Continuing Education

Cannabidiol (CBD) Oil

Authors:

Brandon Hester, Pharm.D. Harrison School of Pharmacy, Auburn University

Matthew Holt, Pharm.D. Harrison School of Pharmacy, Auburn University

Ricarrdo Spencer, Pharm.D. Harrison School of Pharmacy, Auburn University

Corresponding Author:

Wesley Lindsey, Pharm.D.

Associate Clinical Professor

Drug Information and Learning Resource Center

Harrison School of Pharmacy, Auburn University

Universal Activity #: 0178-0000-19-101-H01-P | 1.25 contact hours (.125 CEUs)

Initial Release Date: November 1, 2019 | Expires: April 1, 2022

Alabama Pharmacy Association | 334.271.4222 | www.aparx.org | apa@aparx.org

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Objectives

• Recognize the origin, effects, and usage of cannabidiol (CBD) oil

• Identify federal and state laws governing the use of CBD oil

• Recognize the pharmacokinetics of cannabidiol.

• Discuss the effectiveness of cannabidiol in seizure disorders.

Introduction The Cannabis sativa plant has been evaluated for its use in treating various diseases and disorders, including seizure disorder, anxiety, schizophrenia/psychosis, pain management, and more. A significant barrier to further studies and treatment in these disease states is the altered sensory and time perception (the “high” feeling) provided by the delta-9 tetrahydrocannabinol (delta-9-THC) component of the cannabis sativa plant and extracts.1 This component limits potential wider adoption by

patients and medical professionals because, for example, employers may test current or prospective workers for delta-9-THC in their hair, nails, or urine, with positive findings potentially resulting in suspension, termination, or not being hired.1 Further, federal regulatory restrictions (as well as several states) prohibit possession or transportation of delta-9-THC–containing products across state lines, even for legitimate medical purposes.2,3 Though delta-9 THC produces the “high” feeling and is the most prevalent bioactive constituent of the Cannabis sativa plant, the second most prevalent compound, cannabidiol (CBD), does not convert to delta-9-THC in the human body and therefore does not produce the high feeling as a result.2 Studies performed in vitro, animals, and in humans have suggested various mechanisms of actions of CBD and how it may be directly or indirectly related to the body’s endocannabinoid system. These actions and effects are detailed in Table 1.

Table 1. CBD Receptor Actions and Mediated Effect3

Receptor Impact Potential Pharmacologic Outcome

CB1* Direct antagonism and negative allosteric modulator antagonism

Reduction of impaired learning, memory, hypothermic and psychosis effects

induced by delta-9-THC

CB2* Antagonist and inverse agent Anti-inflammatory effects

GPR55 Antagonist Anti-cancer effects

5HT1-alpha Agonist Pain relief, and antianxiety effects

TPVR-I* Agonist Anti-inflammatory, pain relief, and sebum producing effects

Adenosine A2A Enhanced adenosine concentrations Anti-inflammatory effects CB1=cannabinoid receptor 1; CB2=cannabinoid receptor 2; GPR55=G-coupled protein receptor; 5HT1-alpha=serotonin 1a receptor, TPVR-1=transient receptor potential vanilloid receptor. *CBD increases anandamide concentration, an endogenous CB1, CB2, and TPVR-1 agonist. Adapted from A Review of Human Studies Assessing Cannabidiol's (CBD) Therapeutic Actions and Potential. J Clin Pharmacol. 2019

With the increase in media coverage in recent years on the health benefits of CBD products, many health professionals may be interested in using it as a potentially new or alternative therapy for patients. This could especially be useful when traditional options have failed to adequately treat or control symptoms, or even as an alternative to medical marijuana that

patients may be seeking. Further, this is another topic of interest among healthcare professionals since patients will increasingly ask about the benefits and risks of CBD products, their effects, pharmacokinetics, and potential drug interaction with current medication regimen.

