Effects of β-caryophyllene, A dDietary Cannabinoid, in Animal Models of Drug Addiction

Posted on October 1, 2022 by David

“Background: β-caryophyllene (BCP) is a natural bicyclic sesquiterpene found in Cannabis and other plants. BCP is currently used as a food additive, although pharmacological studies suggest its potential therapeutic application for the treatment of certain brain disorders. The mechanisms of action of BCP remain uncertain, possibly including full agonism at the cannabinoid CB 2 receptor (CB 2 R).

Objective: The study aims to investigate the BCP’s potential as a new drug for the treatment of substance use disorders, by reviewing preclinical studies with animal models.

Results: BCP has been investigated in behavioral paradigms, including drug self-administration, conditioned place preference, and intracranial self-stimulation; the drugs tested were cocaine, nicotine, alcohol, and methamphetamine. Remarkably, BCP prevented or reversed behavioral changes resulting from drug exposure. As expected, the mechanism of action entails CB 2 R activation, although this is unlikely to constitute the only molecular target to explain such effects. Another potential target is the peroxisome proliferator-activated receptor.

Conclusion: Preclinical studies report promising results with BCP in animal models of substance use disorders. Further research, including studies in humans, are warranted to establish its therapeutic potential and its mechanisms of action.”

https://pubmed.ncbi.nlm.nih.gov/36173065/

https://www.eurekaselect.com/article/126579

Medical Cannabis Patients Report Improvements in Health Functioning and Reductions in Opiate Use

Posted on September 28, 2022 by David

“Purpose: Opioid use rates have dropped as North American patients gain access to medical cannabis, indicating a harm reduction role, yet health outcomes remain mostly unexplored. This study presents self-reported medical cannabis use, perceptions of health functioning, and changes in opioid pain medication use in Florida medical cannabis patients.

Methods: Patients (n = 2,183) recruited from medical dispensaries across Florida completed a 66-item cross-sectional survey that included demographic, health, and medication usage items, along with items from the Medical Outcomes Survey (SF-36) to assess health functioning before and after cannabis initiation.

Results: Most participants were between the ages of 20 and 70 years of age (95%), over 54% were female, 47% were employed, and most (85%) were white. Commonly reported ailment groups were Pain and Mental Health combined (47.92%), Mental Health (28.86%) or Pain (9.07%). Health domains of bodily pain, physical functioning, and social functioning improved while limitations due to physical and emotional problems were unchanged. Most patients rated medical cannabis as being important to their quality of life. Many (60.98%) reported using pain medications prior to medical cannabis, 93.36% of these reported a change in pain medication after medical cannabis. The majority of participants (79%) reported either cessation or reduction in pain medication use following initiation of medical cannabis and 11.47% described improved functioning.

Conclusions: The findings suggest that some medical cannabis patients decreased opioid use without harming quality of life or health functioning, soon after the legalization of medical cannabis. The public health implications of medical cannabis as an alternative pain medication are discussed.”

https://pubmed.ncbi.nlm.nih.gov/36168127/

“In conclusion, some patients may reduce or even cease use of OBPM upon access to medical cannabis, potentially without harming quality of life or health functioning. This is suggestive of the harm reduction role and opioid-sparing effects of medical cannabis in a quality-controlled and regulated medical-use only state. Given the great individual and societal costs associated with the opioid crisis (Florence et al., 2021; National Institute on Drug Abuse, n.d.), the public health implications of these findings are important to consider.”

https://www.tandfonline.com/doi/full/10.1080/10826084.2022.2107673

Self-Reported Cannabis Use Is Associated With a Lower Rate of Persistent Opioid Use After Total Joint Arthroplasty

Posted on September 28, 2022 by David

Arthroplasty Today (@ArthroToday) / Twitter

“Background: Legalization of cannabis, along with concern over prescription opiate use, has garnered interest in cannabis for adjuvant pain control. This study examines the relationship between cannabis and opioid consumption after total hip (THA) or knee (TKA) arthroplasty.

