgesic effects and, at the same time, promote bone healing. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

The Impact of Cannabis Use on Clinical Outcomes in Inflammatory Bowel Disease: A Population-based Longitudinal Cohort Study.

BACKGROUND: Cannabis use is common in inflammatory bowel disease (IBD). Recent studies demonstrated that use of cannabis may relieve symptoms; however, it is still unclear how safe cannabis and its derivatives are for IBD patients. We performed this study to evaluate the impact of cannabis use on several key clinical outcomes in IBD. METHODS: We performed a retrospective study using the TriNetX Diamond Network. Cannabis use and noncannabis use subcohorts were identified for 3 patient groups: (1) IBD, (2) Crohn's disease (CD), and (3) ulcerative colitis (UC). Baseline differences between subcohorts for each group were controlled by propensity score matching. In each group, we compared relative incidence of emergency department (ED) visits, hospitalization, corticosteroid use, opioid use, IBD-related surgery, and death between cannabis users and noncannabis users. RESULTS: Inflammatory bowel disease cannabis users demonstrated an increased risk for corticosteroid use (risk ratios [R],1.095; 95% CI, 1.021-1.174; P = .011), ED visits (RR, 2.143; 95% CI, 2.034-2.257; P < .001), hospitalizations (RR, 1.925; 95% CI, 1.783-2.079; P < .001) and opioid use (RR, 1.35; 95% CI, 1.14-1.6); P < .001), but not an increased risk of IBD-related surgery or death. The CD and UC groups exhibited similar outcomes, except only CD demonstrated an increased risk for corticosteroid and opioid use. CONCLUSIONS: Cannabis use in IBD patients is associated with several poor clinical outcomes, including increased risk of corticosteroid and opioid use, ED visits and hospitalization, though not IBD-related surgery or death. It is not clear what drives these risks or whether they are directly related to IBD-associated disease activity or other factors. Further prospective studies are warranted to more carefully investigate these relationships.

Cannabinoids as Potential Cancer Therapeutics: The Concentration Conundrum.

Background: Studies have reported that cannabinoids, in particular Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), significantly reduce cancer cell viability in vitro. Unfortunately, treatment conditions vary significantly across reports. In particular, a majority of reports utilize conditions with reduced serum concentrations (0-3%) that may compromise the growth of the cells themselves, as well as the observed results. Objectives: This study was designed to test the hypothesis that, based on their known protein binding characteristics, cannabinoids would be less effective in the presence of fetal bovine serum (FBS). Moreover, we wished to determine if the treatments served to be cytotoxic or cytostatic under these conditions. Methods: Six cancer cell lines, representing two independent lines of three different types of cancer (glioblastoma, melanoma, and colorectal cancer [CRC]), were treated with 10 µM pure Δ9-THC, CBD, KM-233, and HU-331 for 48 h (in the presence or absence of FBS). Cell viability was measured with the MTT assay. Dose-response curves were then generated comparing the potencies of the four cannabinoids under the same conditions. Results: We found that serum-free medium alone produces cell cycle arrest for CRC cells and slows cell growth for the other cancer types. The antineoplastic effects of three of the four cannabinoids (Δ9-THC, CBD, and KM-233) increase when serum is omitted from the media. In addition, dose-response curves for these drugs demonstrated lower IC50 values for serum-free media compared with the media with 10% serum in all cell lines. The fourth compound, HU-331, was equally effective under both conditions. A further confound we observed is that omission of serum produces dramatic binding of Δ9-THC and CBD to plastic. Conclusions: Treatment of cancer cells in the absence of FBS appears to enhance the potency of cannabinoids. However, omission of FBS itself compromises cell growth and represents a less physiological condition. Given the knowledge that cannabinoids are 90-95% protein bound and have well-known affinities for plastic, it may be ill-advised to treat cells under conditions where the cells are not growing optimally and where known concentrations cannot be assumed (i.e., FBS-free conditions).

Special Issue: Therapeutic Potential for Cannabis and Cannabinoids.

