Journal of Addiction and Dependence | Volume 5 | Issue 1 | 2019-12-30

Is Medical Marijuana a Viable Option for Opioid Replacement Therapy?

Theresa O Doherty

Abstract

The opioid epidemic has become one of the most serious health crises in the United States. Current replacement therapies for opioid use disorder, such as methadone, buprenorphine, and naltrexone, are not sufficient enough to treat recovering opioid users due to disadvantages such as inadequate availability and potential side effects. As a result, new alternatives to these drugs must be addressed. This article addresses the permissibility of using medical marijuana as a potential replacement therapy for Opioid Use Disorder and opioid withdrawal from the pharmacological, medical, legal, and ethical perspectives. Pharmacologically, current replacement therapies are used to decrease the symptoms of withdrawal and lower the risk of overdose but have several limitations. Marijuana, in addition to current replacement therapies, could benefit as a treatment for opioid use disorder because of its safe, non-addictive qualities and effectiveness in inhibiting opioid-seeking behavior. Legally, the policies regarding the use of medical THC and CBD as replacement therapies are shifting in the right direction at the state level. The ethical principle of double effect is used to defend the permissibility of this replacement therapy. Lastly, we propose the institution of a potential medical marijuana clinic in Philadelphia, which offers this drug as a replacement therapy, serving as a paradigm for those suffering from drug addiction to seek alternative therapy and treatment.

Keywords: Addiction, Interpretative phenomenological analysis, IPA, Recovery, Whoonga/nyaope, Townships

Full text

The opioid epidemic is an ongoing national crisis and public health issue. This crisis impacts individuals all over the nation, regardless of race or income status. From 1999 to 2017, over 700,000 people in the U.S. died of drug overdoses; almost 400,000 of those deaths involved opioids [1] . The number of deaths in 2017 due to opioid drug overdose (comprised of both prescription and illicit drugs) was 6 times higher compared to 1999. According to the Centers for Disease Control and Prevention (CDC), 130 opioid-related overdoses occur each day on average [2] . In October 2017, the U.S. Government declared this a public health emergency [3] . Commonly available prescription opioids include oxycodone, hydrocodone, codeine, fentanyl, and morphine. Other opioids are illegal, such as heroine [4] . Clinically, these drugs are commonly used to manage moderate to severe acute pain, such as pain experienced post-operatively or following trauma. They are also utilized to manage severe chronic pain experienced by terminally-ill patients or for easing the effects of pain related to cancer treatment [5] . Although these drugs are effective in managing pain, they are often over-prescribed, overused and misused. Examples of opioid misuse include taking the medication in order to achieve a high, taking another individual s prescription drug, or taking the drug in a manner/dose other than what was prescribed [4] . As a result, healthcare providers are challenged to find a balance between managing genuine pain and avoiding over-prescription [5] . Opioids have potent physiological and psychological effects, as they are able to evoke both euphoria and analgesia when taken acutely [6,7] . Recurrent use of the drugs can result in tolerance (needing to take higher subsequent doses of the drug in order to achieve the same effects) and physical dependence (experiencing withdrawal symptoms after discontinuation of the drug) [8] . With repeated or chronic use, opioids elicit adaptations and modifications in neuronal circuitry, forming a drug-dependent state [6] . The mechanism by which this occurs is the suppression of endogenous neurotransmitter production after chronic stimulation of opioid receptors in the brain. Abrupt cessation of the drug causes unopposed binding of counter-regulatory neurotransmitters to these receptors, contributing to undesirable withdrawal symptoms [7] . These symptoms may vary based on the type of drug used and the method by which it was taken. Withdrawal can produce both psychological and physical symptoms, such as dysphoria, anxiety, insomnia, sweating, shaking, and diarrhea. Many of these physical symptoms are temporary, while several psychological symptoms can persist for months [6] . There are several replacement therapies available for opioid addiction. These drugs agonize, partially agonize, or antagonize the mu-opioid receptor. Many of these drugs are used as maintenance therapy or detoxification agents [11] . Psychosocial therapies such as counseling, therapy, and educational programs are also offered to patients who wish to overcome their addiction. The drugs that we aim to describe are methadone, Suboxone (buprenorphine and naloxone), naltrexone, and medical marijuana. These Food and Drug Administration (FDA)-approved opioid replacement therapies have been effective at alleviating opioid dependence and helping to lessen withdrawal symptoms, however they are not always successful and do not come without risks. Various adverse effects to these drugs must also be considered, such as anxiety, cardiac effects, muscle aches, agitation, insomnia, nausea and diarrhea [9] . Access to these replacement therapies is also a challenge, as there are legal and logistical impediments to acquiring them. Often, the demand for these medications exceeds the supply. In this article, we examine the role of cannabis as a potential replacement therapy in treating opioid withdrawal symptoms and decreasing the probability of relapse. Cannabis and opioids share a common primary use of analgesia. Studies have shown that patients taking opioids for chronic pain who also have access to cannabis decrease their opioid use by 40-60%. Furthermore, cannabis has been shown to consistently decrease the dose of opioids needed to reach suitable pain relief [10] . Although current replacement therapies for opioid addiction seem ideal, there are several limitations which need to be considered, such as availability and potential side effects. The focus of this paper is fivefold. First, the mechanisms of action of methadone, buprenorphine, and naltrexoneare discussed. Second, an analysis of medical marijuana as a viable option for replacement therapy, including both THC and CBD, is considered. Third, the legal ramifications regarding the use of THC and CBD as replacement therapies are explored. Fourth, the implementation of a replacement therapy clinic in Philadelphia offering medical marijuana is presented, insofar that an established clinic could serve as a paradigm for those suffering from drug addiction to seek alternative therapy and treatment. Fifth, an ethical analysis of the problem and solutions is presented. Pharmacotherapy For Opioid Use Disorder Opioid Use Disorder (OUD), previously classified as opioid abuse, is defined as a problematic pattern of opioid use that leads to clinically substantial impairment [11] . Opioids have the potential to depress the central nervous system, which may lead to overdose and death. Replacement therapie s, such as methadone, buprenorphine, and naltrexone, are used to decrease the symptoms of withdrawal and lower the risk of overdose. Methadone Methadone is a full, long-acting opioid receptor agonist. It acts by binding to the same mu receptors as other opioids, but is used to reduce withdrawal symptoms as well as cravings for opioids. This is because patients already addicted to opioids do not achieve a high while on