Methods: Patients undergoing primary THA or TKA with minimum 6-month follow-up who self-reported cannabis use were retrospectively reviewed. A total of 210 patients (128 TKAs and 82 THAs) were matched by age; gender; type of arthroplasty; Charlson Comorbidity Index; and use of nicotine, antidepressants, or benzodiazepines to patients who did not self-report cannabis use. Patients receiving an opioid prescription after 90 days postoperatively were classified as persistent opioid users (POUs). Duration of opioid use (DOU) was calculated for non-POU patients as the time between surgery and their last opioid prescription. Differences in inpatient morphine milligram equivalents (MMEs), outpatient MMEs, POU, and DOU were analyzed.

Results: Cannabis users required equivalent inpatient and outpatient MMEs. There was no difference in DOU. There was a significant difference in POU between cannabis users and matched controls (1.4% [n = 3] vs 9.5% [n = 20], P < .001, respectively). Grouping patients by TKA or THA, there remained a difference in POU for TKA (1.5% [n = 2] vs 10.9% [n = 14], P = .002) and THA (1.2% [n = 1] vs 7.3% [n = 6], P = .04). There was no difference in inpatient or outpatient MMEs or DOU for THA and TKA patients.

Conclusions: There is a reduced rate of POU in patients who self-report perioperative cannabis use. Prospective studies are needed to clarify the role of cannabis as an adjunct to perioperative pain control.”

https://pubmed.ncbi.nlm.nih.gov/36158462/

“This study helps to shed light on what role if any cannabis should play as a part of an opioid-sparing multimodal pain protocol after TJA. Self-reported perioperative cannabis use appeared to significantly reduce the number of patients that persistently used opioids greater than 90 days after TJA from 9.5% to 1.4%.”

https://www.arthroplastytoday.org/article/S2352-3441(22)00164-9/fulltext

Cannabidiol prevents methamphetamine-induced neurotoxicity by modulating dopamine receptor D1-mediated calcium-dependent phosphorylation of methyl-CpG-binding protein 2

Posted on September 26, 2022 by David

“In the past decade, methamphetamine (METH) abuse has sharply increased in the United States, East Asia, and Southeast Asia. METH abuse not only leads to serious drug dependence, but also produces irreversible neurotoxicity. Currently, there are no approved pharmacotherapies for the treatment of METH use disorders. Cannabidiol (CBD), a major non-psychoactive (and non-addictive) cannabinoid from the cannabis plant, shows neuroprotective, antioxidative, and anti-inflammatory properties under METH exposure. At present, however, the mechanisms underlying these properties remain unclear, which continues to hinder research on its therapeutic potential. In the current study, computational simulations showed that CBD and METH may directly bind to the dopamine receptor D1 (DRD1) via two overlapping binding sites. Moreover, CBD may compete with METH for the PHE-313 binding site. We also found that METH robustly induced apoptosis with activation of the caspase-8/caspase-3 cascade in-vitro and in-vivo, while CBD pretreatment prevented these changes. Furthermore, METH increased the expression of DRD1, phosphorylation of Methyl-CpG-binding protein 2 (MeCP2) at serine 421 (Ser421), and level of intracellular Ca²⁺ in-vitro and in-vivo, but these effects were blocked by CBD pretreatment. The DRD1 antagonist SCH23390 significantly prevented METH-induced apoptosis, MeCP2 phosphorylation, and Ca²⁺ overload in-vitro. In contrast, the DRD1 agonist SKF81297 markedly increased apoptosis, MeCP2 phosphorylation, and Ca²⁺ overload, which were blocked by CBD pretreatment in-vitro. These results indicate that CBD prevents METH-induced neurotoxicity by modulating DRD1-mediated phosphorylation of MeCP2 and Ca²⁺ signaling. This study suggests that CBD pretreatment may resist the effects of METH on DRD1 by competitive binding.”