The number of patients reporting the use of cannabis for medical purposes, whether through state-regulated medical marijuana programs or through over-the-counter hemp extracts, continues to grow [...].

Potential Utility of Cannabidiol in Stress-Related Disorders.

Background: The endocannabinoid (eCB) system plays an important role in homeostatic regulation of anxiety and stress responses; however, the eCB system can be disrupted following traumatic stressors. Additionally, traumatic or chronic stressors that occur during adulthood or early life can cause long-lasting disturbances in the eCB system. These alterations interfere with hypothalamic-pituitary-adrenal axis function and may be involved in lifelong increased fear and anxiety behaviors as well as increased risk for development of post-traumatic stress disorder (PTSD). Methods: This review focuses on the implications of trauma and significant stressors on eCB functionality and neural pathways, both in adolescence and into adulthood, as well as the current state of testing for CBD efficacy in treating pediatric and adult patients suffering from stress-induced eCB dysregulation. Articles were searched via Pubmed and included studies examining eCB modulation of stress-related disorders in both clinical settings and preclinical models. Conclusion: Given the potential for lifelong alterations in eCB signaling that can mediate stress responsiveness, consideration of pharmaceutical or nutraceutical agents that impact eCB targets may improve clinical outcomes in stress-related disorders. However, caution may be warranted in utilization of medicinal cannabinoid products that contain delta-9-tetrahydrocannabinol due to pronounced euphorigenic effects and potential to exacerbate stress-related behaviors. Other cannabinoid products, such as cannabidiol (CBD), have shown promise in reducing stress-related behaviors in pre-clinical models. Overall, pre-clinical evidence supports CBD as a potential treatment for stress or anxiety disorders resulting from previously stressful events, particularly by reducing fearful behavior and promoting extinction of contextual fear memories, which are hallmarks of PTSD. However, very limited clinical research has been conducted examining the potential effectiveness of CBD in this regard and should be examined further.

Therapeutic Effects of Non-Euphorigenic Cannabis Extracts in Osteoarthritis.

Introduction: Osteoarthritis (OA) is disabling and degenerative disease of the joints that is clinically characterized by pain and loss of function. With no disease-modifying treatment available, current therapies aim at pain management but are of limited efficacy. Cannabis products, specifically cannabinoids, are widely used to control pain and inflammation in many diseases with no scientific evidence demonstrating their efficacy in OA. Objective: We investigated the effects of non-euphorigenic cannabis extracts, CBD oil and cannabigerol oil (CBG oil), on pain and disease progression in OA mice. Methods and Results: Twelve-week-old male C57BL/6J mice received either sham or destabilization of the medial meniscus (DMM) surgery. DMM mice were treated with vehicle, CBD oil, or CBG oil. The gait of DMM mice was impaired as early as 2 weeks following surgery and continued deteriorating until week 8, which was restored by CBD oil and CBG oil treatments throughout the disease course. Mechanical allodynia developed in DMM mice, however, was not ameliorated by any of the treatments. On the other hand, both CBD oil and CBG oil ameliorated cold allodynia. In open field test, both oil treatments normalized changes in the locomotor activity of DMM mice. CBD oil and CBG oil treatments significantly reduced synovitis in DMM mice. Only CBG oil reduced cartilage degeneration, chondrocyte loss, and matrix metalloproteinase 13 expression, with a significant increase in the number of anabolic chondrocytes. Subchondral bone remodeling found in vehicle-treated DMM mice was not ameliorated by either CBD or CBG oil. Conclusions: Our results show evidence for the therapeutic efficacy of CBD oil and CBG oil, where both oils ameliorate pain and inflammation, and improve gait and locomotor activity in OA mice, representing clinical pain and function. Importantly, only CBG oil is chondroprotective, which may provide superior efficacy in future studies in OA patients.

Antinociceptive Effects of Cannabichromene (CBC) in Mice: Insights from von Frey, Tail-Flick, Formalin, and Acetone Tests.

