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Confused about (CBD)? A Scientific and Rational Examination of Its Risks and Benefits in Psychiatry

Andrew Penn, MS, NP, PMHNP-BC Associate Clinical Professor University of , San Francisco, School of Nursing Williams A. Why Is CBD Everywhere? The New York Times. October 27, 2018. Velasquez-Manoff M. Can CBD Really Do All That? The New York Times. May 14, 2019. CBD Faculty Disclosure

• Andrew Penn, RN, MS, NP, APRN-BC has no financial relationships to disclose relating to the subject matter of this presentation. Disclosure

• The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational use(s) of , products, and/or devices (any use not approved by the US Food and Administration). – The off-label use of CBD, Epidiolex®, nabilone, and THC will be discussed.

• Applicable CME staff have no relationships to disclose relating to the subject matter of this activity.

• This activity has been independently reviewed for balance.

• Brand names are included in this presentation for participant clarification purposes only. No product promotion should be inferred. Learning Objectives

• Describe 3 ways in which the mechanism of action of cannabidiol (CBD) is different than (THC)

• Identify existing clinical trials that have explored the use of CBD for psychiatric indications

• Guide patients in the potential risks and benefits of CBD treatment for psychiatric conditions What is the history of ?

Cannabis fiber, medicine Vilification De facto 2800 BC and legalization? China “I didn’t prohibition inhale”

1 2 3 4 5

Drug is discovered Medical use by subculture, introduces a spreads to the Gray Area wider culture FDA Approved for Dravet syndrome 2013 and Lennox-Gastaut syndrome 2018

Charlotte Figi – namesake of “Charlotte’s Web” high-CBD Is CBD snake oil?

Gupta S. Why I changed my mind on weed. August 8, 2013. www..com/2013/08/08/health/gupta- changed-mind-/index.html. Accessed July 17, 2019. What is the difference between THC and CBD? THC CBD ? • Psychotomimetic ? • Dependency forming • “Nonpsychoactive” • Anxiogenic • Nonintoxicating • Disrupts intellectual development • Counters THC • Panacea Not so simple… Cannabis Botany

Cannabis ruderalis Lower in THC Sometimes used in hybrids

Cannabis indica More “body high” More sedating More “mental high” More anxiolytic More stimulating Lower in THC More anxiogenic Higher in CBD Higher in THC Cannabis hybrids Lower in CBD

CBD = cannabidiol; THC = tetrahydrocannabinol. Pollan M. The Botany of Desire: A Plant’s Eye View of the World. New York, NY: Random House; 2001. are Concentrated in the Flower Buds of the Plant

Formation of trichomes Manipulation of grow cycle/ Removal of males

Flower buds

CloseClose-up-up of of trichomes -rich trichomes

Russo EB. Br J Pharmacol. 2011;163(7):1344-1364. Pollan M. The Botany of Desire: A Plant’s Eye View of the World. New York, NY: Random House; 2001. Dry flower “bud” 113 Cannabinoids Cannabidiol (CBD) 120 Terpenes 9Δ-Tetrahydrocannabinol (THC) (provide odor and flavor) (THCV) Acidic Cannabinoids (CBN) 554 (CBG) phytochemical compounds identified in cannabis

Phenolic Compounds Steroids and Enzymes (flavonoids, lignans)

Aizpurua-Olaizola O, et al. J Nat Prod. 2016;79(2):324-331. Andre CM, et al. Front Plant Sci. 2016;7:19. What are the potential uses of the non-THC cannabinoids (including CBD)?

* CBD is non-intoxicating… * But is certainly PSYCHOACTIVE *

Izzo AA, et al. Trends Pharmacol Sci. 2009;30(10):515-527. In the Future, Cannabinoids May Be Produced Not by Plants, But by Yeast

Luo X, et al. Nature. 2019;567(7746):123-126. Simon M. Forget Growing Weed—Make Yeast Spit Out CBD and THC Instead. Wired. February 2, 2019. Presynaptic What does the neuron do? Go! Vesicles endocannabinoid

receptors (CB1, CB2)

Neurotransmitters

Receptors Wait!

