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

Frontiers - Crunchbase Company Profile & Funding

“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.”

“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.”

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


“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.”

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

Psychological Medicine

“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.”

Cross-talk between neurosteroid and endocannabinoid systems in cannabis addiction

“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.”

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

“Pregnenolone Can Protect the Brain from Cannabis Intoxication”

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

Frontiers - Crunchbase Company Profile & Funding

“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.”

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

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

Behavioural Brain Research

“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.”

“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.”

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


“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.”

“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.”

The effects of acute alcohol administration on circulating endocannabinoid levels in humans

“Several lines of evidence suggest that endocannabinoid signalling may influence alcohol consumption. Preclinical studies have found that pharmacological blockade of cannabinoid receptor 1 leads to reductions in alcohol intake. Furthermore, variations in endocannabinoid metabolism between individuals may be associated with the presence and severity of alcohol use disorder. However, little is known about the acute effects of alcohol on the endocannabinoid system in humans. In this study, we evaluated the effect of acute alcohol administration on circulating endocannabinoid levels by analysing data from two highly-controlled alcohol administration experiments. In the first within-subjects experiment, 47 healthy participants were randomized to receive alcohol and placebo in a counterbalanced order. Alcohol was administered using an intravenous clamping procedure such that each participant attained a nearly identical breath alcohol concentration of 0.05%, maintained over 3 h. In the second experiment, 23 healthy participants self-administered alcohol intravenously; participants had control over their exposure throughout the paradigm. In both experiments, circulating concentrations of two endocannabinoids, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), were measured at baseline and following alcohol exposure. During the intravenous clamping procedure, acute alcohol administration reduced circulating AEA but not 2-AG levels when compared to placebo. This finding was confirmed in the self-administration paradigm, where alcohol reduced AEA levels in an exposure-dependent manner. Future studies should seek to determine whether alcohol administration has similar effects on brain endocannabinoid signalling. An improved understanding of the bidirectional relationship between endocannabinoid signalling and alcohol intake may deepen our understanding of the aetiology and repercussions of alcohol use disorder.”

Medical Cannabis Certification Is Associated With Decreased Opiate Use in Patients With Chronic Pain: A Retrospective Cohort Study in Delaware

Cureus Competition Winners Announced - Synaptive Medical

“Opioid medications are commonly used to treat chronic pain around the world. While these medications are quite effective at reducing pain, they can create opioid dependence and lead to further drug addiction. Long-term opioid use has significantly contributed to the “opioid epidemic” that is currently ravaging the United States, leading to opioid overdoses and unintentional deaths, particularly in Delaware.

Objective To determine if medical marijuana certification helps patients in Delaware with chronic pain reduce their opiate use.

Methods In this study, we examined individuals who were provided with legal; medical cannabis certifications in the state of Delaware between June 2018 and October 2019 and were concurrently being treated with opioid medications for chronic pain at a private pain management practice. Using a posthoc analysis, we conducted a retrospective cohort study on the individuals (n = 81) to determine if there was a decrease in their opioid use following medical cannabis certification. Opioid use was measured in morphine milligram equivalent (MME) through the Delaware prescription monitoring program (PMP) database.

Results Overall, the average change in prescribed opioid use was found to be -12.3 morphine milligram equivalent (MME) units when including all individuals (p < 0.00001). Among the included individuals with baseline opioid use, medical cannabis certification was associated with a 31.3% average decrease in opioid use (n = 63). When examining subgroups based upon pain location, individuals with neck pain displayed a 41.5% average decrease in MME (n = 27), while individuals with low back pain were observed to have a 29.4% decrease in opioid use (n = 58). Similarly, individuals with knee pain (n = 14) reduced their opioid use by 32.6%.

Conclusion The results display an association between medical cannabis certification and a decrease in opiate use among the study group individuals. This study suggests that medical cannabis use may help individuals to reduce their opiate requirements along with physician intervention. More research is needed to validate these findings with appropriate controls and verification of cannabis use.”

“The results of this study indicate that medical marijuana certification is associated with a decrease in prescription opiate use for chronic pain treatment and supports greater use of this adjunct treatment modality. Given the significance of opioid addiction in American society, any treatment or additional resource to reduce opioid overuse can aid in the multifactorial management of chronic pain. Although marijuana use causes a variety of side effects, the findings here suggest that the use of medical cannabis as an adjunct treatment for chronic pain may be beneficial to public health.”

Association between county level cannabis dispensary counts and opioid related mortality rates in the United States: panel data study

The BMJ (@bmj_latest) / Twitter

“Objective: To examine county level associations between the prevalence of medical and recreational cannabis stores (referred to as dispensaries) and opioid related mortality rates.

Participants: The study used US mortality data from the Centers for Disease Control and Prevention combined with US census data and data from on storefront dispensary operations. Data were analyzed at the county level by using panel regression methods.

Main outcome measure: The main outcome measures were the log transformed, age adjusted mortality rates associated with all opioid types combined, and with subcategories of prescription opioids, heroin, and synthetic opioids other than methadone. The associations of medical dispensary and recreational dispensary counts with age adjusted mortality rates were also analyzed.

Results: County level dispensary count (natural logarithm) is negatively related to the log transformed, age adjusted mortality rate associated with all opioid types (β=-0.17, 95% confidence interval -0.23 to -0.11). According to this estimate, an increase from one to two storefront dispensaries in a county is associated with an estimated 17% reduction in all opioid related mortality rates. Dispensary count has a particularly strong negative association with deaths caused by synthetic opioids other than methadone (β=-0.21, 95% confidence interval -0.27 to -0.14), with an estimated 21% reduction in mortality rates associated with an increase from one to two dispensaries. Similar associations were found for medical versus recreational storefront dispensary counts on synthetic (non-methadone) opioid related mortality rates.

Conclusions: Higher medical and recreational storefront dispensary counts are associated with reduced opioid related death rates, particularly deaths associated with synthetic opioids such as fentanyl. While the associations documented cannot be assumed to be causal, they suggest a potential association between increased prevalence of medical and recreational cannabis dispensaries and reduced opioid related mortality rates. This study highlights the importance of considering the complex supply side of related drug markets and how this shapes opioid use and misuse.”

“We studied county level associations between cannabis storefront dispensaries and opioid related mortality rates in the US between 2014 and 2018. Our study found that increased medical and recreational storefront dispensary counts are associated with reduced opioid related mortality rates during the study period. These associations appear particularly strong for deaths related to synthetic opioids such as fentanyl.”