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Legality of CBD Extracts of the Cannabis sativa plant have historically been listed as Schedule I drugs, meaning they have high risk of abuse or harm, have limited or no medicinal value, and they are illegal to possess: however; the Food and Drug Administration (FDA) approved the first CBD product in 2018, Epidiolex® (cannabidiol) for Lennox-Gastaut and Dravet syndrome.4,5 The Drug Enforcement Administration (DEA) subsequently placed Epidiolex® on the list of Schedule V drugs (drugs with a relatively low risk of abuse), making this the first Cannabis sativa-derived product to achieve this status.4,5 The rescheduling was also done in part because Epidiolex® contains less than 0.1% delta-9-THC. In addition to FDA approval for treating the desired disease state, CBD products seeking rescheduling by the DEA must also contain less than 0.1% delta-9-THC. The Rohrabacher-Farr amendment, which has been in force since 2014 but needs periodical renewal in the US Congress, bars the Department of Justice from spending any funds to keep states from implementing their own laws about “the use, distribution, possession or cultivation of medical marijuana.”6 As such, Alabama has instituted its own laws for CBD products and their uses: Carly’s Law and Leni’s Law. Carly’s Law, passed in 2014, aimed to protect people with a debilitating epileptic condition who have a prescription for CBD authorized by the University of Alabama at Birmingham (UAB) Department of Neurology. Under this law, parents and caretakers of children and people with the epileptic condition could not be prosecuted for CBD possession so long as they had a prescription authorized by the UAB Department of Neurology. Leni’s Law, passed in 2016, expanded the protections against prosecution provided by Carly’s Law to include those who are being treated for a chronic or debilitating condition that causes seizures. Under both laws, the CBD product must have been tested by an independent third-party laboratory, parents and guardians of children with debilitating epileptic conditions are also

protected, and the CBD product can only contain up to 3% of delta-9-THC.7,8 UPDATE: Alabama Governor Kay Ivey signed Senate Bill 225 on June 10th, 2019 which allows Alabama pharmacies to sell CBD products if they are labeled to contain no more than 0.3% THC in dry weight. Quality Control A major concern with CBD products is accuracy of labeling of delta-9-THC. It is impossible to know the exact formulation of CBD a patient is taking if they purchase products that are not FDA approved or independently tested by outside laboratories. For example, the FDA-approved CBD product Epidiolex® provides the concentration of CBD specified on the label with little variation over time. Because most of the CBD products that are currently available are not subject to mandatory FDA or third-party testing for approval, this consistent concentration over time may not occur with other products. Several experiments have been conducted to assess consistency and accuracy of CBD product labeling. In 2016, FDA investigators purchased 84 non–FDA-approved CBD products from 31 different companies over the Internet and tested them in triplicate using high-performance liquid chromatography in a commercial laboratory.9 Triplicate test results were averaged and reported by product weight. The average labeled CBD concentration was 15 mg/dL with an overall range between 1.33 to 800 mg/dL in the tested products.9 If the average detected concentration was 90% to 110% of the labeled value, it was considered accurately labeled. With respect to CBD, only 31% (95% confidence interval [CI], 22% to 41%) were classified as labeled accurately, with 43% (95% CI, 33% to 54%) of products under-labeled and 26% (95%CI, 18% to 36%) over-labeled for CBD content. The accuracy of labeling also varied between product types. The frequency of accurate labeling for CBD vaporization liquids, tinctures, and oils was 12.5%, 25%, and 45%, respectively. Products contained unlabeled delta-9-THC at a mean concentration of 0.45

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mg/mL (range 0 to 6.4mg/dL) in 21% of samples.9 This is significant because inhaled doses of 2 to 3 mg and ingested doses of 5 to 20 mg of delta-9-THC can provoke adverse effects and the “high” feeling.10 Whether there was variance within the same product from batch to batch is not known. In addition to the FDA investigators, independent testing company ConsumerLabs has also assessed 19 different CBD products for consistency and accuracy of CBD content.11 Two of the products they tested had less CBD than was labeled, while one of the products had a significantly higher level of CBD compared to the product labeling. They even found that the cost of the products varied widely; 10 mg of CBD ranged from $0.80 to $4.50.11