methadone. Methadone is mostly used for heroin or other opioid dependence [12] . Because of its long half-life, its effects can last up to 24 hours and slowly taper off, so the withdrawal is less intense. This allows patients to be gradually weaned off of opioids entirely. Methadone is usually administered in a once daily dose in liquid or tablet form, though the latter is not as common [13] . This has long been a treatment of choice for chronic opioid addicts, albeit expensive [9] . Methadone is listed as a Schedule II drug. A Schedule II drug (i.e. cocaine, fentanyl) has a high potential for abuse, but has an approved medical use. The remaining Schedules (III, IV, V) are accepted for medical treatment, and have a low likelihood of abuse [14] . The potential for Schedule III drug abuse is lower than Schedule I and Schedule II drugs, but is higher than for Schedule IV [15] . Methadone is mostly ordered for OUD by licensed opioid treatment programs. These programs are required to provide counseling and social services for patients. Patients already on methadone from a licensed program may also be continued on methadone in an inpatient hospital setting to avoid withdrawal. Because the use of methadone is so strictly regulated to licensed centers, demand often exceeds availability [13] . Side effects of methadone include constipation, drowsiness, and overdose, very similar to other drugs in the class of opioids. Sexual dysfunction has also been reported in terms of reduced libido and erectile dysfunction. Lastly, though less frequently, methadone usage has been associated with life threatening arrhythmias in a dose-dependent fashion [13] . Meta-analysis studies have shown that patients receiving methadone are more likely to continue treatment and decrease opioid use compared to non-pharmacological treatment [16] . It has also been found that methadone is more effective than detoxification alone [17] . Methadone use has also reduced the spread of HIV, criminal behavior, and even long-term mortality. Treatment with methadone helps reduce psychological and social harms, as well [18] . Buprenorphine Buprenorphine is a partial mu-opioid receptor agonist. Because it is only a partialagonist, it has similar pharmacological effects to that of full agonists. Its affinity for the opioid receptor is so high that it has the ability to block the effect of other opioids. It can also reduce symptoms of withdrawal, does not give off the euphoria effect, and has been shown to be safer and better tolerated by patients than methadone [19] . However, because it is a partial agonist, it may require tighter doses to follow. It can be as effective as methadone if used in a dose-dependent manner [20] . Additionally, it demonstrates a ceiling effect in which exceeding a certain dose does not provide any added analgesic effect. Because of this, buprenorphine inherently carries a lower risk of overdose and associated adverse effects. However, if a patient is still experiencing the effects of a full opioid agonist, such as morphine, the addition of buprenorphine, a partial agonist, creates an antagonistic effect, thus actually precipitating a withdrawal [21] . Buprenorphine has approximately a 37.5-hour half-life. Because of this long half-life, its effects gradually diminish as it is tapered off; therefore any withdrawal symptoms are less severe. It is typically dosed every 24 hours usually through the sublingual route as this provides the greatest bioavailability [22] . The drug is available as a sublingual tablet or as a film strip that is dissolved under the tongue. Transdermal, intravenous, and intramuscular forms of buprenorphine have been approved for the treatment of acute and chronic pain. A new formulation of buprenorphine is the subcutaneous implant which has shown to be effective for 6 months and as such, increases patient compliance. Buprenorphine may also be administered in combination with naloxone as either a film strip, buccal film, or tablet form, known as Suboxone [21] . When initiated on buprenorphine therapy, the patient must abstain from short acting opioids for at least 12 hours, or 72 hours for long acting opioids, to the point where mild to moderate withdrawal symptoms have begun to manifest. The dose of buprenorphine may then be increased as needed based on degree of withdrawal and the patient s responsiveness to the drug [21] . Buprenorphine is a Schedule III drug, which, according to the DEA, has a moderate to low potential for physical and psychological dependence [15] . Physicians must be specially trained, certified, and registered with the US Center for Substance Abuse Treatment (CSAT) of the Substance Abuse and Mental Health Service Administration (SAMHSA) and with the DEA in order to legally prescribe buprenorphine [23] . Adverse effects of buprenorphine are generally negligible due to its partial agonistic properties. Buprenorphine-related deaths occur secondary to respiratory depression and hypoxia. However, these deaths primarily occur when the drug is ingested concomitantly with another depressant such as benzodiazepines or alcohol [24] . In one study, buprenorphine was proven to be superior to placebo for maintenance therapy for opioid dependence in patients who use heroin at high doses (i.e. 16mg or more) [25] . Patients who received buprenorphine were found to have reduced use of illicit drugs and were more likely to adhere to treatments than those receiving placebo [26] . It was also determined that patients who received at least 12 week s worth of buprenorphine treatment were more successful in preventing relapse than those who received the same drug for only one to three months. Relapse rates in individuals only receiving one to three months was 90% [21] . In another meta-analysis comparing buprenorphine to methadone, researchers found that an 8-12 mg/day dose of buprenorphine was more effective than low dose methadone 40-50mg [26] . However, this study also found that patients were more likely to drop out of the study if they were on buprenorphine rather than methadone, which the researchers attributed to missing the high which methadone provides [19] . Despite some of the challenges associated with buprenorphine, it proves to have several advantages when compared to its counterparts. It is less likely to cause an overdose and physical dependence and is associated with easier detoxification than methadone [22] . Naltrexone Naltrexone is a mu-opioid antagonist that prevents acute opioid intoxication or physiologic dependence with subsequent use, thus reinforcing abstinence [27] . This is an alternative option to the agonists, because instead of controlling withdrawals and cravings, it blocks euphoria [20] . However, despite these benefits, the first-line treatment for moderate to severe OUD is an opioid agonist medication (i.e., methadone or buprenorphine), rather than opioid-antagonist medications [27] . Two formulations of naltrexone exist. The first is a 50 mg tablet taken once daily, which is most effective in patients who are closely supervised or highly motivated. This tablet is equivalent to blocking 25mg of intravenous heroin for more than 24 hours [28] . The second formulation of naltrexone is an extended release or long-actinginjectable (LAI), at 380mg per 4 weeks [29-31] . Naltrexone is considered a Schedule II drug by the DEA, but it requires no special license or training to prescribe [31] . Common adverse effects of naltrexone include nausea, headaches, dizziness, fatigue, elevated ALT, increased creatine phosphokinase, and syncope. With supra-therapeutic doses, cases of liver damage have been reported, but can resolve with discontinuation of