Medical Marijuana and Cannabinoid Use Nursing CE Course for APRNs

, 2023). There are no marijuana access laws currently in Idaho, Nebraska, and Kansas. The Agriculture Improvement Act of 2018, otherwise called the 2018 Farm Bill, removed hemp from the federal controlled substance act, which means that cannabis plants and derivatives that contain no more than 0.3% of THC on a dry weight basis are no longer controlled substances under federal law (FDA, 2023). Refer to the graphic below from the NCSL website. Cannabis is legal for adult use in Canada and parts of Europe (NCSL, 2023).

Figure 1

State Regulated Cannabis Programs, April 2023

(NCSL, 2023)

FDA Approvals

There are many types of synthetic cannabinoid chemicals that are manufactured and sold, though many are banned as illegal by the federal government in the US. Synthetic or purified cannabinoids act on the same receptors in the brain as endogenous cannabinoids. They can be administered by smoking, vaping through electronic delivery devices (i.e., marijuana pens, e-pens, or vaporizers), or ingested in herbal tea or food. The FDA has only approved three synthetic THC formulations (nabilone [Cesamet], dronabinol [Marinol] capsule, dronabinol [Syndros] oral solution) and one cannabis-derived drug product, cannabidiol (Epidiolex). These products are only available with a prescription from a licensed HCP. Nabilone (Cesamet) is a schedule II capsule currently approved by the FDA to treat nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond to conventional antiemetic treatments. Dronabinol is a schedule III medication available in capsule form (Marinol) and oral solution (Syndros). Both are FDA-approved to treat nausea and vomiting related to chemotherapy after failure to respond to conventional antiemetic treatments and for treating anorexia associated with weight loss in patients with HIV/AIDs. Before prescribing these medications, HCPs are encouraged to assess the patient's risk for abuse or misuse. These agents may induce psychiatric and cognitive effects impairing mental or physical abilities. Those with a history of substance abuse, dependence, or psychiatric history are at heightened risk for abuse, misuse, and adverse effects (FDA, 2020, 2023; NCSL, 2023; Sheikh & Dua, 2023; Smith et al., 2015).

In 2018, the FDA approved cannabidiol (Epidiolex) for treating seizures associated with two severe forms of epilepsy, Lennox-Gastaut syndrome (LGS) and Dravet syndrome, in patients 2 years and older. Both conditions are rare, appear early in life, and can cause difficult-to-control and potentially life-threatening seizures. Cannabidiol (Epidiolex) is the first FDA-approved drug containing a purified substance derived from marijuana. The efficacy of cannabidiol (Epidiolex) was evaluated through three randomized, double-blind, placebo-controlled clinical trials involving 516 patients with either LGS or Dravet syndrome. Within these studies, when cannabidiol (Epidiolex) was taken alongside other medications, it reduced the frequency of seizures compared to a placebo. The most common side effects include sedation, sleepiness, fatigue, weakness, malaise, and lethargy. Less common side effects include elevated liver enzymes, decreased appetite, diarrhea, skin rash, and insomnia. Aside from cannabidiol (Epidiolex), no other FDA-approved drug products contain CBD (FDA, 2020). Outside of the US (Canada and Europe), nabiximols (Sativex) is a purified natural combination that includes equal parts of THC and CBD in an oromucosal spray formulation and is administered for the treatment of pain and spasticity (Schrot & Hubbard, 2016; Turner & Agrawal, 2022).

Medicinal Uses

In 2020, the United Nations (UN) finally recognized the medical value of cannabinoids for treating many different diseases. Since this time, there has been a growing interest in research to establish the effectiveness of cannabinoids for various diseases. Bilbao and Spanagel (2022) conducted a systematic review and meta-analysis of medical cannabinoids for efficacy, retention, and adverse effects to help establish the grade of evidence available to inform policy and clinical decisions. Bilbao and Spanagel (2022) acknowledge that previous reviews were limited in their coverage of various diseases and did not consider that medical cannabinoids account for plant-derived and synthetic derivatives, which differ in their pharmacology. The researchers identified 6308 abstracts, narrowed to 152 randomized controlled trials (RCTs), with 53 evaluating dronabinol (Marinol, Syndros), 35 nabilone (Cesamet), 27 CBD, and 37 nabiximols (Sativex). The researchers found that CBD had a significant therapeutic effect on epilepsy (SMD -0.5 [95% CI -0.62 to -0.38]; high grade) and Parkinsonism (-0.41 [95% CI -0.75 to -0.08]; moderate grade). Moderate evidence was found for dronabinol (Marinol, Syndros) for appetite -0.51 (95% CI -0.87 to -0.15), chronic pain -0.31 (95% CI -0.46 to -0.15), and Tourette -1.01 (95% CI -1.58 to -0.44). In addition, moderate evidence was also found for nabiximols (Sativex) on spasticity -0.36 (95% CI -0.54 to -0.19), sleep -0.24 (95% CI -0.35 to -0.14), chronic pain -0.25 (95% CI -0.37 to -0.14), and substance use disorder (SUD) -0.48 (95% CI -0.92 to -0.04). The remaining studies showing a significant therapeutic effect were grade low, very low, or no grade evidence. Bilbao and Spanagel (2022) concluded that additional research and systematic reviews are needed.