There are several potential implications of inaccurately labeled CBD concentrations or variability in CBD concentrations in products over time. Similarly to how a consistent concentration of available drug is necessary for therapeutic effect, a variable CBD concentration can also lead to undesirable outcomes. For example, in a systematic review of non-CBD antiepileptic drugs, the University of Connecticut Evidence-Based Practice Center found that seizure control was impacted by small changes in drug concentration.12 While brand and generic antiepileptic drugs were equally efficacious when started de novo, switching from a brand to a generic or vice versa increased the risk of emergency medical services or hospitalization.12 This suggests that using CBD products for seizure control with differing CBD content or products with variable CBD concentrations over time can be dangerous to patients. It is also speculated that non–FDA-approved CBD products sold in the United States could contain enough delta-9-THC to place the seller or possessor at risk of criminal prosecution under marijuana laws, even if the label does not indicate that delta-9-THC is a component of the product.9 It is a very real possibility that patients and people who claim to use CBD-only products may fail drug tests for delta-9-THC if these products are sourced from outside of the

United States due to varying purity standards. There are reports of people who failed drug tests for delta-9-THC while taking products labeled “CBD-only”.13,14 Another risk of non–FDA-approved CBD products is adulteration and contamination. The International Cannabis and Cannabinoid Institute in the Czech Republic assessed 29 CBD products and found that 69% of them exceeded recommended levels of polycyclic aromatic hydrocarbons, which are class IIa carcinogens and genotoxic mutagens according to the International Agency for Research on Cancer.15,16 Additionally, there is a possibility of pesticide or heavy metal contamination in unregulated CBD products.15 Pharmacokinetics/Drug Interactions CBD Epidiolex® (100mg/ml, 100ml bottle) is highly lipophilic with a large volume of distribution of 20,963 to 42,849 L and a half-life of 56 to 61 hours. Meals high in fat increases exposure by a factor of 5 and measured Cmax by a factor of 4. This has led to concerns regarding whether cannabidiol should be given on an empty stomach, but currently no recommendation exists.3,4,17 Cannabidiol’s drug interaction profile notes a high potential of interactions with medications metabolized hepatically by CYP and glucuronidation.17,18 Specifically, in a phase I trial, it has been shown that in the presence of treatment doses of the CYP inducer rifampin, the AUC decreases 52% to 59%; concomitant therapy with the strong CYP3A4 inhibitor ketoconazole 400mg daily increased drug exposure by 89% to 165%; this study also demonstrated that the CYP2C19 inhibitor, omeprazole, had no discernible effect on exposure.19 Similar to other antiepileptic drugs, CBD is an enzyme inducer and inhibitor.4 Research is lacking regarding the management of patients with complex antiepileptic regimens with CBD, but a high potential for interactions exists. The prescribing information cautions that cannabidiol inhibits enzymes of glucuronidation, and this can lead to increased

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concentrations of other antiepileptics such as lorazepam and lamotrigine. It has the potential to increase serum concentrations of non-seizure related medications as well, such as morphine and fenofibrate. Cannabidiol may act as an inducer and inhibitor of CYP1A2 and CYP2B6 necessitating judicious monitoring when a substrate of one of these enzymes are prescribed. It is also predicted that serum concentrations of phenytoin will be increased via inhibition of CYP2C9.3,4 Special attention has been drawn to cannabidiol’s in vivo action as a CYP2C19 inhibitor, requiring dose reductions of two other antiepileptic medications, diazepam and clobazam, if administered in the same patient.4 Lastly, cannabidiol should not be used with ethanol or opioids due to risk of excessive CNS depression.17 Due to the given risk of drug interactions, it becomes clear why cannabidiol should only be used with oversight from a health-care professional, and a pharmacist, in particular, who is knowledgeable regarding enzymes of drug metabolism and excretion. Efficacy: Seizure Disorders The two FDA-approved indications for Epidiolex® (cannabidiol) are serious seizure disorders characterized by pediatric onset and resistance to most available antiepileptic medications.20,21 Epidemiological data show that Lennox-Gastaut syndrome accounts for 1 to 4% of all pediatric epilepsies. Dravet syndrome is reported to affect 1 in 15,700 persons in the United States.20,21 Dravet syndrome is a rare epileptic disorder usually caused by a genetic mutation of the SCN1A gene. Seizures begin in the first year of life and may be unilateral or generalized; triggers include infection, increases in body temperature (e.g., fever, hot bath water), and visual stimulation. Neurobehavioral impairment is common, with symptoms ranging from minor learning disabilities to global developmental delay.22 Dravet syndrome is notable for being refractory to treatment with most antiepileptic medications. Measurements of health-related quality of life tend to be lower in patient

