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Science & Society and communities is enormous, so are the marijuana in states where marijuana use : economic costs, currently estimated at has been legalized for medicinal pur- US$78 billion yearly. The current opioid poses. Normally, preclinical models pro- Swinging the epidemic has gripped every community in vide the foundation for clinical trials, and the United States and crossed political then – after years of rigorous, structured, Marijuana Pendulum party lines such that there is for the first investigations – accrued evidence is eval- From ‘Weed’ to time complete agreement about the criti- uated by federal agencies to determine cal need to limit production and con- whether a particular compound should be Medication to Treat sumption of opioid medications. It is my approved for the treatment of specific the Opioid Epidemic opinion that bold steps are also required symptoms/disease, with any potential to escalate the pipeline in developing cre- side effects clearly noted to thoroughly Yasmin L. Hurd1,* ative and innovative treatments to help inform the public. For marijuana, such a curb this epidemic. bar has not been met; elections across Epidemics require a paradigm shift the country have been driven in large part in thinking about all possible sol- The Changing Sociopolitical by anecdotal reports and lobbying efforts Pendulum of Medicinal Marijuana by a growing marijuana industry. utions. The rapidly changing The predominant pharmacological treat- sociopolitical marijuana landscape ments currently prescribed for OUDs are Despite this growing movement, pre- provides a foundation for the ther- methadone, buprenorphine, and naltrex- scribing the medical use of a plant within apeutic development of medicinal one, which directly target the opioid sys- our existing clinical structure still has tre- cannabidiol to address the current tem. These medications have been of mendous challenges, but specific constit- opioid abuse crisis. significant clinical value but also have their uents of the plant could be more easily own challenges (often associated with developed for medicinal indications. Of Curbing an Epidemic strict governmental regulations governing the found in the marijuana In an unprecedented report, the US Sur- their use). One emerging solution showing plant, cannabidiol (CBD) is the phytocan- geon General recently released their first potential therapeutic properties is canna- nabinoid with perhaps the greatest poten- state of the science on substance use, binoids. States with legalized marijuana tial for development as a therapeutic addiction, and health to fully recognize laws have reported a reduction in opioid strategy for substance use disorders. substance use and addiction as signifi- use, as evidenced by lower number of There are some early indications from a cant and substantial public health chal- prescriptions for opioid painkillers, few experimental studies, most of which lenges [1]. As emphasized in the report, a reduced number of opioid overdoses, are in the initial phases in the development major component of the current sub- and lower opioid-positive screens asso- pipeline, supporting the benefits of CBD stance use crisis is the misuse and abuse ciated with car fatalities [2]. The reasons for treating certain behaviors both asso- of opioid drugs. The numbers are alarm- for these associations have not been ciated with addiction and relevant to ing. In the United States, approximately established, despite speculations regard- OUD. This, together with the changing 2.5 million people have been diagnosed ing the potential for medicinal properties medical marijuana landscape, provides with an opioid use disorder (OUD). Over of marijuana to reduce opioid use. an impetus to more seriously and expe- 80 people die each day from opioid over- ditiously consider the potential of CBD as dose; that number was even higher the The scientific community has been largely a therapeutic agent. past few years before many lives were missing from most conversations and saved due to the recent availability of policymaking regarding the legalization Making the Case for CBD As a the overdose-reversing agent naloxone. of marijuana for medical purposes. Treatment for Opioid Addiction Disconcertingly, four in five new Indeed, it is clear that the legalization of There is a strong scientific basis for users started out misusing opioid pre- marijuana has outpaced the science; this considering CBD as a therapeutic inter- scription painkillers. This has significant is one of the first times in US history that vention for OUDs. First, in contrast to implications for the current course of the question of whether a plant (or any most current opioid medications, there the opioid epidemic because over 200 drug) is an effective medicine has been is minimal concern about diversion million opioid painkiller prescriptions are decided at the ballot box. Contrary to the to the black market. In contrast to still written each year, a number closely normal course of medication develop- D9-tetrahydrocannabinol (THC), the approximating the entire adult population ment, it is the general public and politi- prominent psychoactive component of in the United States. While the burden cians, not scientists and physicians, marijuana, CBD is not rewarding [3,4] of OUDs for the individual, their families, determining the medical value of and as such has limited misuse and