naltrexone. Patients who discontinue antagonist therapy and resume opioid use should be made aware of the risks associated with an opioid overdose, especially death. This is due to the loss of tolerance to opioids and a resulting misjudgment of dosage at the time of relapse [27] . Several clinical trials have assessed the efficacy of naltrexone, however results were limited due to poor adherence and high dropout rates [32] . Oral naltrexone was found to be more effective than placebo in sustaining abstinence in three trials in which patients were adherent to daily doses of the medication [27] . LAI naltrexonehas also been found to be more effective than placebo for opioid dependence in randomized trials [28,30,32,33] . As previously mentioned, several clinical trials have shown treatment with buprenorphine or methadone to reduce opioid use compared with placebo or other treatments. Studies comparing buprenorphine to naltrexone, however, were limited. One study comparing these determined that naltrexone required a much greater extent of full detoxification prior to initiating the drug than initiating buprenorphine-naloxone treatment. While it showed in this study that naltrexone can be effective for short term opioid abstinence, it requires patients who are highly motivated or under supervised medication administration [27,34] . Two recently published open-label clinical trials comparing monthly LAI naltrexone with daily sublingual buprenorphine found little evidence of a difference in abstinence rates, although it appeared that initial stabilization of buprenorphine may be easier to accomplish. The first clinical trial compared monthly LAI naltrexone and daily sublingual buprenorphine; it found the two medications to be comparable in reducing the use of heroin and other illicit opioids in opioid-dependent patients [34] . The second open-label clinical trial also compared LAI naltrexone with daily sublingual buprenorphine. It included patients who had entered inpatient programs for planned withdrawal from opioids but had not necessarily completed withdrawal at the time of enrollment. Less patients in the naltrexone group were successfully inducted onto medication compared with the buprenorphine group, however more patient staking naltrexone relapsed compared to patients taking buprenorphine [35,36] . Based on published data analysis, a valid approach to medication-assisted treatment with naltrexone for OUD should be as follows: For non-pregnant adults with mild OUD in the post withdrawal phase, naltrexone should be considered. If treatment fails, stop medication and initiate buprenorphine. If subsequent treatment with buprenorphine fails, change to methadone. For patients in the post-withdrawal phase with moderate to severe opioid use, treatment with buprenorphine should be initiated, as it is not an opioid antagonist [24,27] . Treatment Selection As detailed above, there are a variety of medication options for alternative therapies, and in order to successfully prevent relapse, several factors should be considered [Figure 1]. Methadone, buprenorphine, and naltrexone are all approved by the FDA for long-term treatment to prevent relapse, with each medication having its unique outcomes, risks and benefits. Figure 1: Treatment Selection Approach for OUD [12] Severity of the OUD plays a key role in the selection, as buprenorphine and methadone are considered first line for patients who have moderate to severe OUD [24] . In deciding between the two, effectiveness, cost, and the availability need to be considered. Although both medications are effective (retaining patients in treatment and suppression of OUD), methadone is deemed slightly superior overall according to a meta-analysis comparing the two drugs [37] . Even though methadone has a higher efficacy, it is also a full agonist, thereby having a higher potential for abuse and lethal overdose. Taking into account this safety profile, buprenorphine is usually only recommended as the first line treatment [24] . It is reasonable to consider the usage of methadone in situations where buprenorphine is not feasible, such as failure of treatment to patients on buprenorphine or a history of buprenorphine misuse. Cost is also a crucial factor when deciding between the two maintenance therapies, as buprenorphine is more expensive than methadone [38] . Lastly, the regulation of methadone is more stringent than buprenorphine due to its higher schedule classification, and thus can only be given in specialized programs rather than office-based programs. The wider availability of buprenorphine and ease of access for patients makes it more appealing in terms of choice [39] . In patients with a mild OUD, naltrexone is a reasonable alternative to methadone or buprenorphine. Oral pills or LAI naltrexone can be used in patients who are highly motivated with mild opioid disorder, situations where medication use can be supervised, or circumstances in which the use of agonist medication is prohibited in certain occupations [24] . Apart from this, naltrexone should be administered once the patient is free of physiological opioid dependence, or greater than one week without symptoms of acute withdrawal [40] . Medical cannabis as treatment modality for opioid use disorder Medical cannabis and its derivatives, known as cannabinoids, can serve as viable options for patients recovering from opioid addiction. The purpose of this section is threefold; first, to examine the preclinical and clinical evidence surrounding cannabidiol (CBD) and tetrahydrocannabinol (THC) on addictive behaviors as a whole; second, to highlight research establishing cannabidiol and the effectiveness of CBD in inhibiting opioid-seeking behavior; and third, to discuss the safety and pharmacokinetics of CBD when administered concomitantly with high-potency opioids. Effect of CBD and THC on addictive and opioid-seeking behaviors Despite numerous negative consequences, drug addiction continues to be an issue in the United States. Research has uncovered that the endocannabinoid system (ECBS) influences the acquisition and maintenance phase of drug addiction due to its function in reward and brain plasticity [41,42] . The endocannabinoid system is comprised of cannabinoids, endocannabinoid receptors, and various enzymes. CBD acts on the ECBS as a weak inverse agonist on CB1 receptors, stimulates vanilloid receptors, and alters the hydrolysis of anandamide by inhibiting fatty acid amine hydrolase [43-45] . These mechanisms, along with its 5-HT1A serotoninergic agonist properties, have led researchers to believe that CBD helps regulate the stress response as well as compulsive behaviors, and thus can play an important role in substance abuse disorders [46] . CBD is the second most common chemical found in marijuana after THC. Currently, CBD is only approved for the treatment of a severe pediatric epileptic disorder [47] . Since CBD is non-psychoactive, it has not been shown to have any effect on cannabis intoxication when administered with THC [48] . Cessation of daily marijuana use leads to withdrawal symptoms such as increased irritability, anxiety, decreased quality and quantity of sleep, and reduced food intake [49] . Because CBD and THC have similar chemical structures, CBD may be used to bind to endocannabinoid receptors and aid in withdrawal from THC. One case study examined CBD oil and its ability to decrease addictive use of marijuana. The case study includes a twenty-seven-year-old male who was diagnosed with bipolar disorder and used marijuana daily. He self-reported that with the use of CBD oil, he was able to maintain a regular sleep schedule and decrease his overall anxiety. He also