In a 2018 Cochrane systematic review of cannabis-based medicine on neuropathic pain in adults, the researchers found 16 studies with 1,750 patients. Specifically, the researchers wanted to assess the efficacy, tolerability, and safety of cannabis-based medicines (i.e., synthetic, plant-derived, herbal) compared to placebo or conventional drugs for neuropathic pain in adults. The researchers found an increase in the number of patients achieving 50% greater pain relief from the cannabis-based medicine (21%) compared to the placebo (17%). However, the quality of evidence was determined to be low. In addition, Mucke and colleagues (2018) found that more participants withdrew due to adverse events in the cannabis-based medicines versus placebo. They determined that there was insufficient evidence to determine if cannabis-based medicines increase the frequency of serious adverse events. Finally, psychiatric disorders occurred in 17% of participants in the cannabis-based medicines versus 5% in the placebo groups. The researchers concluded that the minor improvements in neuropathic pain might outweigh the potential harm; however, more research is needed (Mucke et al., 2018).

Cannabis use has been studied for numerous symptoms reported by patients diagnosed with Multiple Sclerosis (MS). The American Academy of Neurology reviewed the literature related to patients with MS. It rated the evidence for the use of oral cannabis extract (CBD or combination CBD/THC) in the treatment of patient-reported spasticity, central pain, and painful spasms an "A" (effective). They rated the treatment of the same symptoms with dronabinol (Marinol, Syndros), nabilone (Cesamet), or nabiximols (Sativex) a "B" (probably effective). In the treatment of MS-related bladder frequency, nabiximols (Sativex) treatment also received a rating of "B." Oral cannabis extract was given a "B" rating for probably effective in the treatment of bladder symptoms and tremors in patients with MS. Nabiximols (Sativex) use in the treatment of tremors was given a "C" rating for possibly ineffective, and smoked cannabis was rated a "U" for insufficient evidence (Schrot & Hubbard, 2016). In a separate review of existing literature, 14 studies regarding the use of dronabinol (Marinol, Syndros), nabilone (Cesamet), nabiximols (Sativex), or oral CBD/THC tablets to treat spasticity in 2,280 patients with MS or spinal cord injuries were assessed. These were rated as "moderate" quality and indicated that the cannabinoids tested were associated with more significant improvements in spasticity versus placebo but failed to reach statistical significance (Whiting et al., 2015).

More recently, Filippini and colleagues (2022) conducted a systematic review and meta-analysis to assess the benefit and harm of cannabinoids in reducing symptoms of MS. The researchers found 25 RCTs, with 3763 participants, including 2290 who received cannabinoids. Filippini and colleagues (2022) found that nabiximols (Sativex) probably increase the number of people with perceived reductions in spasticity compared to placebo; moderate quality evidence. In addition, the researchers found that evidence for neuropathic pain associated with MS is very low quality, making it difficult to determine whether there is reduced chronic pain. Despite some of these positive findings, there is currently no evidence that medical cannabis has an overall effect on slowing the progression of MS (Mouhamed et al., 2018).

As previously stated, cannabis and cannabinoid use in treating epilepsy has also been studied, particularly in special populations of pediatric refractory epilepsy syndromes that tend to respond poorly to existing antiepileptic drugs (AEDs). Although there are multiple case reports regarding the use of CBD as an antiepileptic, only a small number of placebo-controlled clinical trials exist. The first, published in 1980 in the Journal of Pharmacology, evaluated 15 patients, 8 of whom received 200 to 300 mg CBD orally daily for 8 to 18 weeks. Four of the eight CBD patients had significant resolution of their seizures, three had a partial resolution, and all tolerated the medication well. Only one placebo patient noted improvement. In this study, three CBD-treated patients had measurable electroencephalographic (EEG) improvements (dos Santos et al., 2015).