samples with Dravet syndrome than those in patients diagnosed with an epileptic disorder not considered Dravet syndrome.23 This is due to the comorbidities of this disease that include discoordination of the autonomic nervous system, nutrition deficiencies, characteristics of autism, and an alarmingly high rate of sudden unexpected death in epilepsy.23 First line therapy for Dravet syndrome includes valproate and clobazam; however, treatment failure is common.24 In one recent multicenter, double-blind, placebo-controlled trial, the researchers utilized Epidiolex® (cannabidiol) in pediatric and adolescent patients (n= 120, mean age = 9.8 years) with Dravet syndrome and treatment refractory seizures.25 Patients were randomized to receive cannabidiol 20mg/kg/day by mouth or placebo in combination with standard antiepileptic medical treatment. The objective of this study was to quantify the difference in convulsive seizure frequency between the two groups over a fourteen-week treatment period compared with a 4-week baseline period. This trial showed a reduction in the rate of convulsive seizures per month in the 14-week period versus baseline in the cannabidiol group (5.9/monthtreatment period vs 12.4/monthbaseline

[adjusted median difference –22.8%; p = 0.01). Additionally, the percentage of patients with ≥ 50% reduction in rate of convulsive seizures was 43% in the cannabidiol treatment group and 27% in the placebo-controlled group, though this finding was not statistically significant (OR 2.00; p = 0.08). This led the authors to recommend cannabidiol, with the precaution to monitor for side effects such as somnolence and elevated liver enzymes.25 Lennox-Gastaut syndrome is a rare (approximately 2 cases per 100,000), severe manifestation of epilepsy with varied etiology. Patients with this syndrome often suffer from “drop” seizures, which are either sudden increases or decreases in motor tone that result in falls and significant injury.21 Other symptoms of Lennox-Gastaut syndrome include significant intellectual, behavioral, and cognitive deficits.24 Valproate, lamotrigine, and topiramate are often prescribed for this disease state with

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marginal success.24 Another recent multicenter, double-blind, placebo-controlled trial, patients (n = 225, age range = 2.6 to 48 years, approximate mean age = 15.5 years) evaluated patients with two or more seizures per week that were refractory to other antiepileptic medications. These patients were randomized to receive cannabidiol 10mg/kg twice daily, cannabidiol 5mg/kg twice daily, or a placebo for 14 weeks. Notably, the number of drop seizures was 85 per 4 weeks at baseline. The results were favorable for cannabidiol in this form of epilepsy: the median reduction of drop seizures from baseline in the cannabidiol 10mg/kg twice daily group was 41.9% (p=0.005); the median reduction from baseline in the cannabidiol 5mg/kg twice daily group was 37.2% (p=0.002).3,21 Initial dosing of Epidiolex® (cannabidiol) for seizure disorders should be 2.5 mg/kg twice daily; if tolerated for at least one week, the patient may be titrated to the maintenance dose of 5 mg/kg twice daily. If needed, the dose may be titrated in weekly increments of 2.5 mg/kg twice daily to a maximum dose of 10 mg/kg twice daily. Discontinuation of Epidiolex® should always occur as a gradual reduction in dose.17,18