reported better relations with his family and friends, and additionally was able to obtain a stable occupation [50] . A 2015 systematic review searched existing preclinical and clinical data on CBD s effect on addictive disorders. Although there were a limited number of studies in this systematic review, many revealed that CBD may be a viable therapeutic solution for addictive behaviors from drugs such as opioids, cocaine, and psychostimulants [51] . One study included in this review investigated the effect of cannabinoids on morphine withdrawal syndrome. Morphine dependence was induced in rats, who were subsequently administered various doses of CBD. Withdrawal was precipitated with naloxone. During withdrawal, the dose of naloxone required to provoke 50% of the mice to jump off of a platform was recorded during the withdrawal, as were defecation and rearing behaviors. CBD was found to inhibit the naloxone withdrawal induced jumping and reduced defecation and rearing behaviors [52] . Furthermore, a randomized, double blind, placebo-controlled study in the systematic review suggested that CBD may even be useful in reducing tobacco addiction. This study determined that in smokers who wanted to quit, those who used a CBD inhaler showed a 40% reduction in the number of cigarettes smoked compared to the placebo group. These results indicate that CBD may be effective helping active smokers reduce the number of cigarettes consumed [53] . Likewise, recent research exploring the use of CBD for drug and alcohol addiction is promising [54,55] . Individuals attempting to end their opioid use are at risk for relapse due to the craving induced by increased stress, anxiety, and impulsivity. The anxiolytic, antidepressant, anti-compulsive, and stress-reducing effects of CBD provide a basis for therapeutic benefit and a potential avenue to reduce the compulsive component of opioid seeking individuals [56,57] . Several studies have examined the effect of CBD on different phases of opioid addiction. One article found that CBD s influence on the intoxication phase of opioid addiction in animals reduces the reward-facilitating effect of morphine [51] . Another study examined the effects of CBD on self-administration and drug-seeking behavior using an experimental rat model. In these experiments, rats were able to self-administer heroin by pressing an active lever resulting in a drug infusion through catheter implantation. Rats who received a single injection of CBD 24 hours prior showed dramatically reduced active lever presses compared to placebo-treated rats. The influence of CBD on heroin-seeking behavior exhibited by the study proposes CBD as a potential treatment strategy to attenuate drug-seeking behavior [58] . Despite the findings in these studies, more research is needed to fully evaluate these relationships. Much of the existing literature suggests that CBD modulates several neuronal circuits involved in addictive processes. If these mechanisms are better understood, it could establish CBD as an effective and beneficial treatment modality for OUD [51] . Safety and Pharmacokinetics of Opioids and CBD Heroin, Morphine, and Fentanyl Heroin and morphine are opioid (mu, delta, and kappa) receptor agonists. Heroin is a semi-synthetic morphine derivative and a powerful opioid analgesic. Heroin can be injected intravenously or intramuscularly, inhaled into the lungs, absorbed intranasally (snorting), or administered and rectally. In order to synthesize heroin, morphine molecules are altered in order to make it more lipophilic than morphine. This molecular alteration allows heroin to pass the blood brain barrier much faster than morphine, resulting in a faster onset of action and a more intense pharmacodynamic effect. Heroin also binds opiate receptors with higher affinity compared to morphine. Heroine has a very short half-life, 1.3-7.8 minutes, and when injected intravenously, blood levels become undetectable after just 10-40 minutes. It is then hydrolyzed into 6-monoacetylmorphine, which is very lipophilic and is thought to have even higher opiate receptor affinity than heroin. Thus, it is considered responsible for all of the acute effects after heroin administration. 6-monoacetylmorphine is then metabolized by various enzymes into morphine, which is then conjugated and excreted in urine and bile [59] . Fentanyl is a man-made opioid that is 50-100 times stronger than morphine. Fentanyl quickly distributes into adipose tissue and is highly protein bound. Its onset of action begins almost immediately with intravenous administration and after 7 8 minutes with intramuscular administration. Fentanyl s half-life ranges from 6-32 hours. Peak effects of the drug are achieved in 5 15 minutes following intravenous injection. Analgesia after IM administration is observed for 1-2 hours. Thus, fentanyl has a faster onset of action but a shorter duration of action than morphine [60] . CBD A 2017 World Health Organization report states that CBD is a naturally occurring cannabinoid found in cannabis plants that can also be produced synthetically. The report explains that CBD is generally well tolerated with a good safety profile, and that there had been no public health-related problems associated with the use of pure CBD since the time of the report. The naturally occurring CBD is a (-)-enantiomer and is the type of CBD receiving a majority of the attention for its potential therapeutic effects. In clinical trials, CBD is generally administered orally as a capsule or dissolved in an oil solution [61,62] . Oral CBD has low bioavailability due to its poor absorption in the gastrointestinal tract and significant first pass metabolism, which causes a varying pharmacokinetic profile [63] . Aerosolized CBD yields a quicker time to peak plasma concentration (5-10 minutes) and has a higher bioavailability compared to oral administration [62] . Similar to THC, CBD is very lipophilic, causing it to preferentially accumulate in adipose tissue [64] . THC and CBD both act on the endocannabinoid system, as discussed earlier. Humans express at least two cannabinoid receptors. First, the CB1 receptor is present in many cell types throughout the body, functioning particularly in the nervous system. Secondly, CB 2 receptors are mainly expressed in immune cells, such as macrophages, B and T-cells, and monocytes. Recent studies have found that CB 2 receptors are often upregulated in non-immune cell types under certain pathological conditions [65] . The exact mechanisms of CBD and THC are not well-known. One study found that CBD demonstrates low affinity at CB 2 receptors but does not directly act on CB1 receptors. There is also evidence suggesting an inhibition of cytochrome p450 enzymes. Effects on the immune system are unclear, with evidence of suppression at high dosages and stimulation at low dosages [66] . However, studies have shown that CBD has several beneficial medical properties, such as anti-inflammatory, antioxidant, antipsychotic, antidepressant, and anti-nausea [61] . Based off of recent updates in the literature, CBD has shown to have a low toxicity [67,68] . Additionally, CBD has no observed effect on embryonic development or hormonal changes. A common concern regarding the use of CBD is its safety profile when taken with other high-potency opioids. One study has found that CBD, when administered concomitantly with fentanyl, was well tolerated with no significant pharmacokinetic changes. Fentanyl did not significantly alter plasma CBD concentrations, and there were no incidents of respiratory depression or cardiovascular compromise [66] . While the need for further research on the effects of CBD is great, there