The American Academy of Neurology and Cochrane reviews completed in 2014 rated the evidence for cannabis use in treating epilepsy as limited, inconclusive, or insufficient. In 2015, Rosenberg and colleagues evaluated four primary clinical trials to examine the efficacy and safety of CBD in seizures. Two studies showed a partial antiseizure effect with CBD, and 2 showed no statistically significant effect. However, these studies were small, with insufficient blinding or randomization and incomplete data sets. A parent survey of 117 children with intractable seizures reported an 85% perceived reduction in seizures using plant-derived enriched CBD (Schrot & Hubbard, 2016). Mouhamed and colleagues (2018) assessed treatment with THC as too broad for therapeutic purposes. However, they found positive findings when they reviewed five trials published between 2013 and 2018 studying the use of CBD in treating drug-resistant epilepsy in children or young adults (3 of which were referenced above in the section on cannabidiol [Epidiolex]). These studies showed a more significant reduction in the frequency of atonic and partial seizures, followed by reductions in tonic/tonic-clonic seizures, with minimal reports of adverse effects. Of note, these studies did not utilize CBD as a replacement for the subjects' AED but as an adjunct. In contrast, Whiting and colleagues (2015) found studies that reported seizures as a possible adverse effect of cannabinoid treatment. More recent studies have confirmed the effectiveness of cannabidiol (Epidiolex) in children and adults with treatment-resistant epilepsy. In a 2018 study of 607 patients, Szaflarski and colleagues (2018) found that add-on CBD may be efficacious long-term for treatment-resistant epilepsy. In another open-label prospective study of 72 children and 60 adults with treatment-resistant epilepsy, cannabidiol (Epidiolex), researchers found a significant reduction in frequency and severity of seizures at 12 weeks sustained over the 48-week duration of treatment (Szaflarski et al., 2018).

Mouhamed and colleagues (2018) found that studies including patients with PTSD showed consistently decreased frequency of nightmares when treated with nabilone (Cesamet) or 5 mg THC in oil, and several case reports of decreased tic severity and frequency in TS when given CBD/THC daily. The American Academy of Neurology review in 2014 assessed oral cannabis extracts such as dronabinol (Marinol, Syndros) and nabilone (Cesamet) as "probably ineffective" for the treatment of Parkinson's disease and tremors, and nabiximols (Sativex) as "possibly ineffective" for tremors. They found insufficient evidence supporting the use of cannabinoids in TS, cervical dystonia, and Huntington's disease. Whiting and colleagues (2015) identified positive but low-quality evidence for using THC capsules in TS. The 2013-2014 Cochrane review found limited/inconclusive evidence for the use of cannabinoids in the treatment of schizophrenia or cannabis use disorder.

Schrot and Hubbard (2016) identified a systematic review from 2015 using plant-derived CBD in the treatment of psychosis that showed "potential" as an antipsychotic but suggested a large randomized clinical trial to support regular clinical use. Whiting and colleagues (2015) identified only low-quality evidence showing no benefit for the use of CBD in psychosis treatment. When the current published evidence was assessed by Mouhamed and colleagues (2018), they concluded that CBD increased quality of life (QOL) scores in patients with Parkinson's and may help treat schizophrenia. However, THC increases symptoms of psychosis. Similarly, a 2015 systematic review of cannabinoids in treating substance abuse/addiction showed "potential" (Schrot & Hubbard, 2016). Due to its therapeutic effects on mood, anxiety, sleep, and pain, CBD has been established as "potentially beneficial" in treating SUD and addiction (Hurd et al., 2015). Whiting and colleagues (2015) identified positive but low-quality evidence for the use of nabilone (Cesamet) or nabiximols (Sativex) in sleep disorders. What they deemed as very low-quality evidence suggested no benefit from using nabiximols (Sativex) in treating depression (Whiting et al., 2015). Unfortunately, Mouhamed and colleagues (2018) found "mixed results" regarding cannabinoids in treating SUD. When considering cannabinoids in the treatment plan for neurological disorders, it is essential to remember that nearly all of the studies reviewed list anxiety, dysphoria, psychosis, hallucinations, paranoia, and possible perceptual changes as potential adverse effects of cannabinoid products that contain THC (Mouhamed et al., 2018).