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diversion potential. In addition, CBD has of G-protein-coupled receptors, including anxiety and negative affect is of significant very low lethality, thus alleviating con- the receptor type 1 (CB1R) importance for its therapeutic properties. cerns about potential overdose. More- (prominent subtype expressed in the cen- over, when combined with a strong tral nervous system) and CB2R (mainly Neuroanatomically, some of the strongest opioid agonist, CBD retains its safe pro- expressed in the periphery); small neuro- evidence observed regarding CBD’s file and does not induce severe adverse modulatory lipid ligands [N-arachidonyle- actions directly pertains to brain regions effects. CBD has been studied in various thanolamide (anandamide; AEA) and 2- highly implicated in negative affect and in vitro systems, in vivo animal models, arachidonoylglycerol (2-AG)]; as well as addiction. The amygdala is a critical struc- and human studies across a broad dose biosynthetic and metabolic enzymes for ture mediating anxiety and fear and has range (even up to 50 mg/kg/daily in the synthesis and[51_TD$IF] degradation [(fatty acid been well established to mediate stress humans) with minimal side effects or amide hydroxylase (FAAH) and monoa- response and encode the processing of any toxicity reported [5,6]. This strong cylglycerol lipase for AEA and 2-AG),[53_TD$IF]49 conditioned cues associated with drug safety profile has made it even suitable respectively] of the ligands [9]. Unlike memories that elicit drug-seeking behav- for use in children, as evidenced by the THC, CBD is not a potent agonist at ior. Animal models have shown that sys- recent epilepsy clinical trials with CBD the CB1R. Rather, CBD has a broad pro- temic administration of CBD specifically (Epidiolex) [5]. file in its pharmacological actions, which decreases the number of c-Fos-positive are not fully established and thus remain neurons (a marker of neuronal activity) in Another important consideration in the controversial. One important feature of the central nucleus of the amygdala and development of medications for addictive CBD’s actions that is not debated and direct CBD infusion into this amygdala disorders is the complexity of the illness (i. highly relevant to its anxiolytic properties nucleus reduces anxiety-like behaviors e., one medication cannot treat all is its ability to enhance AEA (through inhi- [11]. Importantly, neuroimaging studies aspects of the disorder). Addiction is a bition of FAAH and potentially through have shown that administration of CBD chronic illness characterized not just by inhibition of the putative AEA transporter). to humans reduces activation of the the intoxication associated with acute The weak agonist properties of CBD at amygdala during negative emotional drug use, but by disturbances of cogni- the CB1R and its potentiation of AEA, processing [12]. Moreover, other anxi- tion and negative emotional states that which also has low efficacy at the ety-related mesocorticolimbic neural cir- trigger craving and relapse, perpetuating CB1R, is an important consideration for cuits, such as the prefrontal cortex, which the insidious cycle of drug use. Thus, its therapeutic potential, because robust mediates decision making and cognitive although not a panacea, a medication engagement of CB1R signaling normally control, and the striatum, which regulates that specifically modulates behaviors rel- evokes reward and can induce psychosis. goal-directed behavior, motivation, and evant to craving and relapse could have Instead, enhanced eCB tone under closer habit formation, are directly linked to significant medicinal benefits. A highly physiological ranges is associated with addiction psychopathologies and shown reproducible and indisputable finding reduced anxiety. Thus, CBD’s ability to to be affected by CBD. based on human studies and animal discretely modulate eCB ligands to medi- models is the ability of CBD to modulate ate its actions potentially contributes to its The Crosstalk between CBD and anxiety [7], a core behavioral feature of wide therapeutic dose range since it lacks Opioid Addiction addiction that often triggers craving and direct potent receptor effects. What initially made a cannabinoid strategy promotes relapse. The neurobiological intriguing to consider for opiate addiction mechanisms underlying anxiety have Currently, the most consistent pharmaco- is the tight crosstalk and often reciprocal been well studied and key anatomical logical and behavioral evidence relating to interactions that exist between the and cellular components of such net- CBD effects on anxiety, negative affective endogenous opioid and eCB systems. works are highly influenced by CBD, as states, and emotional memory process- For example, (i) animals deficient in emphasized in the following section. ing pertains to its modulation of the 5- CB1R have reduced opioid reward, (ii) HT1A (5-hydroxytryptamine 1A subtype) opioids regulate the release of eCBs CBD to Treat Opioid Addiction: receptor [10]. CBD is an indirect agonist and eCBs alter opioid peptide levels, (iii) Neurobiological Considerations of 5-HT1A receptors and many effective eCB and opioid receptors are expressed The endogenous cannabinoid [endocan- antianxiety drugs have partial agonist in the same cells in discrete neuronal nabinoid (eCB)] system has been well properties at 5-HT1A receptors. Along pathways highly implicated in addiction, documented to contribute to the stress with its effects on 5-HT1A signaling, the and (iv) because they are both coupled to responsivity and negative emotional spectrum of CBD’s modulatory actions at inhibitory Gi/o proteins, opioid and canna- states that dominate substance use dis- multiple other neuromodulator/neuro- binoid receptors share similar intracellular orders [8]. The eCB system is composed transmitter systems highly implicated in signaling cascades. As such, the