Cannabis sativa contains minor cannabinoids that have potential therapeutic value in pain management. However, detailed experimental evidence for the antinociceptive effects of many of these minor cannabinoids remains lacking. Here, we employed artificial intelligence (AI) to perform compound-protein interaction estimates with cannabichromene (CBC) and receptors involved in nociceptive signaling. Based on our findings, we investigated the antinociceptive properties of CBC in naïve or neuropathic C57BL/6 male and female mice using von Frey (mechanical allodynia), tail-flick (noxious radiant heat), formalin (acute and persistent inflammatory pain), and acetone (cold thermal) tests. For von Frey assessments, CBC dose (0-20 mg/kg, i.p.) and time (0-6 h) responses were measured in male and female neuropathic mice. For tail-flick, formalin, and acetone assays, CBC (20 mg/kg, i.p.) was administered to naïve male and female mice 1 h prior to testing. The results show that CBC (10 and 20 mg/kg, i.p.) significantly reduced mechanical allodynia in neuropathic male and female mice 1-2 h after treatment. Additionally, CBC treatment caused significant reductions in nociceptive behaviors in the tail-flick assay and in both phase 1 and phase 2 of the formalin test. Finally, we found a significant interaction in neuropathic male mice in the acetone test. In conclusion, our results suggest that CBC targets receptors involved in nociceptive signaling and imparts antinociceptive properties that may benefit males and females afflicted with diverse forms of acute or chronic/persistent pain.

Efficient Synthesis for Altering Side Chain Length on Cannabinoid Molecules and Their Effects in Chemotherapy and Chemotherapeutic Induced Neuropathic Pain.

(1) Background: Recently, a number of side chain length variants for tetrahydrocannabinol and cannabidiol have been identified in cannabis; however, the precursor to these molecules would be based upon cannabigerol (CBG). Because CBG, and its side chain variants, are rapidly converted to other cannabinoids in the plant, there are typically only small amounts in plant extracts, thus prohibiting investigations related to CBG and CBG variant therapeutic effects. (2) Methods: To overcome this, we developed an efficient synthesis of corresponding resorcinol fragments using the Wittig reaction which, under acid catalyzed coupling with geraniol, produced the desired side chain variants of CBG. These compounds were then tested in an animal model of chemotherapeutic-induced neuropathic pain and to reduce colorectal cancer cell viability. (3) Results: We found that all side-chain variants were similarly capable of reducing neuropathic pain in mice at a dose of 10 mg/kg. However, the molecules with shorter side chains (i.e., CBGV and CBGB) were better at reducing colorectal cancer cell viability. (4) Conclusions: The novel synthesis method developed here will be of utility for studying other side chain derivatives of minor cannabinoids such as cannabichromene, cannabinol, and cannabielsoin.

Secondary Terpenes in Cannabis sativa L.: Synthesis and Synergy.

Cannabis is a complex biosynthetic plant, with a long history of medicinal use. While cannabinoids have received the majority of the attention for their psychoactive and pharmacological activities, cannabis produces a diverse array of phytochemicals, such as terpenes. These compounds are known to play a role in the aroma and flavor of cannabis but are potent biologically active molecules that exert effects on infectious as well as chronic diseases. Furthermore, terpenes have the potential to play important roles, such as synergistic and/or entourage compounds that modulate the activity of the cannabinoids. This review highlights the diversity and bioactivities of terpenes in cannabis, especially minor or secondary terpenes that are less concentrated in cannabis on a by-mass basis. We also explore the question of the entourage effect in cannabis, which studies to date have supported or refuted the concept of synergy in cannabis, and where synergy experimentation is headed, to better understand the interplay between phytochemicals within Cannabis sativa L.

Combinations of Cannabidiol and Δ9-Tetrahydrocannabinol in Reducing Chemotherapeutic Induced Neuropathic Pain.