Synapse

Retrograde signaling control

Hosking RD, et al. Br J Anaesth. 2008;101(1):59-68. Postsynaptic neuron Endocannabinoid System Provides Retrograde Control of Neurotransmission in Response to Increased Intracellular Calcium

Retrograde eCBs hyperpolarize the presynaptic terminal, thus reducing further anterograde neurotransmitter release eCB = endocannabinoid. Hosking RD, et al. Br J Anaesth. 2008;101(1):59-68. Why do we even have an endocannabinoid system? Endocannabinoid Homeostasis Regulation

Relaxation and Sleep Appetite Regulation

Memory/Forgetting Pain Modulation

McPartland JM, et al. PLoS One. 2014;9(3):e89566. Di Marzo V. Biochim Biophys Acta. 1998;1392(2-3):153-175. The Endocannabinoid System: CB1 receptor is the most common GPCR in the CNS CBD has multiple targets

CB1 CB1 Presynaptic AEA = anandamide; 2-AG = 2- arachidonoylglycerol; CB1 = type 1; CB1, CB2 = cannabinoid receptor type 1, 2; CNS = central nervous system; DAG= diacylglycerol; FAAH = AEA fatty acid amide hydrolase; GPCR = G (anandamide) protein-coupled receptors; MGL = monoacylglycerol lipase; NAPE = N- Partial agonist CB1, CB2 arachidonoylphosphatidylethanolamine; THC TRPV1 = transient receptor potential vanilloid type 1. Partial agonist CB1, CB2 Marco EM, et al. Front Behav Neurosci. FAAH 2011;5:63. ElSohly M. In: Grotenhermen MGL F, et al (Eds). Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. New York, NY: The Haworth Integrative Healing Press; 2002:27-36. Seely KA, et al. Mol Interv. 2011;11(1):36-51. Ohno- CBD CBD Shosaku T, et al. Neuroscientist. TRPV-1 5-HT 2012;18(2):119-132. Zhornitsky S, et al. 1A Pharmaceuticals. 2012;5(5):529-552. agonist agonist Kathmann M, et al. Naunyn Schmiedebergs Arch Pharmacol. 2006;372(5):354-361. Postsynaptic

TRPV-1 DAG NAPE 5-HT1A CBD Limits the Activity of THC/AEA/2-AG on the CB1 Receptor through Negative Allosteric Modulation Orthosteric site (2-AG, AEA,THC) Orthosteric agonism with 2-AG, AEA, or THC initiates a GPCR intracellular process

CB1

Allosteric site (CBD) Allosteric inverse agonism with CBD changes the shape of the orthosteric site and reduces the secondary intracellular process initiated by THC or endogenous ligand: Negative Allosteric Modulation (NAM) Extracellular Intracellular (non-competitive anatagonist) Laprairie RB, et al. Br J Pharmacol. 2015;172(20):4790-4805. THC Reduces Activity at the Default Mode and Salience Networks Creating Experience of Cannabis Intoxication CBD + THC prevent this.

• Disruptions largely at the prefrontal cingulate cortex (PCC) and the anterior insula (AI) • THC disruptions at SAL and DMN correlate with subjective experience of “stoned”

• Long-term cannabis use may lead to downregulation of CB1 receptors at PCC. CBD may mitigate this • SAL may be key network in switching between DMN and executive network. Disruptions here are associated with and addictive disorders

Wall MB, et al. J Psychopharmacol. 2019 Apr 23; [Epub ahead of print]. Users Often Report They Substitute Cannabis for Other Prescriptions (opiates, benzodiazepines, antidepressants, hypnotics)

Corroon JM Jr, et al. J Pain Res. 2017;10:989-998. We areIs now CBD in aa legitimate medicine? pre-post marketing world

Clinical trial research data

We should be looking to anecdotal dataThe for ideasscientific on hypotheses community to istest way behindin clinical cannabis trials. users in understanding possible benefits of In the meantime,this let’s drug keep learning from our patients

Anecdotal user data www.ted.com/talks/david_casarett_a_doctor_s_case_for_medical_marijuana. Accessed June 20, 2019. However, for many years, many states have been ignoring federal law. Is CBD legal? This continues with all state-legalization laws

December 20, 2018, The Farming Act of 2018:

• Hemp = all parts of Cannabis sativa < 0.3% THC dry weight • Hemp cultivation overseen by states and USDA • Hemp removed from CSA Until 2018 Farm Bill: • THC remains Schedule I CBD, THC Schedule I • Hemp-derived CBD removed from CSA • CBD ONLY legal if from industrial hemp or from FDA approved medicine 2018

Schedule V Map of Marijuana Legality by State. https://disa.com/map-of-marijuana-legality-by-state. Accessed June 25, 2019. S.2667 . 115th Congress (2017–2018). www.congress.gov/bill/115th-congress/senate-bill/2667/text. Accessed June 25, 2019. Hudak J. The Farm Bill, hemp legalization and the status of CBD: An explainer. December 14, 2018. www.brookings.edu/blog/fixgov/2018/12/14/the-farm-bill-hemp-and-cbd-explainer. Accessed June 25, 2019. Federal Register. Schedules of Controlled Substances: Placement in Schedule V of Certain FDA-Approved Drugs Containing Cannabidiol; Corresponding Change to Permit Requirements. September 28, 2018. www.federalregister.gov/documents/2018/09/28/2018-21121/schedules-of-controlled-substances-placement-in-schedule-v-of-certain-fda-approved- drugs-containing. Accessed June 25, 2019. HEMP SEED OIL Derived from cannabis seeds

