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 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 | [email protected] Page 2 of 12

Objectives patients and medical professionals because, for • Recognize the origin, effects, and usage example, employers may test current or of cannabidiol (CBD) oil prospective workers for delta-9-THC in their • Identify federal and state laws hair, nails, or urine, with positive findings governing the use of CBD oil potentially resulting in suspension, termination, • Recognize the pharmacokinetics of or not being hired.1 Further, federal regulatory cannabidiol. restrictions (as well as several states) prohibit • Discuss the effectiveness of cannabidiol possession or transportation of delta-9-THC– in seizure disorders. containing products across state lines, even for legitimate medical purposes.2,3 Introduction Though delta-9 THC produces the “high” The Cannabis sativa plant has been evaluated feeling and is the most prevalent bioactive for its use in treating various diseases and constituent of the Cannabis sativa plant, the disorders, including seizure disorder, anxiety, second most prevalent compound, cannabidiol schizophrenia/psychosis, pain management, (CBD), does not convert to delta-9-THC in the and more. A significant barrier to further human body and therefore does not produce studies and treatment in these disease states is the high feeling as a result.2 Studies performed the altered sensory and time perception (the in vitro, animals, and in humans have suggested “high” feeling) provided by the delta-9 various mechanisms of actions of CBD and how tetrahydrocannabinol (delta-9-THC) component it may be directly or indirectly related to the of the cannabis sativa plant and extracts.1 This body’s . These actions component limits potential wider adoption by and effects are detailed in Table 1.

Table 1. CBD Actions and Mediated Effect3 Receptor Impact Potential Pharmacologic Outcome CB1* Direct antagonism and negative Reduction of impaired learning, memory, antagonism hypothermic and psychosis effects induced by delta-9-THC CB2* Antagonist and inverse agent Anti-inflammatory effects GPR55 Antagonist Anti-cancer effects 5HT1-alpha 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= 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 patients may be seeking. Further, this is another years on the health benefits of CBD products, topic of interest among healthcare many health professionals may be interested in professionals since patients will increasingly ask using it as a potentially new or alternative about the benefits and risks of CBD products, therapy for patients. This could especially be their effects, pharmacokinetics, and potential useful when traditional options have failed to with current medication adequately treat or control symptoms, or even regimen. as an alternative to medical marijuana that Page 3 of 12

Legality of CBD protected, and the CBD product can only Extracts of the Cannabis sativa plant have contain up to 3% of delta-9-THC.7,8 historically been listed as Schedule I , UPDATE: Alabama Governor Kay Ivey signed meaning they have high risk of abuse or harm, Senate Bill 225 on June 10th, 2019 which allows have limited or no medicinal value, and they are Alabama pharmacies to sell CBD products if illegal to possess: however; the Food and Drug they are labeled to contain no more than 0.3% Administration (FDA) approved the first CBD THC in dry weight. product in 2018, Epidiolex® (cannabidiol) for Lennox-Gastaut and Dravet syndrome.4,5 The Quality Control Drug Enforcement Administration (DEA) A major concern with CBD products is subsequently placed Epidiolex® on the list of accuracy of labeling of delta-9-THC. It is Schedule V drugs (drugs with a relatively low impossible to know the exact formulation of risk of abuse), making this the first Cannabis CBD a patient is taking if they purchase sativa-derived product to achieve this status.4,5 products that are not FDA approved or The rescheduling was also done in part because independently tested by outside laboratories. Epidiolex® contains less than 0.1% delta-9-THC. For example, the FDA-approved CBD product In addition to FDA approval for treating the Epidiolex® provides the concentration of CBD desired disease state, CBD products seeking specified on the label with little variation over rescheduling by the DEA must also contain less time. Because most of the CBD products that than 0.1% delta-9-THC. are currently available are not subject to The Rohrabacher-Farr