Neuropathic pain is a condition that impacts a substantial portion of the population and is expected to affect a larger percentage in the future. This type of pain is poorly managed by current therapies, including opioids and NSAIDS, and novel approaches are needed. We used a cisplatin-induced model of neuropathic pain in mice to assess the effects of the cannabinoids THC and CBD alone or in varying ratios as anti-nociceptive agents. In addition to testing pure compounds, we also tested extracts containing high THC or CBD at the same ratios. We found that pure CBD had little impact on mechanical hypersensitivity, whereas THC reduced mechanical hypersensitivity in both male and female mice (as has been reported in the literature). Interestingly, we found that high CBD cannabis extract, at the same CBD dose as pure CBD, was able to reduce mechanical hypersensitivity, although not to the same level as high THC extract. These data suggest that, at least for CBD-dominant cannabis extracts, there is an increase in the anti-nociceptive activity that may be attributed to other constitutes of the plant. We also found that high THC extract or pure THC is the most efficacious treatment for reducing neuropathic pain in this model.

Cannabigerol (CBG) attenuates mechanical hypersensitivity elicited by chemotherapy-induced peripheral neuropathy.

BACKGROUND: Cannabigerol (CBG) is a non-psychoactive phytocannabinoid produced by the plant Cannabis sativa with affinity to various receptors involved in nociception. As a result, CBG is marketed as an over-the-counter treatment for many forms of pain. However, there is very little research-based evidence for the efficacy of CBG as an anti-nociceptive agent. METHODS: To begin to fill this knowledge gap, we assessed the anti-nociceptive effects of CBG in C57BL/6 mice using three different models of pain; cisplatin-induced peripheral neuropathy, the formalin test, and the tail-flick assay. RESULTS: Using the von Frey test, we found that CBG-attenuated mechanical hypersensitivity evoked by cisplatin-induced peripheral neuropathy in both male and female mice. Additionally, we observed that this CBG-induced reduction in mechanical hypersensitivity was attenuated by the α2 -adrenergic receptor antagonist atipamezole (3 mg/kg, i.p.) and the CB1 R antagonist, AM4113 (3 mg/kg, i.p.), and blocked by the CB2 R antagonist/inverse agonist, SR144528 (10 mg/kg, i.p.). We found that the TRPV1 antagonist, SB705498 (20 mg/kg, i.p.) was unable to prevent CBG actions. Furthermore, we show that CBG:CBD oil (10 mg/kg, i.p.) was more effective than pure CBG (10 mg/kg) at reducing mechanical hypersensitivity in neuropathic mice. Lastly, we show that pure CBG and CBG:CBD oil were ineffective at reducing nociception in other models of pain, including the formalin and tail flick assays. CONCLUSIONS: Our findings support the role of CBG in alleviating mechanical hypersensitivity evoked by cisplatin-induced peripheral neuropathy, but highlight that these effects may be limited to specific types of pain. SIGNIFICANCE: There are few effective treatments for neuropathic pain and neuropathic pain is projected to increase with the aging population. We demonstrate that CBG (cannabigerol) and CBG:CBD oil attenuate neuropathy-induced mechanical hypersensitivity mice. Second, we identify receptor targets that mediate CBG-induced reduction in mechanical hypersensitivity in neuropathic mice. Third, we demonstrate that an acute injection of CBG is anti-nociceptive specifically for neuropathic pain rather than other forms of pain, including persistent pain and thermal pain.

Acute Cannabigerol Administration Lowers Blood Pressure in Mice.