https://pubmed.ncbi.nlm.nih.gov/36147353/

“In conclusion, our results suggest that METH induces neurotoxicity via DRD1-mediated calcium-dependent phosphorylation of MeCP2 at Ser421. Moreover, CBD significantly prevents METH-induced neurotoxicity via modulation of DRD1.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.972828/full

Preoperative cannabis use does not increase opioid utilization following primary total hip arthroplasty in a propensity matched analysis

Posted on September 26, 2022 by David

“Purpose: The recreational and medical use of cannabis is being legalized worldwide. Its use has been linked to an increased risk of developing opioid use disorders. As opioids continue to be prescribed after total hip arthroplasty (THA), the influence that preoperative cannabis use may have on postoperative opioid consumption remains unknown. The purpose of this study was to assess the relationship between preoperative cannabis use and opioid utilization following primary THA.

Methods: We identified all patients over the age of 18 who underwent unilateral, primary THA for a diagnosis of osteoarthritis at a single institution from February 2019 to April 2021. Our cohort was grouped into current cannabis users (within 6 months of surgery) and those who reported never using cannabis. One hundred and fifty-six current users were propensity score matched 1:6 with 936 never users based on age, sex, BMI, history of chronic pain, smoking status, history of anxiety/depression, ASA classification and type of anesthesia. Outcomes included inpatient and postdischarge opioid use in morphine milligram equivalents.

Results: Total inpatient opioid utilization, opioids refilled, and total opioids used within 90 postoperative days were similar between the groups.

Conclusion: In propensity score matched analyses, preoperative cannabis use was not independently associated with an increase in inpatient or outpatient, 90-days opioid consumption following elective THA.”

https://pubmed.ncbi.nlm.nih.gov/36129515/

https://link.springer.com/article/10.1007/s00402-022-04619-7

Social stress under binge-like alcohol withdrawal in adolescence: evidence of cannabidiol effect on maladaptive plasticity in rats

Posted on September 8, 2022 by David

“Background: Alcohol binge drinking may compromise the functioning of the nucleus accumbens (NAc), i.e. the neural hub for processing reward and aversive responses.

Methods: As socially stressful events pose particular challenges at developmental stages, this research applied the resident-intruder paradigm as a model of social stress, to highlight behavioural neuroendocrine and molecular maladaptive plasticity in rats at withdrawal from binge-like alcohol exposure in adolescence. In search of a rescue agent, cannabidiol (CBD) was selected due to its favourable effects on alcohol- and stress-related harms.

Results: Binge-like alcohol exposed intruder rats displayed a compromised defensive behaviour against the resident and a blunted response of the stress system, in addition to indexes of abnormal dopamine (DA)/glutamate plasticity and dysfunctional spine dynamics in the NAc. CBD administration (60 mg/kg) was able to: (1) increase social exploration in the binge-like alcohol exposed intruder rats, at the expenses of freezing time, and in control rats, which received less aggressive attacks from the resident; (2) reduce corticosterone levels independently on alcohol previous exposure; (3) restore DA transmission and (4) facilitate excitatory postsynaptic strength and remodelling.

Conclusions: Overall, the maladaptive behavioural and synaptic plasticity promoted by the intersection between binge-like alcohol withdrawal and exposure to adverse social stress can be rescued by a CBD détente effect that results in a successful defensive strategy, supported by a functional endocrine and synaptic plasticity. The current data highlight CBD’s relevant therapeutic potential in alcohol- and stress-related harms, and prompt further investigation on its molecular targets.”

https://pubmed.ncbi.nlm.nih.gov/36065905/

https://www.cambridge.org/core/journals/psychological-medicine/article/abs/social-stress-under-bingelike-alcohol-withdrawal-in-adolescence-evidence-of-cannabidiol-effect-on-maladaptive-plasticity-in-rats/0A68E4159FDCAF5592BD10DEC4DAC9F8

Cross-talk between neurosteroid and endocannabinoid systems in cannabis addiction

Posted on September 1, 2022 by David

“Steroids and endocannabinoids are part of two modulatory systems and some evidence has shown their interconnections in several functions.