The use of cannabinoids in cancer patients has been moderately successful when used to treat cancer-related pain; however, studies have used smoked THC and nabiximols (Sativex) only, neither of which are currently FDA-approved. Otherwise, despite FDA approval for this indication, there remains low-quality evidence that dronabinol (Marinol, Syndros) is effective for nausea and vomiting related to chemotherapy agents (Whiting et al., 2015). The National Cancer Institute (NCI) reports a beneficial effect of the cannabinoids dronabinol (Marinol, Syndros) and nabilone (Cesamet) when used for nausea and vomiting related to chemotherapy but found inconclusive evidence on the use of smoked/inhaled cannabis for chemotherapy-related nausea and vomiting (NCI, 2022). According to the American Cancer Society (ACS), there is potential evidence based on in vitro studies that THC and CBD can slow growth and even cause cell death in specific cancer cells. In preclinical trials, cannabinoids reduced the spread of some forms of cancers. While early clinical trials of cannabinoid use in cancer patients indicate it is safe, they have not established its effectiveness in curing or helping to control the disease (ACS, 2022). A study conducted in Israel assessed the potential effect of THC and CBD in neuroblastoma, the most common extracranial solid tumor in pediatric patients. The in vitro portion of the study indicated that both THC and CBD had antitumor activity, reducing the viability and invasiveness of the tumor cells and, in some cases inducing apoptosis. CBD was the more effective of the two compounds. In the in vivo portion of their study, neuroblastoma tumors were induced in non-obese diabetic immunodeficient mice. The mice were treated for 14 days with either THC, CBD, or pure ethanol (control) or were untreated. CBD slowed the growth of the tumors, as did THC, but to a lesser degree. While the exact mechanisms for how these drugs produced the observed effects are yet to be fully understood, the authors understandably suggested more extensive, in-depth studies in the future to explore this potential further (Fisher et al., 2016).

Due to CB1 receptors in the GI tract, specific GI effects have been credited to and therapeutically tested in cannabinoids, such as nausea and vomiting. Four studies were reviewed for appetite stimulation and weight gain, included 255 participants, and compared dronabinol (Marinol, Syndros) with a placebo, megestrol acetate (Megace), and one study compared cannabis. The trials all showed improved weight gain with dronabinol (Marinol, Syndros) or cannabis versus placebo, but the study comparing megestrol acetate (Megace) found less weight gain with dronabinol (Marinol, Syndros). Combining dronabinol (Marinol, Syndros) with megestrol acetate (Megace) did not seem to have an additive benefit (Whiting et al., 2015). Further, megestrol acetate (Megace) is a synthetic progesterone associated with an increased risk for blood clots and cardiac infarction, making it a riskier adjunctive medication in the oncologic setting (OncoLink, 2021). According to Mohammed and colleagues (2018), cannabinoid products performed at least as well and sometimes better than ondansetron (Zofran) but had higher rates of adverse effects. Two trials evaluated THC in postoperative nausea and vomiting and found no significant difference compared to the placebo, and unacceptable adverse effects were reported. In patients diagnosed with inflammatory bowel disease (IBD), self-medicating users reported decreased abdominal pain, nausea, diarrhea, joint pain, and increased appetite with cannabis use. However, there is a lack of reliable clinical evidence as these are the results of self-report observations and are not premised on data compiled from clinical trials. The use of cannabis in IBD patients also correlated to higher rates of surgical procedures, leading the authors to question if the cannabis could be masking disease activity and progression (Mouhamed et al., 2018).

 

Adverse Effects and Patient Counseling

Potential adverse effects of cannabinoids vary greatly depending on the composition of the individual product being evaluated. In epilepsy studies, adverse effects of CBD were reported as fatigue/somnolence, diarrhea, and decreased appetite, while cannabis and THC cause nausea, dizziness, weakness, behavioral/mood changes, hallucinations, suicidal ideations, fatigue, and feelings of intoxication (Rosenberg et al., 2015). In addition to the effects listed above, Schrot and Hubbard (2016) also list anxiety, dysphoria, psychosis, impairment of memory, coordination, judgment, attention and/or perception, tachycardia, hypertension, increased cardiac output, redness of the conjunctiva, increased appetite, dryness of mouth, and increased risk of being involved in a motor vehicle accident as potential acute adverse effects of THC/cannabis. Chronic use also carries the risk for memory and cognitive deficits, psychosis, respiratory and immune system effects that increase the risk for infections, airway inflammation and bronchitis, social dysfunction, difficulty in school for adolescents, decreased job performance, increased unemployment, decreased income levels, and decreased satisfaction with life. While the addiction potential is lower for cannabis than other illicit substances, there does exist a roughly 9% risk for physical/psychological addiction in adults. A 2007 Lancet study ranking controlled substances for a "mean harm score" ranked cannabis #11 out of 20 (Schrot & Hubbard, 2016). A 2015 meta-analysis in JAMA reviewed acute adverse effects published in 62 studies and corroborated the effects mentioned above, as well as reports of euphoria, paranoia, and seizures (Whiting et al., 2015). According to multiple large studies, there does not appear to exist a clear epidemiological link between marijuana and lung cancer, such as with tobacco users. It remains inconclusive and a topic for further exploration, as "heavy use" of cannabis (more than 50 times in a lifetime) may carry some increased risk of testicular, prostate, or squamous cell carcinomas (NCI, 2022).

