Weekly Cannabis News
September 2nd – September 9th, 2022
Cannabidiol (CBD) & Anxiogenic/Compulsive Behaviors Following a High-Carbohydrate (HC) Diet
The study showed that sub-chronic CBD treatment attenuated the compulsive and anxiogenic-like behaviors induced by HC diet in mice.
The World Health Organization (WHO) defines obesity and being overweight as “abnormal or excessive fat accumulation that presents a risk to health.”  It is a major health problem worldwide and especially in the US, ranked as the fifth most common leading cause of death globally. According to the CDC, the US obesity prevalence was 41.9% in 2017 – March 2020, making it a global health issue.  Additionally, obesity is known to be associated with an increased number of health co-morbidities including asthma, cancer, diabetes, and cardiovascular diseases. 
Excess fat consumption leads to chronic low-grade systemic inflammation, producing pro-inflammatory mediators which can influence the brain and result in behavioral changes.  Previous reports have shown that mice fed on a high-refined carbohydrate diet (HC diet) can develop anxiety-like behaviors associated with changes in specific brain regions.  While treatments are available, limited efficacy and increased side effects are motivating researchers to find alternative therapeutic agents. One that is gaining interest and attention is the cannabis plant, and most specifically, the non-euphoric compound cannabidiol (CBD), known to have anxiolytic, anti-inflammatory and antidepressant properties.  However, additional research investigating the use of CBD in ameliorating anxiety-like behavior following HC diet in mice is needed.
A group of researchers in Brazil administered CBD or vehicle in HC or control mice for 12 weeks and assessed their behaviors using the Marble Burying test (MBT) and Novel Suppressing Feeding test (NSF), which are good experimental methods to study repetitive, compulsive-like behaviors, and depression-like behaviors in mice.  After confirming the effect of HC diet consumption via increased adiposity, the group found that sub chronic treatment with CBD counteracted and reduced the effect induced by the consumption of HC diet in the MBT and NSF tests, respectively.
The authors concluded: “Our results reinforce the compulsive and anxious-like behavior induced by the chronic consumption of the high-carbohydrate diet… Moreover, we did not investigate the exact mechanisms that account for CBD effects. Nevertheless, our data reinforce the potential of CBD pharmacotherapy for obesity-associated diseases like anxiety and obsessive-compulsive disorder.”
Cannabinoid Receptor 1 (CB1R) & Ketamine in Depression and Locomotion
CB1R played a role in mediating the hyperlocomotion effects following ketamine use without modifying ketamine’s effects on depression, a new study suggests.
The endocannabinoid system (ECS) is one of the newly discovered systems in the human body, known to regulate a wide array of key critical functions from sleep, mood, appetite, and homeostasis.  It is composed of endogenous cannabinoids, synthesis, and degradation enzymes and cannabinoid receptors 1 and 2 (CB1R, CB2R), expressed throughout the body. CB1R is mostly expressed in the central nervous system (CNS), in brain regions involved in motivation, reward, and emotion, and is one of the key targets of the psychoactive compound of the cannabis plant, Δ9-tetrahydrocannabinol (Δ9-THC). , Additionally, animal and human studies have shown that the CB1R also plays key roles in regulating mood disorders such as depression, defined by the National Institute of Mental Health as “common but serious mood disorder. It causes severe symptoms that affect how you feel, think, and handle daily activities, such as sleeping, eating, or working.” ,  While treatments are available (e.g., selective serotonin reuptake inhibitors (SSRIs), brain stimulation therapy), they are often associated with unwanted side effects. One compound that is gaining interest the powerful anesthetic ketamine, which induces a rapid and sustained antidepressant effects and is effective in patients by decreasing suicidality. , Along those lines, the FDA has approved the intranasal use of Spravato®, an esketamine-based compound, for adults with treatment-resistant depression and depressive symptoms in adults with major depressive disorder with suicidal thoughts or actions.  However, additional research investigating CB1R involvement in the antidepressant effect followed by ketamine administration is needed.
Gobira et al., tested the effects of ketamine in wild type mice (no genetic alteration) and in mice with a CB1R deficiency (CB1R KO) in the open-field and forced swim tests (FSTs), used in research to determine general/locomotor activity levels, and monitor depressive-like behavior, respectively. ,,Firstly, the group found that following ketamine administration, motor hyperactivity was impaired in the CB1R KO mice and when injected with rimonabant, a compound that blocked CB1R activity. Secondly, treatment with ketamine and rimonabant reduced the immobility time in the FST compared to vehicle-treated mice, suggesting that both drugs had an antidepressant-like effect.