Homeostasis is a common steady-state described in the body, which is settled by regulatory systems to counterbalance deregulated or allostatic set points towards an equilibrium. This regulation is of primary significance in the central nervous system for maintaining neuronal plasticity and preventing brain-related disorders.

In this context, the recent discovery of the shutdown of the endocannabinoid system (ECS) overload by the neurosteroid pregnenolone has highlighted new endogenous mechanisms of ECS regulation related to cannabis-induced intoxication.

These mechanisms involve a regulatory loop mediated by overactivation of the central type-1 cannabinoid receptor (CB1R), which triggers the production of its own regulator, pregnenolone. Therefore, this highlights a new process of regulation of steroidogenesis in the brain.

Pregnenolone, long considered an inactive precursor of neurosteroids, can then act as an endogenous negative allosteric modulator of CB1R. The present review aims to shed light on a new framework for the role of ECS in the addictive characteristics of cannabis with the novel endogenous mechanism of ECS involving the neurosteroid pregnenolone.

In addition, this new endogenous regulatory loop could provide a relevant therapeutic model in the current context of increasing recreational and medical use of cannabis.”

https://pubmed.ncbi.nlm.nih.gov/36043319/

https://onlinelibrary.wiley.com/doi/10.1111/jne.13191

“Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice”

https://pubmed.ncbi.nlm.nih.gov/28220044/

“Pregnenolone Can Protect the Brain from Cannabis Intoxication”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057431/

Cannabidivarin alleviates neuroinflammation by targeting TLR4 co-receptor MD2 and improves morphine-mediated analgesia

Posted on August 29, 2022 by David

“Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that regulates the activation of immune cells, which is a target for treating inflammation.

In this study, Cannabidivarin (CBDV), an active component of Cannabis, was identified as an antagonist of TLR4. In vitro, intrinsic protein fluorescence titrations revealed that CBDV directly bound to TLR4 co-receptor myeloid differentiation protein 2 (MD2). Cellular thermal shift assay (CETSA) showed that CBDV binding decreased MD2 stability, which is consistent with in silico simulations that CBDV binding increased the flexibility of the internal loop of MD2.

Moreover, CBDV was found to restrain LPS-induced activation of TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced pro-inflammatory factors NO, IL-1β, IL-6 and TNF-α. Hot plate test showed that CBDV potentiated morphine-induced antinociception. Furthermore, CBDV attenuated morphine analgesic tolerance as measured by the formalin test by specifically inhibiting chronic morphine-induced glial activation and pro-inflammatory factors expression in the nucleus accumbent.

This study confirms that MD2 is a direct binding target of CBDV for the anti-neuroinflammatory effect and implies that CBDV has great translational potential in pain management.”

https://pubmed.ncbi.nlm.nih.gov/36032146/

“The results imply that CBDV could be a potential therapeutic agent for improving morphine-mediated analgesia.”

https://www.frontiersin.org/articles/10.3389/fimmu.2022.929222/full

Cannabidiol enhances the antinociceptive effects of morphine and attenuates opioid-induced tolerance in the chronic constriction injury model

Posted on August 29, 2022 by David

“Neuropathic pain (NP) is a complex health problem that includes sensorial manifestations such as evoked and ongoing pain. Cannabidiol (CBD) has shown potential in the treatment of NP and the combination between opioids and cannabinoids has provided promising results on pain relief. Thus, our study aimed to investigate the effect of treatment combination between CBD and morphine on evoked and ongoing pain, and the effect of CBD on morphine-induced tolerance in the model of chronic constriction injury (CCI) of the sciatic nerve in rats.

Mechanical thresholds (i.e., evoked pain) were evaluated before and 7 days after surgery. We also employed a 4-day conditioned place preference (CPP) protocol, to evaluate relief of ongoing pain (6 to 9 days after surgery). Treatment with morphine (2 and 4mg/kg) or CBD (30mg/kg) induced a significant antinociceptive effect on evoked pain.