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significant convergence for opioid/canna- not sufficient to make sweeping conclu- *Correspondence: [email protected] (Y.L. Hurd). binoid interactions opens up opportuni- sions about the potential efficacy of CBD http://dx.doi.org/10.1016/j.tins.2016.12.006 ties to assess potential cannabinoid to inhibit heroin craving and drug use in References interventions for OUD. Since THC is not addicted individuals. However, it serves 1. Office of the Surgeon General (2016) Facing Addiction in a suitable treatment option, given that it as an important foundation, along with America: The Surgeon General’s Report on Alcohol, Drugs, and Health, U.S. Department of Health and Human can even enhance opioid reward self- accumulating evidence in animal models, Services (HHS), Office of the Surgeon General administration and induce other psycho- to warrant expedited efforts for additional 2. Kim, J.H. et al. (2016) State medical marijuana laws and the prevalence of opioids detected among pathologies, CBD is the most optimal clinical studies to evaluate the potential fatally injured drivers. Am. J. Public Health 106, 2032– phytocannabinoid candidate. therapeutic benefits of CBD as a treat- 2037 ment for OUDs. 3. Katsidoni, V. et al. (2013) Cannabidiol inhibits the reward- facilitating effect of morphine: involvement of 5-HT1A Accumulating evidence supports this receptors in the dorsal raphe nucleus. Addict. Biol. 18, contention. Preclinical animal models Concluding Remarks . . . So 286–296 4. Vann, R.E. et al. (2008) Divergent effects of cannabidiol on have long demonstrated that, in addition Where Do We Go from Here? the discriminative stimulus and place conditioning effects to reducing the rewarding properties of It is important to move with a deep sense of of Delta(9)-tetrahydrocannabinol. Drug Alcohol. Depend. 94, 191–198 opioid drugs and withdrawal symptoms urgency to leverage the opportunity pre- 5. Devinsky, O. et al. (2016) Cannabidiol in patients with [13], CBD directly reduces heroin-seeking sented by increased legalization of medical treatment-resistant epilepsy: an open-label interventional behavior [14]. Importantly, these effects marijuana to expedite the development of trial. Lancet Neurol. 15, 270–278 6. Hess, E.J. et al. (2016) Cannabidiol as a new treatment are related to conditioned cue-induced CBD for therapeutic interventions for for drug-resistant epilepsy in tuberous sclerosis complex. reinstatement of heroin-seeking behavior, OUDs, thus curbing the opioid epidemic. Epilepsia 57, 1617–1624 an effect that was evident weeks after Clinical trials must be of the highest priority 7. Blessing, E.M. (2015) Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics 12, CBD was initially administered. This to establish the most appropriate formu- 825–836 long-lasting effect is an important consid- lations, entourage effects with other can- 8. Parsons, L.H. and Hurd, Y.L. (2015) Endocannabinoid signalling in reward and addiction. Nat. Rev. Neurosci. eration in developing practical strategies nabinoids, routes of administration, and 16, 579–594 for substance use disorders, in which treatment regimens for the use of CBD 9. Mechoulam, R. (2014) Early phytocannabinoid chemistry drug craving increases over the course by individuals with OUDs. Although signifi- to endocannabinoids and beyond. Nat. Rev. Neurosci. 15, 757–764 of the drug abstinence phase. Interest- cant momentum in the general public has 10. Campos, A.C. et al. (2016) Cannabidiol, neuroprotection ingly, CBD normalizes heroin-induced moved the pendulum regarding marijuana, and neuropsychiatric disorders. Pharmacol. Res. 112, 119–127 impairment of the CB1R and glutamate the scientific and medical communities 11. Hsiao, Y.T. et al. (2012) Effect of cannabidiol on sleep receptors in the striatum, suggesting that now need to play a more leading role via disruption induced by the repeated combination tests it normalizes synaptic plasticity in this evidence-based studies. In this way, sci- consisting of open field and elevated plus-maze in rats. Neuropharmacology 62, 373–384 fi region [14]. Importantly, a pilot human enti c and medical evidence will once 12. Fusar-Poli, P. et al. (2009) Distinct effects of D9-tetrahy-[50_TD$IF] investigation also documented findings again serve to inform the public and to drocannabinol and cannabidiol on neural activation fi during emotional processing. Arch. Gen. 66, consistent with those observed in the ani- develop ef cacious and safe therapies. 95–105 mal model, demonstrating that CBD However, such advances will require sig- 13. Hine, B. et al. (1975) Differential effect of cannabinol reduced heroin-related cue-induced nificant and immediate actions to be taken and cannabidiol on THC-induced responses during abstinence in morphine-dependent rats. Res. Commun. craving in heroin abusers [15]. Moreover, by the National Institutes of Health and Chem. Pathol. Pharmacol. 12, 185–188 similar to the protracted effects seen in other federal agencies to help develop a 14. Ren, Y. et al. (2009) Cannabidiol, a nonpsychotropic ’ component of , inhibits cue-induced heroin the animals, CBD s attenuation of general structure for fast-tracking the clinical use of seeking and normalizes discrete mesolimbic neuronal craving lasted even a week after its last ‘medical CBD’. disturbances. J. Neurosci. 29, 14764–14769 administration. Interestingly, CBD’s 15. Hurd, Y.L. et al. (2015) Early phase in the development of cannabidiol as a treatment for addiction: opioid 1Friedman Brain Institute, Departments of Psychiatry and strongest effects were on the attenuation relapse takes initial center stage. Neurotherapeutics 12, , Icahn School of Medicine at Mount Sinai, 807–815 of the anxiety induced by heroin cues. Center for Addictive Disorders, Mount Sinai Behavioral Unfortunately, one small clinical study is Health System, New York, NY, USA

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