Cannabigerol is a cannabinoid compound synthesized by Cannabis sativa, which in its acid form acts as the substrate for both Δ9-tetraydrocannabinol and cannabidiol formation. Given its lack of psychoactive effects, emerging research has focused on cannabigerol as a potential therapeutic for health conditions including algesia, epilepsy, anxiety, and cancer. While cannabigerol can bind to classical cannabinoid receptors, it is also an agonist at α2-adrenoreceptors (α2AR) which, when activated, inhibit presynaptic norepinephrine release. This raises the possibility that cannabigerol could activate α2AR to reduce norepinephrine release to cardiovascular end organs to lower blood pressure. Despite this possibility, there are no reports examining cannabigerol cardiovascular effects. In this study, we tested the hypothesis that acute cannabigerol administration lowers blood pressure. Blood pressure was assessed via radiotelemetry at baseline and following intraperitoneal injection of cannabigerol (3.3 and 10 mg/kg) or vehicle administered in a randomized crossover design in male C57BL/6J mice. Acute cannabigerol significantly lowered mean blood pressure (-28 ± 2 mmHg with 10 mg/kg versus -12 ± 5 mmHg vehicle, respectively; p = 0.018), with no apparent dose responsiveness (-22 ± 2 mmHg with 3.3 mg/kg). The depressor effect of cannabigerol was lower in magnitude than the α2AR agonist guanfacine and was prevented by pretreatment with the α2AR antagonist atipamezole. These findings suggest that acute cannabigerol lowers blood pressure in phenotypically normal mice likely via an α2AR mechanism, which may be an important consideration for therapeutic cannabigerol administration.

Therapeutic Potential of Cannabis, Cannabidiol, and Cannabinoid-Based Pharmaceuticals.

BACKGROUND: There is a growing interest in the use of cannabis (and its extracts), as well as CBD oil (hemp extracts containing cannabidiol), for therapeutic purposes. While there is reason to believe that cannabinoids may be efficacious for a number of different diseases and syndromes, there exist limited objective data supporting the use of crude materials (CBD oil, cannabis extracts, and/or cannabis itself). SUMMARY: In the present review, we examined data for pure cannabinoid compounds (dronabinol, nabilone, and CBD), as well as partially purified medicinal cannabis extracts (nabiximols), to provide guidance on the potential therapeutic uses of high-THC cannabis and CBD oil. In general, data support a role for cannabis/cannabinoids in pain, seizure disorders, appetite stimulation, muscle spasticity, and treatment of nausea/vomiting. Given the biological activities of the cannabinoids, there may be utility in treatment of central nervous system disorders (such as neurodegenerative diseases, PTSD, and addiction) or for the treatment of cancer. However, those data are much less compelling. Key Message: On balance, there are reasons to support the potential use of medical cannabis and cannabis extract (Δ9-THC-dominant or CBD-dominant), but much more careful research is required.

Evaluating the Antinociceptive Efficacy of Cannabidiol Alone or in Combination with Morphine Using the Formalin Test in Male and Female Mice.

Introduction: Phytocannabinoids have emerged as a potential alternative treatment option for individuals experiencing persistent pain. However, evidence-based research regarding their clinical utility in both males and females remains incomplete. In addition, it is unknown whether combining readily available cannabinoids with opioids has a synergistic or subadditive effect on pain modulation. To begin to fill this knowledge gap, we investigated the antinociceptive effects of the phytocannabinoid, CBD, either alone or in combination with opioids in male and female C57BL/6J mice. Results: Using the formalin test, our results show that CBD (10 mg/kg, i.p.) treatment evoked antinociception in phase I, but not in phase II, of the formalin test in male mice. However, in female mice, CBD showed no significant antinociceptive effect. In addition, a direct sex comparison showed that CBD evoked a significant increase in nociceptive behaviors in female versus male mice during phase I of the formalin test. Furthermore, we show that CBD (10 mg/kg, i.p.) in combination with low-dose morphine (1 mg/kg, i.p.) was ineffective at eliciting a synergistic antinociceptive response in both male and female mice. Lastly, consistent with previous literature, we showed that females treated with a relatively higher dose of morphine (10 mg/kg, i.p.) displayed a significant increase in the variability of nociceptive behaviors compared to morphine-treated male mice. Conclusion: Overall, our results suggest that CBD treatment may have beneficial antinociceptive effects during the acute phase of persistent pain, but these effects are more beneficial to males than females. We provide further pre-clinical support that treatments geared toward reducing nociceptive behaviors differentially affect males and females.