is at least evidence that suggests that the drug could function as an adjunctive treatment to assist patients struggling with OUD and opioid withdrawal, or possibly even as a primary treatment modality. Given the promising evidence that CBD is safe and well-tolerated, it is imperative that additional quality clinical trials be conducted to investigate what role CBD could play in the management of OUD. There is an extremely high level of need for OUD treatment in the U.S., making it critical that any novel therapeutic approaches be evaluated without delay. Legal Analysis The medical applications of cannabis cannot be fully discussed without mentioning the complex legal dimensions surrounding marijuana. While federal regulations pertaining to cannabis have remained steadfast for nearly five decades, state legislation has rapidly evolved over that same period, especially within the past 20 years. As a result, fierce political debate, not medical merits, has dominated the conversation regarding marijuana. In this section, the various legal aspects of medical marijuana in the U.S., including the evolution of federal legislation, the spectrum of state law, federal versus state law, and the influence of public opinion on marijuana legislation, will be discussed. The birth of the federal government s legal history with marijuana dates back to more than a century ago [69] . The passage of the Pure Food and Drug Act of 1906 required all over-the-counter medicines containing cannabis, cocaine, morphine or opium that crossed state lines to list these ingredients on the label. This marked the first law identifying marijuana as a dangerous drug. However, at this time, physicians were still allowed to prescribe marijuana to patients for various ailments. This changed in 1937 when the U.S. legislature passed the Marihuana Tax Act [70] . This statute limited the possession of marijuana to individuals who paid an occupation (medical or industrial) excise tax to utilize the drug, essentially criminalizing marijuana. Subsequently, the 1950s saw the passage of the Boggs Act (1951) and Narcotics Control Act (1956), which included mandatory sentences for drug-related offenses, such as the possession or distribution of marijuana [71] . Under these laws, a first-time offender convicted of marijuana possession faced a minimum sentence of 2-10 years and a fine as much as $20,000 [72] . The current day legal battles regarding marijuana take their roots in the 1970 Uniform Controlled Substances Act, which created five schedules of drugs (Schedule I, II, III, IV, and V), and classified marijuana as a Schedule I drug [73] . In addition to marijuana, other Schedule I drugs include heroin, lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (ecstasy), methaqualone, and peyote. As discussed earlier, the DEA defines Schedule I drugs as substances with no acceptable medicinal use and a high likelihood of abuse [74] . These drugs can only be used in a research setting, and possession of any Schedule I substance is illegal [75] . While the federal government has continued its prohibitory stance on cannabis, state laws vary drastically from prohibition to legal for recreational use. Following the Controlled Substances Act of 1970, the first state to pass legislation contradicting the federal policy was Oregon, which decriminalized the possession of small amounts of marijuana [75] . While several other states passed similar laws over the next decade, the first medical marijuana law was not passed until 1996 when California voted on the Compassion Use Act (Proposition 215), which afforded seriously ill patients the right to use marijuana for medical purposes [76] . Subsequently, 33 other states, the District of Columbia, Puerto Rico, and the U.S. Virgin Islands followed suit and enacted their own medical marijuana laws [77] . In 2012, Colorado became the first state to move beyond medicinal marijuana and legalize marijuana for recreational use [78] . Currently, ten states (Alaska, California, Colorado, Maine, Massachusetts, Michigan, Nevada, Oregon, Vermont, and Washington) and the District of Columbia have legalized both medicinal and decriminalized use of marijuana [14] . With respect to cannabis legislation, state laws have clearly taken steps that challenge federal policy. Consequently, this leads to the logical question about which policy (state or federal) holds more weight and should be followed. This question was first addressed by the Founding Fathers in the Supremacy Clause (Article VI paragraph 2) of the Constitution, which states that federal law supersedes state law [79] . Based on this legal precedence, it seems clear that the federal policy of marijuana illegality should trump conflicting state laws. However, the reality is not black and white. The federal government has jurisdiction over states like Colorado and Maine where the recreational use of marijuana is legal and can assert this authority to penalize individuals breaking federal law, but enforcement poses an issue. First, the resources necessary to apprehend, charge, and prosecute marijuana violations across the country would be vast; and second, with public opinion supporting some form of marijuana legalization, political fallout could be extremely damaging to an individual politician or political party [80] . Furthermore, there are now protections for medical marijuana in place that prevents federal intervention at the state level. New developments within the Trump Administration and Senate have been encouraging for legalization advocates. During his Senate confirmation hearing in January of 2019, AG William Barr vowed not to prosecute marijuana companies in compliance with state law [81] . Moreover, in a written response to questions from senators, AG Barr voiced support for an increased number of legal growers of marijuana for scientific research. AG Barr has also testified that he endorses the Strengthening the Tenth Amendment Through Entrusting States Act (STATES Act), a bipartisan bill aimed at granting states the right to enact the best approach to marijuana legislation within its borders [82,83] . The bill would amend the Controlled Substances Act such that it would no longer apply to any individual adhering to state or tribal marijuana laws [84] . A newly proposed version of this bill has gained significant support among Democrats and Republicans, but no vote in either chamber of Congress has happened yet. Additionally, as of November 2019, the House Judiciary Committee approved a bill that could legalize marijuana use at the federal level, allowing states to have more freedom in creating unique individual laws. The piece of legislature would also remove marijuana from Schedule I of the Controlled Substances Act [85] . We hope this bill will be approved by the House and Senate, and ultimately signed by the president. Beyond the challenges of states passing their own laws, the federal government has also faced legal battles from groups of individuals advocating for an end to the Controlled Substances Act. In July 2017, a group of patients using cannabis for medical reasons and cannabis activists brought a lawsuit for legalization against the federal government, arguing that the Controlled Substances Act violates their constitutional rights [86] . The plaintiffs in the case of Washington, et.al v. Sessions, et.al. [87] contended that current federal law violated the 1 st , 5 th , 9 th , 10 th , and 14 th Amendments because it threatened their rights to travel, engage in commerce, and due process. The five plaintiffs included Jose Belen, an Iraq War veteran with PTSD, Alexis Bortell, a 12-year-old with intractable seizures, Jagger