amendment, which has mandatory FDA or third-party testing for been in force since 2014 but needs periodical approval, this consistent concentration over renewal in the US Congress, bars the time may not occur with other products. Department of Justice from spending any funds Several experiments have been conducted to to keep states from implementing their own assess consistency and accuracy of CBD product laws about “the use, distribution, possession or labeling. In 2016, FDA investigators purchased cultivation of medical marijuana.”6 As such, 84 non–FDA-approved CBD products from 31 Alabama has instituted its own laws for CBD different companies over the Internet and products and their uses: Carly’s Law and Leni’s tested them in triplicate using high- Law. performance liquid chromatography in a Carly’s Law, passed in 2014, aimed to protect commercial laboratory.9 Triplicate test results people with a debilitating epileptic condition were averaged and reported by product weight. who have a prescription for CBD authorized by The average labeled CBD concentration was 15 the University of Alabama at Birmingham (UAB) mg/dL with an overall range between 1.33 to Department of Neurology. Under this law, 800 mg/dL in the tested products.9 If the parents and caretakers of children and people average detected concentration was 90% to with the epileptic condition could not be 110% of the labeled value, it was considered prosecuted for CBD possession so long as they accurately labeled. With respect to CBD, only had a prescription authorized by the UAB 31% (95% confidence interval [CI], 22% to 41%) Department of Neurology. Leni’s Law, passed in were classified as labeled accurately, with 43% 2016, expanded the protections against (95% CI, 33% to 54%) of products under-labeled prosecution provided by Carly’s Law to include and 26% (95%CI, 18% to 36%) over-labeled for those who are being treated for a chronic or CBD content. The accuracy of labeling also debilitating condition that causes seizures. varied between product types. The frequency of Under both laws, the CBD product must have accurate labeling for CBD vaporization liquids, been tested by an independent third-party tinctures, and oils was 12.5%, 25%, and 45%, laboratory, parents and guardians of children respectively. Products contained unlabeled with debilitating epileptic conditions are also delta-9-THC at a mean concentration of 0.45 Page 4 of 12 mg/mL (range 0 to 6.4mg/dL) in 21% of United States due to varying purity standards. samples.9 This is significant because inhaled There are reports of people who failed drug doses of 2 to 3 mg and ingested doses of 5 to 20 tests for delta-9-THC while taking products mg of delta-9-THC can provoke adverse effects labeled “CBD-only”.13,14 and the “high” feeling.10 Whether there was Another risk of non–FDA-approved CBD variance within the same product from batch to products is adulteration and contamination. The batch is not known. International Cannabis and Cannabinoid In addition to the FDA investigators, Institute in the Czech Republic assessed 29 CBD independent testing company ConsumerLabs products and found that 69% of them exceeded has also assessed 19 different CBD products for recommended levels of polycyclic aromatic consistency and accuracy of CBD content.11 Two hydrocarbons, which are class IIa carcinogens of the products they tested had less CBD than and genotoxic mutagens according to the was labeled, while one of the products had a International Agency for Research on significantly higher level of CBD compared to Cancer.15,16 Additionally, there is a possibility of the product labeling. They even found that the pesticide or heavy metal contamination in cost of the products varied widely; 10 mg of unregulated CBD products.15 CBD ranged from $0.80 to $4.50.11 There are several potential implications of Pharmacokinetics/Drug Interactions inaccurately labeled CBD concentrations or CBD Epidiolex® (100mg/ml, 100ml bottle) is variability in CBD concentrations in products highly lipophilic with a large volume of over time. Similarly to how a consistent distribution of 20,963 to 42,849 L and a half-life concentration of available drug is necessary for of 56 to 61 hours. Meals high in fat increases therapeutic effect, a variable CBD concentration exposure by a factor of 5 and measured Cmax by can also lead to undesirable outcomes. For a factor of 4. This has led to concerns regarding example, in a systematic review of non-CBD whether cannabidiol should be given on an antiepileptic drugs, the University