The authors concluded: “Our results support the hypothesis that CB1R mediates the hyperlocomotion effects induced by ketamine since the hyperactivity promoted by this drug in the open-field test was impaired by pharmacological and genetic inhibition of CB1R… our results shed light on an essential aspect behind ketamine antidepressant effects by demonstrating that it can be dissociated from its psychostimulant properties.”
Mechanisms Behind Cannabidiol (CBD)-Induced Suppression of Methamphetamine Seeking Behavior
This study showed that CBD was able to suppress the methamphetamine-induced reinstatement and was mediated by dopamine receptor 1 (D1R).
Methamphetamine is a highly addictive psychostimulant drug that is derived from amphetamine. [19 ] It acts by both facilitating the release of important neurotransmitters (e.g., noradrenaline, serotonin, and dopamine) and inhibiting their uptake leading to an increase concentration and subsequent stimulation of receptors.  According to the National Institute on Drug Abuse (NIDA), overdose deaths involving methamphetamine nearly tripled from 2015 to 2019 in US adults between 18-64, posing a significant health problem worldwide.  Overuse of methamphetamine can lead to physical and cognitive impairments along with a high rate of relapse due to increased withdrawal symptoms.  Because of ineffective treatments and the huge burden, it imposes on health, there is a need to investigate other agents. One that is promising is cannabidiol (CBD), shown in reports to reduce vulnerability to substance use and relapse and could be effective in preventing meth-induced rewards in animal studies. ,Additionally, the endocannabinoid system (ECS) and the mesolimbic dopamine system play important roles in the reinforcing/rewarding effects of methamphetamine, and as such, may represent a great therapeutic avenue to reduce drug seeking behaviors.  However, the exact mechanism of action by which CBD may help in drug addiction and relapse is not known.
Mirmohammadi et al., aimed to determine the effects of CBD administration and examine the roles of dopamine receptor 1 and 2 (D1R, D2R) in the nucleus accumbens (NAc), key brain region involved in motivation and reward behaviors, on methamphetamine-induced conditioned place preference (CPP) in mice.  This experimental method is based on the premise that a mouse comes to prefer one place more than others because the preferred location has been paired previously with rewarding events (in this case methamphetamine), and as such, is a great method to evaluate the aversive and rewarding effects of drugs.  Results showed that CBD injections at 10 and 50 μg/5 μL suppressed the methamphetamine-induced reinstatement and decreased the extinction latency compared to vehicles and untreated mice. Additionally, these results were reversed by the addition of a D1R but not D2R antagonist in the NAc.
The authors concluded: “The obtained results demonstrated that (i). CBD treatment during the extinction phase could result in shorter extinction latencies (ii). CBD administration on reinstatement day can prevent METH-induced CPP relapse (iii). Intra-accumbal administration of SCH23390 can reverse the effects of CBD on the extinction and reinstatement of the METH-induced CPP; (iv). Intra-accumbal administration of sulpiride had no significant effect on the decreasing effects of CBD on extinction latency and reinstatement of the METH-induced CPP. (v). Intraaccumbal administration of SCH23390 and sulpiride in the absence of CBD did not affect the extinction and reinstatement of the METH-induced CPP.”
Two Medical Cannabis Bills Signed by Californian Governor
On September 2nd, 2022, Californian Governor Gavin Newson, signed two new bills that would enhance protection for patients taking cannabis: Assembly Bill 1954 (AB 1954) and Senate Bill 988 (SB 988).
On one hand, the AB 1954 aims to prevent medical cannabis patients from being discriminated by doctors and surgeons who may deny medical treatment because they tested positive for cannabis. The AB 1954 states: “This bill would prohibit a physician and surgeon from automatically denying treatment or medication to a qualified patient, as defined, based solely on a positive drug screen for tetrahydrocannabinol (THC) or report of medical cannabis use without first completing a case-by-case evaluation of the patient that includes a determination that the qualified patient’s use of medical cannabis is medically significant, as defined, to the treatment or medication. The bill would provide that use of medical cannabis that has been recommended by a licensed physician and surgeon shall not constitute the use of an illicit substance in such an evaluation.” 
On the other hand, SB 988, which was introduced by Senator Ben Huesco as an amendment to the existing bill called Ryan’s Law (SB 311), which allowed the use of medical cannabis on healthcare facilities for terminally ill patients with a valid medical cannabis card. The SB 988 states: “This bill would repeal the requirement that health care facilities permitting patient use of medical cannabis comply with other drug and medication requirements, as specified. The bill would require a health facility to require a patient or a primary caregiver, as defined, to be responsible for acquiring, retrieving, administering, and removing medicinal cannabis and would require medicinal cannabis to be stored securely at all times. The bill would require the patient or the patient’s primary caregiver to, upon discharge, remove all remaining medicinal cannabis and, if a patient cannot remove the medicinal cannabis and does not have a primary caregiver, would require the storage of the product in a locked container until it is disposed of, as specified.” 