As with any treatment plan in medicine, especially one that may include a medication that carries the risk of adverse effects, full disclosure of risks to the patient, extensive counseling, and screening is vital to upholding safety and ensuring positive outcomes. Addiction risk factors include genetic inheritance (at least 50%) and comorbid psychiatric disorders. In adolescents, risk factors include peer usage and academic difficulties in school (Schrot & Hubbard, 2016). When considering whether cannabinoid treatment is appropriate for a particular patient, the patient characteristics listed in Table 1 should be considered.

Table 1

Criteria to Consider when Certifying Cannabinoid Use

state regulations presence of a qualifying condition interaction with other medications age (extreme caution with patients under 18) severity/nature of the disorder ("debilitating or terminal condition") prior or current psychiatric or SUD (including a personal or family history of psychosis or cannabis use disorder) failure of standard medical therapies and/or approved cannabinoid products (dronabinol [Marinol, Syndros]/nabilone [Cesamet]) underlying cardiac and pulmonary disease agreement to regular follow-up visits acceptance of detailed explanation of risks, both physical and legal

(Buppert, & Klein, 2021; Schrot & Hubbard, 2016)

Regarding counseling patients within states that allow the recreational use of cannabis for adults, the American Journal of Public Health developed some evidence-based recommendations for safe cannabis use. These are identified as the Lower-Risk Cannabis Use Guidelines (LRCUG) and could be utilized by HCPs as a framework for counseling patients who elect to use cannabis recreationally. Their ten recommendations are listed in Table 2; these guidelines are intended to reduce the overall risk of adverse effects from cannabis use. However, they are not a guarantee against adverse effects in any particular patient and instead strive to inform patients who may be willing to modify their use to reduce some of the health risks (Fischer et al., 2017).

Table 2

Ten Major Recommendations for Counseling Patients on Cannabis 

abstinence is the safest option avoid early age of onset (before age 16) choose low-potency THC products or those balanced in CBD/THC composition abstain from using synthetic cannabinoids choose nonsmoking methods/avoid cannabis inhalation avoid deep inhalation avoid high-frequency use (daily or near-daily) refrain from driving while using cannabis products high-risk populations should avoid use altogether (personal or family history of psychosis or SUD, pregnant individuals) avoid combining aforementioned high-risk behaviors (such as early age of onset and driving)

 (Fischer et al., 2017)

HCPs should also be aware that CBD can interact with many medications. CBD is metabolized by the cytochrome p450 (CYP) enzymes CYP3A4 and CYP2C19; coadministration with other medications metabolized or inhibited by CYP3A4 or CYP2C19 can increase or decrease the effectiveness of the medication or the CBD (Shane-McWhorter, 2023). CBD may increase the concentration and effects of the following medications:

• antiseizure medications (e.g., clobazam [Sympazan], topiramate [Topamax], carbamazepine [Tegretol], brivaracetam [Briviact])
• immunosuppressants (e.g., cyclosporin [Neoral], tacrolimus [Prograf])
• tricyclic antidepressants
• proton pump inhibitors (e.g., omeprazole [Prilosec])
• nicotine
• lithium (Lithobid)
• anticoagulants (e.g., warfarin [Coumadin])
• methadone (Dolophine)
• levothyroxine (Synthroid)
• ketamine (Ketalar; Shane-McWhorter, 2023)

CBD can also cause drowsiness, so caution should be taken if the patient takes other sedatives (e.g., benzodiazepines, alcohol, opioids). Since CBD can cause liver injury, caution should be taken when combined with other hepatotoxic medications, such as acetaminophen (Tylenol) or valproic acid (Depakene, Depacon; Shane-McWhorter, 2023).