of empty stomach, but currently no Connecticut Evidence-Based Practice Center recommendation exists.3,4,17 found that seizure control was impacted by Cannabidiol’s drug interaction profile notes a small changes in drug concentration.12 While high potential of interactions with medications brand and generic antiepileptic drugs were metabolized hepatically by CYP and equally efficacious when started de novo, glucuronidation.17,18 Specifically, in a phase I switching from a brand to a generic or vice trial, it has been shown that in the presence of versa increased the risk of emergency medical treatment doses of the CYP inducer rifampin, services or hospitalization.12 This suggests that the AUC decreases 52% to 59%; concomitant using CBD products for seizure control with therapy with the strong CYP3A4 inhibitor differing CBD content or products with variable ketoconazole 400mg daily increased drug CBD concentrations over time can be dangerous exposure by 89% to 165%; this study also to patients. demonstrated that the CYP2C19 inhibitor, It is also speculated that non–FDA-approved omeprazole, had no discernible effect on CBD products sold in the United States could exposure.19 contain enough delta-9-THC to place the seller Similar to other antiepileptic drugs, CBD is an or possessor at risk of criminal prosecution inducer and inhibitor.4 Research is under marijuana laws, even if the label does not lacking regarding the management of patients indicate that delta-9-THC is a component of the with complex antiepileptic regimens with CBD, product.9 It is a very real possibility that patients but a high potential for interactions exists. The and people who claim to use CBD-only products prescribing information cautions that may fail drug tests for delta-9-THC if these cannabidiol inhibits of products are sourced from outside of the glucuronidation, and this can lead to increased Page 5 of 12 concentrations of other antiepileptics such as samples with Dravet syndrome than those in lorazepam and lamotrigine. It has the potential patients diagnosed with an epileptic disorder to increase serum concentrations of non- not considered Dravet syndrome.23 This is due seizure related medications as well, such as to the comorbidities of this disease that include morphine and fenofibrate. Cannabidiol may act discoordination of the autonomic nervous as an inducer and inhibitor of CYP1A2 and system, nutrition deficiencies, characteristics of CYP2B6 necessitating judicious monitoring autism, and an alarmingly high rate of sudden when a substrate of one of these enzymes are unexpected death in epilepsy.23 First line prescribed. It is also predicted that serum therapy for Dravet syndrome includes valproate concentrations of phenytoin will be increased and clobazam; however, treatment failure is via inhibition of CYP2C9.3,4 Special attention has common.24 In one recent multicenter, double- been drawn to cannabidiol’s in vivo action as a blind, placebo-controlled trial, the researchers CYP2C19 inhibitor, requiring dose reductions of utilized Epidiolex® (cannabidiol) in pediatric and two other antiepileptic medications, diazepam adolescent patients (n= 120, mean age = 9.8 and clobazam, if administered in the same years) with Dravet syndrome and treatment patient.4 Lastly, cannabidiol should not be used refractory seizures.25 Patients were randomized with ethanol or due to risk of excessive to receive cannabidiol 20mg/kg/day by mouth CNS depression.17 or placebo in combination with standard Due to the given risk of drug interactions, it antiepileptic medical treatment. The objective becomes clear why cannabidiol should only be of this study was to quantify the difference in used with oversight from a health-care convulsive seizure frequency between the two professional, and a pharmacist, in particular, groups over a fourteen-week treatment period who is knowledgeable regarding enzymes of compared with a 4-week baseline period. This drug and excretion. trial showed a reduction in the rate of convulsive seizures per month in the 14-week Efficacy: Seizure Disorders period versus baseline in the cannabidiol group The two FDA-approved indications for (5.9/monthtreatment period vs 12.4/monthbaseline Epidiolex® (cannabidiol) are serious seizure [adjusted median difference –22.8%; p = 0.01). disorders characterized by pediatric onset and Additionally, the percentage of patients with ≥ resistance to most available antiepileptic 50% reduction in rate of convulsive seizures was medications.20,21 Epidemiological data show