Efficacy: Anxiety There are numerous studies assessing the impact of CBD on feelings of anxiety, however these studies have limited applicability due to small sample sizes. Exaggerated responses or lack of significant effects could be due to lack of statistical power. Further, chronic impact of CBD oil is difficult to determine since the studies use a single-dose CBD before or after an anxiety-provoking event.26–34 Study subjects were normal volunteers in all but three trials, so the extent of their anxiety given the prescribed stressor might be different from that seen in patients with anxiety disorders. Responses from normal volunteers to a stressor might be less severe than people with anxiety disorders, diminishing the extent of benefit that could result from effective treatment.26–34 Table 2 summarizes three studies assessing CBD on anxiety caused by public speaking. Other studies were excluded because delta-9-THC was the stressor in one group of studies, while the other group of studies did not show significant benefits with CBD compared to clonazepam.26-29, 34

Table 2. Studies on CBD’s Effects on Public Speaking Anxiety30-32

Study Name & Subject Number

Study Design and Duration CBD Dose,

Control Dose, and Route

Results

Bergamaschi 2011

Subjects (n=24) with untreated social anxiety disorder. R, DB, PC; single dose. CBD or placebo was also included for comparative purposes. Evaluations: baseline, 80 minutes after ingestion (pretest), immediately before speech (anticipatory), during speech, and 15 and 35 minutes post speech.

CBD 600 mg or placebo by mouth

CBD 600 mg significantly reduced anxiety, discomfort, and cognitive impairment during the speech vs placebo. No significant benefits occurred vs placebo during the pretest, anticipatory phase, or 15 and 35 minutes after speech.

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Study Name & Subject Number

Study Design and Duration CBD Dose, Control Dose, and Route

Results

Zuardi 2017 Normal volunteers (n=60). R, DB, PC, AC; single dose. Evaluations: baseline, 80 minutes after ingestion (pretest), during speech, and 60 minutes after speech.

CBD 100, 300, 900mg placebo or clonazepam 1 mg by mouth

Anxiety was significantly reduced with clonazepam during and 1 hour after the speech, and it was reduced with CBD 300 mg 1 hour after speech vs placebo. CBD 300 mg subjects had higher BP during public speaking than clonazepam subjects.

Linares 2018 Normal volunteers (n=57). R, DB, PC; single dose. Evaluations: baseline, 90 minutes after ingestion (pretest), immediately before speech (anticipatory), during speech, immediately after speech, and 30 minutes after speech.

CBD 150, 300, 600 mg or placebo by mouth

Anxiety significantly reduced with CBD 300 mg during the speech vs placebo but not with the other 2 doses of CBD.

AC, active controlled; DB, double blind; CBD, cannabidiol; DBP, diastolic blood pressure; PC, placebo controlled; R, randomized; SBP, systolic blood pressure; SSPS-N, Negative Self-Statement Public Speaking Scale; VAMS, Visual Analog Mood Scale. Adapted from A Review of Human Studies Assessing Cannabidiol's (CBD) Therapeutic Actions and Potential. J Clin Pharmacol. 2019

Prophylaxis with CBD several minutes to hours before public speaking (the anxiety stressor) might provide relieve from anxiety during or shortly after the speech.30–32 The studies comparing multiple CBD dose levels were likely underpowered to assess all doses adequately, but the 300-mg dose might provide greater benefits than smaller or larger doses. This relationship between CBD dose and efficacy could suggest a single effective dose.30–32 In another study comparing anxiolytic affects between CBD products and clonazepam, the benefits derived from CBD were not as robust as clonazepam, but clonazepam did significantly induce sedation, whereas CBD did not.30–32 Acute use of CBD before undergoing stressful or anxiety-provoking situations (aside from public speaking) was assessed in multiple trials in subjects with or without chronic anxiety issues.33–38 Unfortunately, the results of the