Prescriptive Authority

To qualify for a medical use cannabis license, patients must have an authorized HCP to certify that they have a qualifying condition and obtain their license from the state. Medical cannabis patient registries have been devised to monitor these patients as an added layer of regulation; however, the programs are governed by each state, and there is tremendous variation between programs. For instance, California collects minimal or no data in voluntary registries, whereas states like Arizona collect and publish detailed reports. There is also a significant variability between what designates a qualifying patient condition and an authorized prescriber, as these are additionally subjected to state regulations (Boehnke et al., 2019). Currently, 17 states and Washington DC permit APRNs as providers to certify a patient with a qualifying medical condition to use medical marijuana. According to Act 21-565, Medical Marijuana Omnibus Amendment Act of 2016, this does not confer prescriptive authority, as marijuana is listed as a Schedule I controlled substance by the DEA. Instead, designated APRNs in these states have the authority to recommend the use of this substance as described by each state's law (Haney, 2023). Each state has a list of qualifying medical diagnoses to certify the use of medical marijuana. A few of the most common qualifying conditions are listed in Table 3. However, this list is not comprehensive, and HCPs are encouraged to refer to individual state policies for an accurate list of qualifying diagnoses in the designated state of interest (Buppert & Klein, 2021; Leafly, 2023).

Table 3

Common Qualifying Medical Conditions for Medical Marijuana Use

Cancer Cachexia Glaucoma HIV/AIDS Hepatitis C Amyotrophic lateral sclerosis/Lou Gehrig's disease Parkinson's disease Crohn's disease PTSD Seizures/epilepsy

 (Leafly, 2023)

The American Nurses Association (ANA) has openly supported the use of medical marijuana since 1996. In a 2021 reaffirmed position statement, the ANA supports reviewing and reclassifying marijuana's status Schedule I drug under federal law to facilitate urgently needed research regarding the efficacy of marijuana and related cannabinoids. Federal regulations impede the necessary research to determine the therapeutic benefits of marijuana and related cannabinoids for disease-related symptoms and side effects. The ANA position statement does not extend to the current debate about legalizing marijuana for recreational purposes (ANA, 2021). In their position statement, the ANA emphasizes support for the following:

• "Scientific review of marijuana's status as a federal Schedule I controlled substance and relisting marijuana as a federal Schedule II controlled substance for purposes of facilitating research;
• Development of prescribing standards that includes indications for use, specific dose, route, the expected effect, and possible side effects, as well as indications for stopping a medication;
• Establishing evidence-based standards for the use of marijuana and related cannabinoids;
• Protection from criminal or civil penalties for patients using therapeutic marijuana and related cannabinoids as permitted under state laws;
• Exemption from criminal prosecution, civil liability, or professional sanctioning, such as loss of licensure or credentialing, for health care practitioners who discuss treatment alternatives concerning marijuana or who prescribe, dispense, or administer marijuana in accordance with professional standards and state laws." (ANA, 2016, p. 1-2).

Future Research

Regarding the future of cannabis and cannabinoid use in healthcare, many researchers feel that the future of cannabis in healthcare is not likely with cannabis as a whole but instead in distilling and purifying the most therapeutic components to ensure a reliable, pure, and consistent product that can stand up to the strict standards put forth by the FDA. This may include products containing CBD that may function as antipsychotics, antiepileptics, or treatments for addiction. Other suggestions for future research include a CB1 antagonist for obesity or addiction treatment, a synthetic CB2 agonist as an anti-inflammatory in the treatment of scleroderma, or a mixture of cannabinoids for the treatment of diabetes or metabolic syndrome. Alternatives for pain medications could also explore drugs that inhibit the enzymatic degradation of the endogenous receptor agonists anandamide or 2-AG (Schrot & Hubbard, 2016; Shane-Whorter, 2023). More extensive randomized clinical trials are suggested on the use of cannabinoids for weight gain in HIV/AIDs patients, depression, sleep disorders, anxiety disorders, psychosis, glaucoma, and TS. Between 50% to 99% of the study participants were European American/white, and thus future research should also aim to broaden our understanding of any potential variability in effect amongst different races. The consensus amongst the medical community is that the use of cannabinoids and the manipulation of the endocannabinoid system holds immense medical potential. However, at the current time, additional research is needed to confirm with whom and how this should be done for optimal benefit and minimal risk (National Institute of Health [NIH], 2020; Whiting et al., 2015).

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