that 43% in the cannabidiol treatment group and Lennox-Gastaut syndrome accounts for 1 to 4% 27% in the placebo-controlled group, though of all pediatric epilepsies. Dravet syndrome is this finding was not statistically significant (OR reported to affect 1 in 15,700 persons in the 2.00; p = 0.08). This led the authors to United States.20,21 recommend cannabidiol, with the precaution to Dravet syndrome is a rare epileptic disorder monitor for side effects such as somnolence usually caused by a genetic mutation of the and elevated liver enzymes.25 SCN1A gene. Seizures begin in the first year of Lennox-Gastaut syndrome is a rare life and may be unilateral or generalized; (approximately 2 cases per 100,000), severe triggers include infection, increases in body manifestation of epilepsy with varied etiology. temperature (e.g., fever, hot bath water), and Patients with this syndrome often suffer from visual stimulation. Neurobehavioral impairment “drop” seizures, which are either sudden is common, with symptoms ranging from minor increases or decreases in motor tone that result learning disabilities to global developmental in falls and significant injury.21 Other symptoms delay.22 Dravet syndrome is notable for being of Lennox-Gastaut syndrome include significant refractory to treatment with most antiepileptic intellectual, behavioral, and cognitive deficits.24 medications. Measurements of health-related Valproate, lamotrigine, and are quality of life tend to be lower in patient often prescribed for this disease state with Page 6 of 12 marginal success.24 Another recent multicenter, double-blind, placebo-controlled trial, patients Efficacy: Anxiety (n = 225, age range = 2.6 to 48 years, There are numerous studies assessing the approximate mean age = 15.5 years) evaluated impact of CBD on feelings of anxiety, however patients with two or more seizures per week these studies have limited applicability due to that were refractory to other antiepileptic small sample sizes. Exaggerated responses or medications. These patients were randomized lack of significant effects could be due to lack of to receive cannabidiol 10mg/kg twice daily, statistical power. Further, chronic impact of cannabidiol 5mg/kg twice daily, or a placebo for CBD oil is difficult to determine since the 14 weeks. Notably, the number of drop seizures studies use a single-dose CBD before or after an was 85 per 4 weeks at baseline. The results anxiety-provoking event.26–34 Study subjects were favorable for cannabidiol in this form of were normal volunteers in all but three trials, so epilepsy: the median reduction of drop seizures the extent of their anxiety given the prescribed from baseline in the cannabidiol 10mg/kg twice stressor might be different from that seen in daily group was 41.9% (p=0.005); the median patients with anxiety disorders. Responses from reduction from baseline in the cannabidiol normal volunteers to a stressor might be less 5mg/kg twice daily group was 37.2% severe than people with anxiety disorders, (p=0.002).3,21 diminishing the extent of benefit that could Initial dosing of Epidiolex® (cannabidiol) for result from effective treatment.26–34 Table seizure disorders should be 2.5 mg/kg twice 2 summarizes three studies assessing CBD on daily; if tolerated for at least one week, the anxiety caused by public speaking. Other patient may be titrated to the maintenance studies were excluded because delta-9-THC was dose of 5 mg/kg twice daily. If needed, the dose the stressor in one group of studies, while the may be titrated in weekly increments of 2.5 other group of studies did not mg/kg twice daily to a maximum dose of 10 show significant benefits with CBD compared mg/kg twice daily. Discontinuation of Epidiolex® to clonazepam.26-29, 34 should always occur as a gradual reduction in dose.17,18

Table 2. Studies on CBD’s Effects on Public Speaking Anxiety30-32 Study Name CBD Dose, & Subject Study Design and Duration Control Dose, Results Number and Route Bergamaschi Subjects (n=24) with untreated CBD 600 mg or CBD 600 mg significantly 2011 social anxiety disorder. R, DB, placebo by reduced anxiety, discomfort, PC; single dose. CBD or placebo mouth and cognitive impairment was also included for during the speech vs placebo. comparative purposes. No significant benefits Evaluations: baseline, 80 occurred vs placebo during the minutes after ingestion pretest, anticipatory phase, or (pretest), immediately before 15 and 35 minutes after speech (anticipatory), during speech. speech, and 15 and 35 minutes post speech.