Legal in (cannot be derived from flowers or leaves) all states Used in cooking, a nutritional supplement, or on skin Does NOT contain CBD or THC

HEMP-DERIVED CBD OIL Derived from industrial hemp (cannabis) Federally legal if produced Hemp used as bioremediator, beware of heavy metals under terms of 2018 farm bill FDA has jurisdiction over health claims if > 0.3% THC, but may be illegal under state law Often vaguely labeled with unclear CBD content Oral, topical routes

CANNABIS-DERIVED CBD OIL Legal in states with Derived from cannabis flowers cannabis legalization. Various strengths are available If > 0.3% THC OR not grown Often described in ratio to THC (eg, 4:1) under terms of 2018 farm bill, illegal under federal law Can be vaporized, topical, or oral Expensive

US Department of Justice; Drug Enforcement Administration. Diversion Control Division. Clarification of the New Drug Code (7350) for Marijuana Extract. www.deadiversion.usdoj.gov/schedules/marijuana/m_extract_7350.html. Accessed June 25, 2019. Hudak J. The Farm Bill, hemp legalization and the status of CBD: An explainer. December 14, 2018. www.brookings.edu/blog/fixgov/2018/12/14/the-farm-bill-hemp-and-cbd-explainer. Accessed June 25, 2019. US Food and Drug Administration. FDA Regulation of Cannabis and Cannabis-Derived Products: Questions and Answers. www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-questions-and-answers. Accessed June 25, 2019. How is cannabis-derived CBD delivered and dosed? These products are generally available in states that have legalized or medicalized cannabis

Orally Inhaled Topically CBD Pharmacokinetics

bioavailability

Oral 13%–19%

Inhaled Mostly metabolized at 31% CYP450 GT

2C9 1A9 2C19 2B7 2D6 2B17 Variable % Transdermal 2E Relevant DDI: 3A4 • Ketoconazole = ↑ CBD/THC 3A5 • Cannabis = ↓ Theophylline Scuderi C, et al. Phytother Res. 2009;23(5):597-602. Stout SM, et al. Drug Metab Rev. 2014;46(1):86-95. Geffrey AL, et al. Epilepsia. 2015;56(8):1246-1251. Zendulka O, et al. • CBD = ↑ Clobazam Curr Drug Metab. 2016;17(3):206-226. Is CBD safe? In healthy volunteers, CBD (red line) did not significantly increase heart rate, intoxicate, sedate, or cause anxiety more than placebo (black line).

THC (blue line) did increase heart rate, sedate, intoxicate, and was anxiogenic.

Martin-Santos R, et al. Curr Pharm Des. 2012;18(32):4966-4979. CBD Appears to Have Antipsychotic Effects in Animal Models and in Clinical Studies

AEA levels have been found elevated (up to 8× normal) in the CSF of prodromal and acutely psychotic patients with schizophrenia

This may be an adaptive activity, an attempt by the brain to “put the brakes on” increased DA activity through endocannabinoid modulation

Cannabidiol may enhance AEA signaling, thus resulting in reduction of psychotic symptoms

Rimonabant (CB1 receptor inverse agonist, reverses endocannabinoid signaling) was ineffective against schizophrenia

CSF = cerebral spinal fluid. Campos AC, et al. Philos Trans R Soc Lond B Biol Sci. 2012;367(1607):3364-3378. Giuffrida A, et al. Neuropsychopharmacology. 2004;29(11):2108-2114. Leweke FM. Curr Pharm Des. 2012;18(32):5188-5193. Meltzer HY, et al. Am J Psychiatry. 2004;161(6):975-984. Leweke FM, et al. Transl Psychiatry. 2012;2:e94. CBD was as Effective of an Antipsychotic as Amisulpride, but with less weight gain, hyperprolactinemia, and EPS

EPS = extrapyramidal symptom. Leweke FM, et al. Transl Psychiatry. 2012;2:e94. Englund A, et al. J Psychopharmacol. 2013;27(1):19-27. Russo EB, et al. Neurochem Res. 2005;30(8):1037-1043. High Dose Oral CBD Added to Antipsychotics Reduced Positive Symptoms of Schizophrenia, But Did Not Improve Negative Symptoms or Cognition

McGuire P, et al. Am J Psychiatry. 2018;175(3):225-231. Study Replication Found No Benefit in Cognition or in Psychotic Symptoms (at lower dose – 600 mg/day) • 6-week study, N=36 • Used the Matrics Consensus Cognitive Battery (MCCB), Positive and Negative Syndrome Scale (PANSS), Hopkins Verbal Learning Test (HVLT) • Lower dose of CBD (300 mg BID) added to stable antipsychotic dose • CBD well tolerated, • Both groups PANSS (+/- ) improved over time, but CBD was not significantly effective for cognitive improvement.