Cotte, a seven-year-old with tremendous pain due to Leigh s Disease, Marvin Washington, a former NFL player and cannabis activist, and the Cannabis Cultural Association, an organization that advocates for minority leaders within the cannabis industry. The lawsuit argued its case for legalization from a collection of constitutional laws and from a plethora of historical examples of medicinal marijuana dating back to thousands of years ago. Judge Hellerstein of the Southern District of New York agreed with the plaintiff s argument that marijuana has medical benefits, but ultimately granted the federal government s motion to dismiss the case by concluding that Congress and the DEA have the right to regulate marijuana by classifying it as a Schedule I drug [88] . In response to numerous petitions requesting the rescheduling of marijuana from a Schedule I drug to a lesser Schedule, the DEA published its reasoning for the denial of these petitions in 2016 [89] . The crux of their rationale was the recommendations of the FDA and Department of Health and Human Services (HHS). Based on the information provided to the DEA by the FDA and HHS, the DEA concluded that marijuana should remain a Schedule I substance for three main reasons: (1) Marijuana has a high potential for abuse; (2) Marijuana has no currently accepted medical use in treatment in the United States; and, (3) Marijuana lacks accepted safety for use under medical supervision [89] . The filing went on to note there are no studies establishing that marijuana is useful in the medical treatment a specific disorder. This position directly contradicts the numerous studies demonstrating the medical benefits of marijuana stated earlier. The DEA also used the FDA s conclusion that there is a lack of consensus among qualified experts, or individuals qualified by scientific training and experience to evaluate the safety and effectiveness of a drug [89] . To support its third and final point for denial of reclassification, the DEA noted that there were no FDA-approved marijuana products. While true in 2016, this has changed recently. In June of 2018, the FDA approved Epidiolex (cannabidiol), a CBD-containing drug, to treat seizures caused by two forms of epilepsy. Epidiolex is the first FDA-approved drug to contain active ingredients from marijuana and is classified as a Schedule V drug under the Controlled Substances Act [90] . As the debate surrounding the legal status of marijuana has evolved, so too has public opinion. For example, a March 2019 Quinnipiac University Poll found that 93% of Americans supported medical marijuana prescribed by a doctor [91] . Support for recreational marijuana is at record highs, with nearly two out of three Americans supporting legalization in recent Gallup and Pew Research polls [93,94] . As more Americans continue to look favorably on marijuana for medical and recreational use, an important distinction must be made: these are two separate issues and should not be conflated. The research on the medical applications of marijuana and marijuana-related products is promising. Nevertheless, the caution shown by the federal government is warranted. The DEA s assertion that marijuana has a high potential for abuse is supported by recent federally funded studies that saw an increased prevalence of marijuana use disorder, particularly among adolescents [95,96] . This is a major concern in the US especially given the current opioid epidemic grappling the nation. This crisis began when pharmaceutical companies assured physicians that opioids (Schedule II drugs) did not have a high addiction potential, and physicians started prescribing at much higher rates [74,97] . However, before increased marijuana usage is viewed as the next opioid epidemic, it is important to highlight key differences between cannabis and opioids. First, opioid abuse is associated with a high risk of overdosing; marijuana has minimal risk of increased mortality [98] . Second, the addiction potential of opioids is great; developing marijuana use disorder is a concern, but the risk is much lower than that from opioids [99] . As discussed earlier, the efficacy of marijuana in the treatment of chronic pain and the decreased opioid use in patients using medical marijuana demonstrate that cannabis is a promising alternative to opioids [100-103] . The FDA now recognizes this fact and supports the investigation of medical marijuana through adequate and well-controlled clinical trials [90] . As long as physicians understand the wide array of benefits and harms associated with marijuana before prescribing, patients can make informed medical decisions. Political momentum and public opinion are moving in a direction that favors not only marijuana for medical usage, but for recreational use as well. The increasing number of states passing laws permitting the use of both decriminalized and medical marijuana necessitates an increase in quality research on marijuana [14] . If this is made possible and current federal restrictions are lifted, medical marijuana has great potential to benefit patients as replacement therapy for OUD. Establishment of a Medical Marijuana Clinic in Philadelphia Opioid Crisis in Philadelphia Philadelphia is one of the cities greatly affected by the opioid epidemic. In May 2014, it was estimated that 50,000 people have overused prescription painkillers and opioids in one year and that there were about 70,000 heroin users in the Philadelphia area [104] . The population of people who inject drugs (PWID) in Philadelphia alone is as high as 26,400 [105] . In 2017, there were 1,217 drug-related deaths documented, 1,074 of which involved the use of opioids [106] . Moreover, drug overdoses were the leading cause of death, killing four times as many people as homicides [107] . Even the AIDS epidemic, at its worse, fell 200 deaths short of the number of drug-overdose related deaths in 2017 [104] . At the epicenter of this epidemic is Kensington, a once bustling working-class neighborhood where immigrants could find affordable housing and stable factory jobs; now, it is one of the East Coast s largest open air drug markets [108] . Originally, the main focal point of the crisis was Kensington, but it has now spread throughout the city where no subpopulation has remained unaffected. With estimates nearing 1,200 lives cut short in 2017, Philadelphia takes its place as the number one major city hardest hit in the United States [109] . One way for individuals with substance use disorder to pursue sobriety is through pharmacotherapies. As of January 2019, the Mayor s Task Force has begun a four-part series of initiatives to combat the opioid crisis which includes prevention and education, treatment, overdose prevention and harm reduction, and involvement of the criminal justice system. One recommendation is to increase the provision of MAT, or medication-assisted treatment [110] . The Department of Behavioral Health and Intellectual Disability Services (DBHIDS) issued three policies in an attempt to increase education, individual choice and availability of MATs [110] . As of December 2018, the total DBHIDS in-network MAT Program capacity was 12,479 slots, 2,906 of which were available [110] . Most of these programs implement opioid maintenance treatments using methadone or Suboxone. However, less than 25% of all individuals affected by substance abuse disorder who quit opioids are able to remain sober without relapsing [111] . Even though these maintenance therapies help lower the amount of heroin used by individuals with substance use disorder, many individuals remain on methadone or Suboxone treatment for months or years. Additionally, approximately 