trials are inconsistent, so it is unclear whether patients taking CBD before non–public speaking anxiety-provoking events is an effective strategy. The variances in CBD doses, manufacturers, routes of administration, durations between CBD dosing and stressor, total evaluative times, anxiety rating scales, and stressors can all introduce heterogeneity and further complicate the decision of best-choice CBD product.26-34 Efficacy: Pain and Spasticity Cannabinoids are becoming increasing popular for pain management. One article reviewed 16 clinical trials involving 1,750 people and assessed cannabis-based medication use in neuropathic pain.39 This compilation of studies’ assessment of cannabis-based medication included: 10 studies using an oromucosal spray consisting of plant-derived

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tetrahydrocannabinol (THC) and cannabidiol (CBD), two studies using a synthetic cannabinoid (nabilone) that mimics THC, two studies using inhaled cannabis, and finally two studies using plant derived THC (dronabinol).39

This study had a primary outcome of reported pain relief of 50% or greater while evaluating eight of the studies for a sample of 1,001 participants. The study also included a secondary outcome of reported pain relief of 30% or greater looking at 10 studies with a sample of 1,586 participants.39 These studies resulted in 110/526 (20.9%) of participants in the cannabis-based medicine groups and 82/475 (17.3%) in the placebo groups reporting that they had greater than 50% reduction in pain. [Risk difference 0.05, 95% Confidence Interval (0.00 to 0.09)].39 In 10 analyzed studies evaluating the secondary endpoint, 323/819 (39.4%) of the cannabis-based medicine group and 251/767 (32.7%) of the placebo group reported a pain relief reduction of 30% or greater, therefore indicating statistically superior outcomes when using cannabis-based medicine [Risk difference 0.09, 95% Confidence Interval (0.03 to 0.15); NNT: 15].39 Another study assessed using CBD for chronic pain relief in patients who had received a kidney transplant greater than a year prior to the study.40 This trial contained seven participants who ranged in age from 58 to 75 years.40 They were given CBD doses initially at 100 mg per day and were increased to 300 mg daily.40 One patient had to be decreased to 50 mg per day due to persistent nausea.40 At day 15 of the study two patients had optimal pain control, four patients had a partial response in controlling pain, and in one patient there was actually increased pain with increased CBD dose. It was found that CBD was well-tolerated and there were only mild adverse reactions with CBD that required individualization of treatment.40 A third study, a preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms compared delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD),

THC and CBD, and placebo to determine the effects of improving neurological symptoms.41 Twenty patients completed the study with 14 having multiple sclerosis, four having a spinal cord injury, one had a brachial plexus lesion, and one had an amputation with phantom pain.41 Of this sample, 13 patients had pain, 17 had muscle spasms, and nine had spasticity.41 Patients kept a daily diary tracking target symptoms using a visual analogue scale.41 The visual analogue scale’s rating ranges from 0 being the worst possible to 100 being the best possible. Specifically looking at CBD versus placebo, data from the daily visual analogue scale that the patients completed showed that CBD had a statically significant difference from placebo in reducing pain (54.8 vs 44.5; p < 0.05); however even though there was improvement seen with muscle spasms (54.6 vs 47.3; p >0.05) and spasticity (47.8 vs 42.3; p > 0.05) with those patients on CBD, these improvements were not statically significant.41 When comparing THC vs placebo, pain (54.6 vs 44.5; p < 0.05), spasms (58.4 vs 47.3; p < 0.05), and spasticity (57.3 vs 42.3; p < 0.05) was significantly reduced by THC.41 While analyzing CBD plus THC vs placebo only spasms (55.8 vs 47.3; p < 0.05) showed a significant reduction with treatment, whereas pain (51.3 vs 44.5; p> 0.05) and spasticity (43.8 vs 42.3; p > 0.05) did not show a significant reduction.41 Efficacy: Parkinson’s Disease CBD has the potential to offer support in the treatment of Parkinson’s disease due to its anti-inflammatory and antioxidant properties. One study evaluated 21 patients with Parkinson’s disease and divided them into three different treatment groups. They compared placebo to CBD at doses of 75 mg/day and 300 mg/day for six weeks. They assessed patients using the assessment tool found in Table 3.42

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Table 3. Tools used for evaluating Parkinson’s Disease43-45

Assessment Scales

Unified Parkinson’s Disease Rating Scale

This scale is rate 0-4 with 0 being no problems and 4 being severe problems. The scores are added together to indicate the severity of the disease, the scores range from no disability (0) to total disability (199).