Additional bills are expected to be signed by Governor Newsom this month, including AB 2188 which would forbid employers from discriminating an employee who use cannabis outside of the job. 
 https://www.who.int/health-topics/obesity#tab=tab_1, assessed on September 9th, 2022
 https://www.cdc.gov/obesity/data/adult.html, assessed on September 9th, 2022
 Hu L, Huang X, You C, Li J, Hong K, Li P, et al. Prevalence of overweight, obesity, abdominal obesity and obesity-related risk factors in southern China. PLoS One 2017;12(9):e0183934
 Yang L, Wang M, Guo YY, Sun T, Li YJ, Yang Q, et al. Systemic inflammation induces anxiety disorder through CXCL12/CXCR4 pathway. Brain Behav Immun 2016;56:352-62.
 Santos CJ, Ferreira AVM, Oliveira AL, Oliveira MC, Gomes JS, Aguiar DC. Carbohydrate-enriched diet predispose to anxiety and depression-like behavior after stress in mice. Nutr Neurosci 2018;21(1):33-9.
 Campos AC, Fogaca MV, Scarante FF, Joca SRL, Sales AJ, Gomes FV, et al. Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders. Front Pharmacol 2017;8:269.
 Marcal AP, Soares N, Asth L, Moreira FA, Ferreira AVM, Aguiar DC. Cannabidiol ameliorates the anxiogenic and compulsive-like behaviors induced by chronic consumption of a high-carbohydrate diet in male mice. Metab Brain Dis 2022.
 Schulz P, Hryhorowicz S, Rychter AM, Zawada A, Slomski R, Dobrowolska A, et al. What Role Does the Endocannabinoid System Play in the Pathogenesis of Obesity? Nutrients 2021;13(2).
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 https://www.nimh.nih.gov/health/topics/depression, assessed on September 9th, 2022
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 Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A, et al. Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial. Am J Psychiatry 2019;176(5):401-9.
 https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified, assessed on September 9th, 2022
 Gobira PH, LaMar J, Marques J, Sartim A, Silveira K, Santos L, et al. CB1 Receptor Silencing Attenuates Ketamine-Induced Hyperlocomotion Without Compromising Its Antidepressant-Like Effects. Cannabis Cannabinoid Res 2022.
 Can A, Dao DT, Arad M, Terrillion CE, Piantadosi SC, Gould TD. The mouse forced swim test. J Vis Exp 2012(59):e3638.
 Kraeuter AK, Guest PC, Sarnyai Z. The Open Field Test for Measuring Locomotor Activity and Anxiety-Like Behavior. Methods Mol Biol 2019;1916:99-103.
Richards JR, Laurin EG. Methamphetamine Toxicity. StatPearls. Treasure Island (FL); 2022.
 Downey LA, Loftis JM. Altered energy production, lowered antioxidant potential, and inflammatory processes mediate CNS damage associated with abuse of the psychostimulants MDMA and methamphetamine. Eur J Pharmacol 2014;727:125-9.
 Karimi-Haghighi S, Haghparast A. Cannabidiol inhibits priming-induced reinstatement of methamphetamine in REM sleep deprived rats. Prog Neuropsychopharmacol Biol Psychiatry 2018;82:307-13.
 Prud’homme M, Cata R, Jutras-Aswad D. Cannabidiol as an Intervention for Addictive Behaviors: A Systematic Review of the Evidence. Subst Abuse 2015;9:33-8.
Calpe-Lopez C, Garcia-Pardo MP, Aguilar MA. Cannabidiol Treatment Might Promote Resilience to Cocaine and Methamphetamine Use Disorders: A Review of Possible Mechanisms. Molecules 2019;24(14).
 Mirmohammadi M, Eskandari K, Koruji M, Shabani R, Ahadi R, Haghparast A. Intra-Accumbal D1- But not D2-Like Dopamine Receptor Antagonism Reverses the Inhibitory Effects of Cannabidiol on Extinction and Reinstatement of Methamphetamine Seeking Behavior in Rats. Cannabis Cannabinoid Res 2022.
 Huston JP, Silva MA, Topic B, Muller CP. What’s conditioned in conditioned place preference? Trends Pharmacol Sci 2013;34(3):162-6.
 https://leginfo.legislature.ca.gov/faces/billTextClient.xhtml?bill_id=202120220AB1954, assessed on September 9th, 2022
 https://leginfo.legislature.ca.gov/faces/billTextClient.xhtml?bill_id=202120220SB988, assessed on September 9th, 2022
 https://leginfo.legislature.ca.gov/faces/billTextClient.xhtml?bill_id=202120220AB2188, assessed on September 9th, 2022