Boggs DL, et al. Psychopharmacology. 2018;235(7):1923-1932. Is CBD an anxiolytic? Anxiolytic Effects of CBD in Animal Models

• Possible mechanisms

– Postsynaptic 5-HT1A agonism by CBD

– Increased AEA levels • Inhibiting catabolic enzymes • Inhibiting AEA reuptake

Campos AC, et al. Philos Trans R Soc Lond B Biol Sci. 2012;367(1607):3364-3378. Patel S, et al. Neurosci Biobehav Rev. 2017;76(Pt A):56-66. 400 mg PO CBD Reduced Social Anxiety and Reduced Limbic and Paralimbic Activity Associated with Anxiety

Crippa JA, et al. J Psychopharmacol. 2011;25(1):121-130. Oral CBD for Social Anxiety Disorder 600 mg taken 90 minutes before public speaking

Bergamaschi MM, et al. Neuropsychopharmacology. 2011;36(6):1219-1226. Moderate (300 mg) PO Doses of CBD Reduced Public Speaking Anxiety Similar to 1 mg Clonazepam and Was Well Tolerated low (100 mg) and high (900 mg) CBD doses did not

• N=60 (18–35 years) • Healthy normal participants • Public speaking test • Clonazepam more sedating than CBD • Placebo/1 mg clonazepam 100/300/900 mg CBD

Zuardi AW, et al. Front Pharmacol. 2017;8:259. PTSD Associated with Greater CB1 Receptor Availability and Lower AEA Levels: Could CBD be a treatment?

• Abnormal CB1 receptor-mediated AEA signaling is implicated in PTSD etiology

• PTSD is associated with CB1 receptor upregulation at limbic structures

• Even without trauma, women have higher CB1 receptor availability than men (greater vulnerability to PTSD?)

• Lower CB1 occupancy, low AEA, and low cortisol correlated 85% with clinical PTSD Dx

• CBD is able to increase AEA availability (through catabolic enzyme inhibition and AEA reuptake inhibition) without directly stimulating CB1 (like THC) PTSD = posttraumatic stress disorder. Neumeister A, et al. Mol Psychiatry. 2013;18(9):1034-1040. Adding CBD to PTSD Treatment

• Oral CBD added to treatment as usual in a small (N=11) series of patients with PTSD for 8 weeks – 48.64 mg (range: 2–100 mg/day) – PTSD Checklist for the DSM-5 (PCL-5) reduced from 52 at entry to 37 at endpoint – CBD well tolerated – Noted improvement in nightmares

• Nabilone (synthetic THC) 0.2–4.0 mg HS reduced or eliminated nightmares in 72% of an open-label PTSD study population

Elms L, et al. J Altern Complement Med. 2019;25(4):392-397. Fraser GA. CNS Neurosci Ther. 2009;15(1):84-88. What about lower dose CBD for treating anxiety and sleep in clinical practice? • Case series of 72 patients with anxiety or sleep issues who had PO CBD (25–175 mg/day) added to treatment as usual in open-label study

• Generally well tolerated

• Improvements in sleep were less significant and sustained than changes in anxiety

• Larger, blinded studies are needed

Shannon S, et al. Perm J. 2019;23:18-041. Does CBD improve sleep? CBD may have a biphasic effect with low doses being more stimulating and higher doses being more sedating Low oral CBD with low THC provided (compared to placebo): Increased sleep time And no reduction in sleep latency

Slightly fewer awakenings

But no increase in deep sleep

Higher THC doses can lead to next day impairment

Babson KA, et al. Curr Psychiatry Rep. 2017;19(4):23. Nicholson AN, et al. J Clin Psychopharmacol. 2004;24(3):305-313. Carlini EA, et al. J Clin Pharmacol. 1981;21(S1):417S-427S. Zuardi AW. Braz J Psychiatry. 2008;30(3):271-280. Is CBD an antidepressant? Antidepressant Effects of CBD in Animal Models

Campos AC, et al. Philos Trans R Soc Lond B Biol Sci. 2012;367(1607):3364-3378. How might CBD exert antidepressant and anxiolytic effects?