Parkinson’s Disease Questionnaire – 39

This questionnaire assesses the frequency of difficulties with relationships, social situations, and communication in people with Parkinson’s to determine functioning and well-being.

Udvalg for kliniske undersøgelser

This is a rating scale that assesses side effects and the influence they have on daily life

There was no statistical difference with the Unified Parkinson’s Disease Rating Scale scores and no significant interactions reported with the Udvalg for kliniske undersøgelser side effect rating scale.42 However, the Parkinson’s Disease Questionnaire – 39 found a statistically significant improvement in measures of functioning and well-being when patients were taking CBD 300 mg/day compared with placebo (p=0.05).42 Statistical significance improvement was found for the subgroups 1) activities of daily living and 2) stigma from placebo to CBD 300 mg/day (p=0.02) as well as from CBD 75 mg/day to CBD 300 mg/day (p=0.04).42

Adverse Events Several adverse drug reactions were reported in the two recent randomized controlled trials of cannabidiol in the treatment of Lennox-Gastaut syndrome and Dravet syndrome. In the trial for Dravet syndrome, side effects occurring at a higher rate in the cannabidiol intervention group were somnolence (36% vs 10%), diarrhea (31% vs 10%), and decreased appetite (28% vs 5%).25 Similarly, these adverse effects occurred more frequently in the cannabidiol group in the trial investigating the drug’s role in preventing drop seizures in Lennox-Gastaut syndrome.21 A notable finding in the trials was an increase in aminotransferase levels > 3X the upper limit of normal in the cannabidiol group of the trial. In one trial enrolling 120 patients, 12 patients had clinically significantly high aminotransferase levels compared to 1 patient in the control group.25 The researchers made a notable observation that the elevations of hepatic aminotransferase levels occurred exclusively in patients also taking valproate, suggesting a likely drug interaction.25 Further, in another randomized controlled trial that analyzed cannabidiol in Lennox-Gastaut syndrome in which two doses of CBD were used (20mg/kg/day and 10mg/kg/day) and compared to placebo, 11 patients in the high-dose CBD group and 3 patients in the low-dose CBD group had measured aminotransferase levels >3X the upper limit with no occurrences in patients not receiving CBD. Of the 14 incidents, 11 of the patients were taking concomitant valproate.21 Due to these reports, LFTs should be monitored at 1, 3, and 6 months after initiation.24 If AST/ALT is >3X the upper limit of normal (ULN) and total bilirubin is >2x ULN, therapy should be discontinued.17 Lastly, while new-onset suicidality is associated with antiepileptic medications, no reports of suicidal ideation were reported in the aforementioned studies. Health-care professionals should be aware of and monitor for this potential risk.24 Regarding psychoactive effects as a whole, the effects of cannabidiol are minimal. Cannabidiol does not potentiate endogenous cannabinoid receptors, therefore

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feelings of reward and euphoria are nil, leading to low risks of abuse or dependence.24 Conclusion Cannabidiol appears to be an effective and safe medication to treat seizure disorders that were previously refractory to any intervention. Additionally, this medication shows future promise for treating anxiety, pain, and

Parkinson’s disease; however, it is yet not FDA approved for these disease states. Pharmacists can serve their patients and fellow healthcare providers by teaching them cannabidiol’s place in therapy, emphasizing that while it is derived from Cannabis sativa, cannabidiol is minimally psychoactive and poses a low risk of dependence.

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