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Study Name CBD Dose, & Subject Study Design and Duration Control Dose, Results Number and Route Zuardi 2017 Normal volunteers (n=60). R, CBD 100, 300, Anxiety was significantly DB, PC, AC; single dose. 900mg placebo reduced with clonazepam Evaluations: baseline, 80 or clonazepam during and 1 hour after the minutes after ingestion 1 mg by mouth speech, and it was reduced (pretest), during speech, and 60 with CBD 300 mg 1 hour after minutes after speech. speech vs placebo. CBD 300 mg subjects had higher BP during public speaking than clonazepam subjects. Linares 2018 Normal volunteers (n=57). R, CBD 150, 300, Anxiety significantly reduced DB, PC; single dose. Evaluations: 600 mg or with CBD 300 mg during the baseline, 90 minutes after placebo by speech vs placebo but not with ingestion (pretest), immediately mouth the other 2 doses of CBD. before speech (anticipatory), during speech, immediately after speech, and 30 minutes after speech. 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 trials are inconsistent, so it is unclear whether before public speaking (the anxiety stressor) patients taking CBD before non–public speaking might provide relieve from anxiety during or anxiety-provoking events is an effective shortly after the speech.30–32 The studies strategy. The variances in CBD doses, comparing multiple CBD dose levels were likely manufacturers, routes of administration, underpowered to assess all doses adequately, durations between CBD dosing and stressor, but the 300-mg dose might provide greater total evaluative times, anxiety rating scales, and benefits than smaller or larger doses. This stressors can all introduce heterogeneity and relationship between CBD dose and efficacy further complicate the decision of best-choice could suggest a single effective dose.30–32 In CBD product.26-34 another study comparing anxiolytic affects between CBD products and clonazepam, the Efficacy: Pain and Spasticity benefits derived from CBD were not as robust are becoming increasing as clonazepam, but clonazepam did significantly popular for pain management. One article induce sedation, whereas CBD did not.30–32 reviewed 16 clinical trials involving 1,750 people Acute use of CBD before undergoing stressful and assessed cannabis-based medication use in or anxiety-provoking situations (aside from neuropathic pain.39 This compilation of studies’ public speaking) was assessed in multiple trials assessment of cannabis-based medication in subjects with or without chronic anxiety included: 10 studies using an oromucosal spray issues.33–38 Unfortunately, the results of the consisting of plant-derived Page 8 of 12 tetrahydrocannabinol (THC) and cannabidiol THC and CBD, and placebo to determine the (CBD), two studies using a synthetic effects of improving neurological symptoms.41 cannabinoid (nabilone) that mimics THC, two Twenty patients completed the study with 14 studies using inhaled cannabis, and finally two having multiple sclerosis, four having a spinal studies using plant derived THC (dronabinol).39 cord injury, one had a brachial plexus lesion, This study had a primary outcome of reported and one had an amputation with phantom pain relief of 50% or greater while evaluating pain.41 Of this sample, 13 patients had pain, 17 eight of the studies for a sample of 1,001 had muscle spasms, and nine had spasticity.41 participants. The study also included a Patients kept a daily diary tracking target secondary outcome of reported pain relief of symptoms using a visual analogue scale.41 The 30% or greater looking at 10 studies with a visual analogue scale’s rating ranges from 0 sample of 1,586 participants.39 These studies being the worst possible to 100 being the best resulted in 110/526 (20.9%) of participants in possible. Specifically looking at CBD versus the cannabis-based medicine groups and placebo, data from the daily visual analogue 82/475 (17.3%) in the placebo groups reporting scale that the patients completed showed that that they had greater than 50% reduction in CBD had a statically significant difference from pain. [Risk difference 0.05, 95% Confidence placebo in reducing pain (54.8 vs 44.5; p < 0.05); Interval (0.00 to 0.09)].39 In 10 analyzed studies however even though there was improvement evaluating the secondary endpoint, 323/819 seen with muscle spasms (54.6 vs 47.3; p >0.05) (39.4%) of the cannabis-based medicine group and spasticity (47.8 vs 42.3; p > 0.05) with those and 251/767 (32.7%) of the placebo group patients on CBD, these improvements were not reported a pain relief reduction of 30% or statically significant.41 When comparing THC vs greater, therefore indicating statistically placebo, pain (54.6 vs 44.5; p < 0.05), spasms superior outcomes when using cannabis-based (58.4 vs 47.3; p < 0.05), and spasticity (57.3 vs medicine [Risk difference 0.09, 95% Confidence 42.3; p < 0.05) was significantly reduced by Interval (0.03 to 0.15); NNT: 15].39 THC.41 While analyzing CBD plus THC vs placebo Another study assessed using CBD for chronic only spasms (55.8 vs 47.3; p < 0.05) showed a pain relief in patients who had received a significant reduction with treatment, whereas kidney transplant greater than a year prior to pain (51.3 vs 