The combination of CBD (30mg/kg) and morphine (1mg/kg) produced an enhanced antinociceptive effect, when compared to morphine alone (1mg/Kg). Treatment with morphine (1 and 2mg/kg) or CBD (30mg/kg) alone failed to induce significant scores in the CPP test. However, combined treatment of CBD (30mg/kg) and morphine (1mg/kg) provided significant positive scores, increased the number of entrances in the drug-paired chamber in the CPP test and did not alter locomotor activity in rats. Lastly, treatment with CBD partially attenuated morphine-induced tolerance.

In summary, our results support the indication of CBD as an adjuvant to opioid therapy for the attenuation of NP and opioid-induced analgesic tolerance.”

https://pubmed.ncbi.nlm.nih.gov/36028000/

“Taken together, the present results demonstrate that CBD or morphine exert antinociceptive effects in both mechanically evoked pain and ongoing pain after CCI in rats. The treatment combination of CBD and a sub-therapeutic dose of morphine, provided marked antinociceptive effects in both evoked and ongoing pain.”

https://www.sciencedirect.com/science/article/abs/pii/S0166432822003448?via%3Dihub

Cannabinoids-Perspectives for Individual Treatment in Selected Patients: Analysis of the Case Series

Posted on August 26, 2022 by David

“Cannabinoids can be successfully used in the treatment of many symptoms and diseases; however, most often they are not the drugs of first choice. They can be added to the primary therapy, which can improve its effectiveness, or be introduced as the basic treatment when the conventional methods have failed. Small clinical trials and case reports prove the benefits of applying medicinal cannabis in various indications; however, clinical trials in larger groups of patients are scarce and often controversial. Due to limited scientific evidence, it is essential to conduct further experimental trials. Understanding the role of endocannabinoids, as well as the composition of cannabis containing both phytocannabinoids and terpenes plays an important role in their clinical use. The clinical effects of cannabinoids depend, among other things, on the activity of the endocannabinoid system, the proportion of phytocannabinoids, such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), and the dosage used. The article discusses the role of phytocannabinoids and the potential of using them in different clinical cases in patients suffering from chronic pain, opioid dependence, depression and migraine, who did not respond to the conventional therapeutic methods. In each of the presented cases, the implementation of cannabinoids altered the course of the disease and resulted in symptom relief. Every decision to introduce cannabinoids to the treatment should be made individually with careful attention paid to details. Additionally, it is worth taking care of good clinical communication and education so that the implemented therapy is safe, effective and properly perceived by the patient.”

https://pubmed.ncbi.nlm.nih.gov/36009411/

“Evidence derived from observational studies suggest that using cannabis may help to reduce symptoms, alleviate the course of many diseases, as well as withdrawal symptoms in substance abuse disorder, such as opioid abuse and dependence. The endocannabinoid system undoubtedly plays a vital role in the modulation of functioning of many systems, but further observations and clinical trials are necessary to assess both efficacy and dosage of cannabinoids in certain disorders. Unfortunately, so far there is still not enough clinical data, which would enable us to draw credible conclusions and establish standardized doses in the selected disorders. Every patient should be approached individually with careful assessment of their condition and treated according to the “start low, go slow” principle in order to determine the lowest effective dose. In the series of presented cases cannabinoids were not used as a first-line therapy, but proved their efficacy as a complementary or alternative approach when other available treatment methods did not deliver expected and satisfactory results. Prospective approach to using cannabis in everyday clinical practice, devoid of bias and apprehension on the physicians’ part, aims to study the research and other countries’ experience, where both plant form and pure extract already have medical usage. Although today it may seem unlikely, in the near future cannabis may become widely accessible and remarkably beneficial for our patients.”

https://www.mdpi.com/2227-9059/10/8/1862/htm

www.thctotalhealthcare.com

Category Archives: Addiction