40-60% is expected to relapse at least once within the first year [111] . Thus, these pharmacological therapies are usually unsuccessful for long-term sobriety and are not enough. This section will propose a replacement therapy clinic that integrates standard pharmacological treatments (i.e. methadone, Suboxone) with medicinal cannabis in conjunction with psychological and social avenues that could help individuals in Philadelphia with substance use disorder [112] . Planning Clinic Layout The Medical Marijuana for Opioid Replacement Therapies Clinic (MMORT Clinic) is intentionally designed in a manner that promotes safety, effectiveness, and community worth. This comprehensive treatment center will incorporate Suboxone, methadone, and medical marijuana and will be stationed in the heart of Philadelphia, particularly in Kensington. The general design of the MMORT Clinic will be adapted from Coatesville Comprehensive Treatment Center in Coatesville, PA. A kiosk will be present at the entrance which patients can enter an ID code, which will allow entry into the waiting room. Patients will wait there for a nurse or receptionist to assist them with their prescriptions. Once inside, there will be window bays staffed by a nurse to provide safe administration of the treatment. Beyond the area of drug administration are rooms where the patient can receive treatment and counseling from other members of the overall care team such as psychiatrists, physicians, counselors, and social workers. The clinic will have additional services for the patients as well as several safety features. The clinic s layout must be wheelchair accessible, providing ramps in place of stairs. Next to the care team offices will be a play area for children so they can be supervised while the patients are being seen. The MMORT Clinic will have security checkpoints throughout the facility to ensure its safety. The first entrance will have a basic lock-and-key and metal gate to be secured at night, but open during designated hours. A second door will be placed prior to entry to the bay windows requiring a provided member ID. Once inside the clinic, there will be surveillance in all of the general spaces. Lastly, there will be keypads in each of the private rooms, record rooms, and the drug storage rooms. Only the clinic staff will have the pass codes to these rooms. Staff The MMORT Clinic must be composed of an interdisciplinary treatment team devoted to serving their patients. This team will consist of psychiatrists, physicians, nurses, counselors, social workers, receptionists, and security guards. Psychiatrists provide the initial evaluation of the patient, gauging the amount of medical, psychological, and social needs of the patient. Physicians provide wound care and address any major health concerns for the patient. A psychological counselor provides sessions to address the patient s mental health needs. The nurse provides the drug regimen for patients and any immediate needs of the patient. The social worker assists with the familial, communal, and economical dimensions of the patient. Each member of this unit will work together cohesively to develop a safe, efficient, and effective environment and care plan for the patient. Types of Treatment The MMORT Clinic would offer a holistic treatment approach to best care for its patients, which would include wound care, psychopharmacological treatment, and psychological counseling. Wound care Chronic repeated injections of IV drugs can lead to venous sclerosis, in which the vein is no longer patent and a viable route to administer the drugs [113] . Individuals typically resort to intramuscular and subcutaneous methods of using opioids. Compounded with the effects of opioids, wounds and lacerations can be inflicted from improper technique [113] . As a result, comorbid conditions can arise via the use of needles such as necrotizing fasciitis, wound botulism, gas gangrene, and tetanus. Additionally, a high prevalence of sharing needles has led to an increase in spread of HIV, Hepatitis B, Hepatitis C, and tuberculosis in this population [113] . Therefore, the MMORT Clinic would have wound care service staff alongside healthcare personnel to provide immediate care for the wounds at the site to minimize the spread and progression of secondary infections. Psychopharmacology The psychopharmacological approach at the clinic seeks to create a collaborative effort between the healthcare staff and the patients. Psychopharmacology incorporates the use of medications and psychology to monitor the pharmacokinetics and pharmacodynamics of the drugs that impact an individual and their mental health. Psychopharmacology plays a crucial role in the detoxification and minimizing withdrawal symptoms that individual s experience. The focus is to eliminate the effects of opioids in a safe and effective manner. Here, physicians will work with the patients to create a treatment regimen that consists of opioid agonists or antagonists with medical marijuana. The aim for this combination is to wean patients off of opiates initially with the use of methadone or Suboxone. The methadone or Suboxone would be paired with medical marijuana until patients would eventually be transitioned to non-steroidal anti-inflammatory drugs (NSAIDS) for pain management. Psychological Counseling There is a high prevalence of mental illness among patients with substance abuse issues. Studies indicate that of the individuals with substance use disorder, 28% had co-occurring anxiety disorders, 26% had mood disorders, 18% had antisocial personality disorder, and 7% suffered from schizophrenia [114] . Individuals with mood disorders are more susceptible to succumb to drug abuse and addiction due to underlying brain deficits, genetic disposition, and/or early exposure to stress or trauma [115] . Furthermore, social determinants of health, socioeconomic factors, and the physical environment can have a strong impact on a patient s mental health. The NIDA states that stress is the leading cause of relapse while in recovery [116] . However, mental illness and substance abuse are treated separately as opposed to a dual-diagnosis program in the U.S. In 2016, only 6.9% of adults were treated for both mental illness and substance abuse [114] . Therefore the implementation of psychological counseling is pertinent in order to address the co-morbid conditions of mental illness and substance use disorder. Psychological counseling will consist of individual and group therapies as well as cognitive-behavioral therapy and dialectical-behavior therapy to address the harmful beliefs and maladaptive behaviors to reduce harmful behaviors and drug abuse. The psychological counselors will also work closely with social work to address the background of the individual in recovery to help mitigate stress. Phases of Treatment Initial assessment If no immediate wound care is needed, individuals would be examined for history of abuse, and patterns of consumption. Triggers and the patient s attitude towards abstinence and motivation for change will also be evaluated. After assessment, the patient and the team can develop a plan consisting of detoxification and a pharmacological regimen. Psychological co-morbities and socioeconomic factors would also be considered. It is also important to offer or establish a support group and community network in which that the patient feels comfortable during and even after treatment. Detoxification and maintenance Although opioid detoxification is a crucial first step in the recovery process, it alone is not sufficient to free a dependent person from addiction. However, the detoxification process