44.5; p> 0.05) and spasticity (43.8 the study.40 This trial contained seven vs 42.3; p > 0.05) did not show a significant participants who ranged in age from 58 to 75 reduction.41 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 Efficacy: Parkinson’s Disease mg per day due to persistent nausea.40 At day CBD has the potential to offer support in the 15 of the study two patients had optimal pain treatment of Parkinson’s disease due to its anti- control, four patients had a partial response in inflammatory and antioxidant properties. One controlling pain, and in one patient there was study evaluated 21 patients with Parkinson’s actually increased pain with increased CBD disease and divided them into three different dose. It was found that CBD was well-tolerated treatment groups. They compared placebo to and there were only mild adverse reactions CBD at doses of 75 mg/day and 300 mg/day for with CBD that required individualization of six weeks. They assessed patients using the treatment.40 assessment tool found in Table 3.42 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), Page 9 of 12

Table 3. Tools used for evaluating Parkinson’s Adverse Events Disease43-45 Several adverse drug reactions were reported Assessment Scales in the two recent randomized controlled trials Unified Parkinson’s This scale is rate 0-4 of cannabidiol in the treatment of Lennox- Disease Rating Scale with 0 being no Gastaut syndrome and Dravet syndrome. In the problems and 4 being trial for Dravet syndrome, side effects occurring severe problems. The at a higher rate in the cannabidiol intervention scores are added group were somnolence (36% vs 10%), diarrhea together to indicate (31% vs 10%), and decreased appetite (28% vs 25 the severity of the 5%). Similarly, these adverse effects occurred disease, the scores more frequently in the cannabidiol group in the range from no trial investigating the drug’s role in preventing 21 disability (0) to total drop seizures in Lennox-Gastaut syndrome. disability (199). A notable finding in the trials was an increase Parkinson’s Disease This questionnaire in aminotransferase levels > 3X the upper limit Questionnaire – 39 assesses the of normal in the cannabidiol group of the trial. frequency of In one trial enrolling 120 patients, 12 patients difficulties with had clinically significantly high aminotransferase relationships, social levels compared to 1 patient in the control 25 situations, and group. The researchers made a notable communication in observation that the elevations of hepatic people with aminotransferase levels occurred exclusively in Parkinson’s to patients also taking valproate, suggesting a 25 determine likely drug interaction. Further, in another functioning and well- randomized controlled trial that analyzed being. cannabidiol in Lennox-Gastaut syndrome in Udvalg for kliniske This is a rating scale which two doses of CBD were used undersøgelser that assesses side (20mg/kg/day and 10mg/kg/day) and compared effects and the to placebo, 11 patients in the high-dose CBD influence they have group and 3 patients in the low-dose CBD group on daily life had measured aminotransferase levels >3X the upper limit with no occurrences in patients not There was no statistical difference with the receiving CBD. Of the 14 incidents, 11 of the 21 Unified Parkinson’s Disease Rating Scale scores patients were taking concomitant valproate. and no significant interactions reported with Due to these reports, LFTs should be monitored 24 the Udvalg for kliniske undersøgelser side effect at 1, 3, and 6 months after initiation. If rating scale.42 However, the Parkinson’s Disease AST/ALT is >3X the upper limit of normal (ULN) Questionnaire – 39 found a statistically and total bilirubin is >2x ULN, therapy should be 17 significant improvement in measures of discontinued. functioning and well-being when patients were Lastly, while new-onset suicidality is taking CBD 300 mg/day compared with placebo associated with antiepileptic medications, no (p=0.05).42 Statistical significance improvement reports of suicidal ideation were reported in the was found for the subgroups 1) activities of aforementioned studies. Health-care daily living and 2) stigma from placebo to CBD professionals should be aware of and monitor 24 300 mg/day (p=0.02) as well as from CBD 75 for this potential risk. Regarding psychoactive mg/day to CBD 300 mg/day (p=0.04).42 effects as a whole, the effects of cannabidiol are minimal. Cannabidiol does not potentiate endogenous cannabinoid receptors, therefore Page 10 of 12

feelings of reward and euphoria are nil, leading Parkinson’s disease; however, it is yet not FDA to low risks of abuse or dependence.24 approved for these disease states. Pharmacists can serve their patients and fellow healthcare Conclusion providers by teaching them cannabidiol’s place Cannabidiol appears to be an effective and in therapy, emphasizing that while it is derived safe medication to treat seizure disorders that from Cannabis sativa, cannabidiol is minimally were previously refractory to any intervention. psychoactive and poses a low risk of Additionally, this medication shows future dependence. promise for treating anxiety, pain, and

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