is vital for the complete rehabilitation and ultimately abstinence. The detoxification process, for our purposes, will serve as bridge between overcoming withdrawal and beginning replacement therapy. As discussed earlier, the symptoms experienced from opioid withdrawal can be severe and quick acting. Therefore, the best method of action to cope with these symptoms are to enroll in inpatient treatment programs that can closely monitor the individual s vitals as they progress through the pharmacological and psychological treatment plans. Preventative care and support Preventative care plays an essential role in addiction recovery, providing information and counseling on addiction and the recovery process. For recovering individuals, the program seeks to address their individual needs physically, mentally, and emotionally. It helps patients understand the intricacies of opioid addiction and provide a regimented plan to taper them from the dependency of substances using psychopharmacology. For the family and/or support group, it enhances the understanding of the disease concept, dependency, and the effect on relationships. The support counseling also addresses the implications behind their role as caregivers and allows the unit to seek advice in order to give proper support. The aim of preventative care is to 1) keep individuals from relapsing, 2) provide information and counseling on the overall impact of addiction and the psychopharmacology that the clinic provides, 3) establish concrete goals of care, 4) open the dialogue between parties, and 5) strengthen both individuals and their supportsystems. After interacting with individuals alone and within support groups, counselors will assess and provide realistic short and long-term goals so that the patient can achieve his or her desired quality of life. Rehabilitation and integration Other determinants that affect the overall health of patients and their propensity for drug use are low socioeconomic status, low income, lack of education, unemployment, inaccessibility to resources, community disorder, etc. [117] . According to recent studies, 75% of homeless patients were also suffering from substance abuse. Furthermore, those homeless individuals were nine times more likely to overdose than those who had a form of stable housing [118] . The opioid Crisis Response Act of 2018 not only aims to expand access to rehabilitation and recovery centers, but also pushes for Medicaid-funded housing for those suffering from substance abuse [119] . While this is a step in the right direction, more can be done. This clinic will help serve as a resource for individuals to be informed on housing opportunities at shelters or programs that specifically house people with substance abuse disorder. The MMORT Clinic will partner with programs such as Project HOME to help these individuals in getting back on their feet by providing affordable and safe housing, education, employment opportunities, the option to rebuild resumes and practice interview skills, and the support they need to recover. Social work can also assist with the reintegration of individuals back into society through both community service and providing resources to help assist in their milieus. Additionally, it is important to connect individuals with safe housing and vocational supports to facilitate healthy and positive outcomes. The focus of these rehabilitation and integration options is to work closely with patients in order to keep them in recovery and lay a solid foundation so that they can achieve positive outcomes and qualities of life. Additional Services Hepatitis-C Screenings Hepatitis C virus infections are one of the most commonly acquired blood-borne diseases among IV drug users. In Philadelphia, it is estimated that between 20,000 and 45,000 of residents are living with hepatitis. In 2018, 928 new cases were documented, 60% of which reported IV drug use [120] . Prolonged exposure to the virus can lead to fatigue, fever, jaundice, muscle aches, and liver cirrhosis [121] . Treatment for symptomatic chronic hepatitis entails a relatively new 12-week antiviral regiment that ranges from $63,000 to $94,500 per person [122] . Therefore, the clinic will offer Hepatitis C screenings as proactive measure andencourage patients to seek treatment early to minimize costs for both the patient and the healthcare system. HIV Screenings HIV (human immunodeficiency virus) is another virus that can be spread through sharing needles and unsafe injections. In Philadelphia, the rate of newly acquired HIV infection is five times the national average [123] . HIV infects the body s CD 4 + T cells which help the immune system fight infections. If left untreated, the reduction of CD 4 cells leaves the body defenseless and susceptible to secondary infection or cancers that can lead to acquired immune deficiency syndrome (AIDS) [124] . No effective cure for HIV currently exists, but there are treatment plans that reduce the HIV viral load. PWID have a tendency to seek emergency medical attention once the symptoms have progressed to later stages, putting a substantial burden on healthcare systems. Additionally, according to the CDC, the cost for one treatment over a lifetime for an HIV infection is estimated at $379,668 per individual [125,126] . One article compared the lifetime cost of patients infected with HIV at age 35 (antiretroviral medications and other treatments) to that of non-infected individuals who are at high risk for infection. It was estimated that approximately $229,800 is saved by avoiding one HIV infection, which highlights the significance of HIV prevention [127] . Therefore, offering HIV screenings in addition to Hepatitis C screenings would be beneficial for both PWIDs and healthcare systems in reducing healthcare costs. Recovery/Support Groups Clinics will offer support groups for those seeking further help. The clinic will provide various options for recovery groups, including but not limited to community, outpatient, inpatient and sober living community programs [128] . These sessions, if applicable, will be held directly at the facility. If a patient is seeking a more permanent home-style facility, the clinic will connect the individual with options that satisfy their needs. If patients choose to utilize a community recovery group outside of the clinic, various locations and times of the meetings will be provided. It is important to remember that it is only up to the individual to get the help they want. Recovery group meetings held at the clinic or a facility nearby will have a tight, regulated schedule. There will be multiple group meetings throughout the week at varying times to give options to those with different schedule conflicts. Trained leaders will direct the sessions and reward members with recovery chips as they achieve milestones in their sobriety. Members involved with the program will be appointed a sponsor to act like a guide in the recovery process. Any individual that does not participate in a recovery program provided by the clinic will have to abide by any procedures and processes set forth by that facility. Childcare and Youth Education A safe space will be provided for children while their parents are receiving counseling or administering their dosage. This space will be secluded from the waiting room and will include a childcare specialist to watch over the area and activities to keep children occupied (puzzles toys, books, movies, etc.). The clinics will also partner with various universities to offer responsible student volunteers the opportunity to babysit, assist the children with schoolwork, and provide general company. Furthermore, the...