Pretreatment with 5-HT1A antagonist WAY-100635 blocks antidepressant effect in stress- response animal models

In animal model (FST) CBD + Fluoxetine (5-HT) reduced depressive symptoms. CBD + Desipramine (NE) did not, pointing towards at the necessity of serotonergic activation for antidepressant effect

Silote GP, et al. J Chem Neuroanat. 2019;98:104-116. Sales AJ, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2018;86:255-261. BDNF CBD activates 5-HT1A receptor

Hypothesis If pretreated with a TrKB receptor antagonist (K252a), then increased spine density does not occur BDNF TrkB receptor BDNF translation is turned on = BDNF

BDNF stimulates TkrB receptors

Increased dendritic spine density

BDNF = brain-derived neurotrophic factor. Sales AJ, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2018;86:255-261. mTOR Hypothesis If rapamycin is given before CBD, then increased spine density does not occur Increased mTOR signaling

Within 30–120 min synaptic growth factors activate

Increased dendritic spine density

=  neuronal growth mTOR = mammalian target of rapamycin. Sales AJ, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2018;86:255-261. Could CBD have a similar impact on synaptogenesis and depression as ketamine?

↓ immobility time = antidepressant response

Antidepressant effect was High dose (nmol/μL-1) CBD produced rapid blocked by preadministration reduction in immobility during the FST of TrkB or mTOR antagonists (a sign of antidepressant effect)

Human studies are needed

Sales AJ, et al. Mol Neurobiol. 2019;56(2):1070-1081. Could CBD help with behavioral issues in children with autism? • N=63 (83% boys) age 5–18 years with ASD

• Open-label, retrospective design

• Parent rated measures of behavior, anxiety, and communication

• 20:1 CBD:THC dosed bid-tid – (1.8–3.8/kg/day CBD and 0.22–0.29 mg/kg/day THC) • Generally well tolerated, except 1 treatment-emergent brief psychosis (on 0.72 mg/day THC) NCT03900923 at NYU is recruiting for dose finding trial ASD = autism spectrum disorder. Aran A, et al. J Autism Dev Disord. 2019;49(3):1284-1288. Poleg S, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2019;89:90-96. ClinicalTrials.gov Identifier: NCT03900923. Could cannabinoids be helpful in treating eating disorders? • Endocannabinoid signaling likely related to appetite regulation

• CB1 is richly expressed in the ventral tegmental area and nucleus accumbens and may modulate the hedonic aspects of eating

• Small studies of showed promise in increasing food intake in anorexia nervosa

• Rimonabant (a CB1 receptor antagonist may inhibit this reward signal from food consumption) was given FDA approval for treatment of obesity, but was pulled from the market after approval (increased anxiety, depression, suicidal ideation)

• A role for CBD has not been examined

Andries A, et al. Int J Eat Disord. 2014;47(1):18-23. Scherma M, et al. Curr Pharm Des. 2014;20(13):2089-2099. What should we be telling our patients about CBD? • Our database of clinical studies is limited in number and largely focused on CBD doses larger than is commonly available (or affordable)

• As such, CBD will likely, for the time being, remain a folk medicine

• Avoid either-or thinking about CBD. CBD can be a compliment to existing psychiatric medicine

• Start low, go slow, self titrate, and gather data

• Avoiding significant THC dose will reduce cognitive, anxiogenic, psychotomimetic, and intoxication risks What should we be telling our patients about CBD?

• Oral preparations reduce risk of respiratory Transparent bars: claimed content irritation from inhalation Solid bars: actual content*

• Current labeling and marketing practices add CBD+CBDA to the confusion

• Use products with clear lab analysis, understanding this is largely unregulated – A recent study found only 31% of online products tested to be accurate for CBD content** • (26% less than labeled, 42% had more THC+THCA than label) *Hazekamp A. The Trouble with CBD Oil. Med Cannabis Cannabinoids. 2018;1:65-72. **Bonn-Miller MO, et al. JAMA. 2017;318(17):1708- 1709. US Food and Drug Administration. FDA Regulation of Cannabis and Cannabis-Derived Products: Questions and Answers. www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-questions-and-answers. Accessed June 25, 2019. Can we just prescribe CBD?

Formulation: 1:1 THC/CBD Formulation: CBD only

Indication: MS Spasticity/Pain Indications: Dravet syndrome Lennox-Gastaut syndrome Not yet FDA approved (Phase 3 MS. Phase 2 neuropathic pain.) FDA approved, Schedule V $32,000/year MS = multiple sclerosis. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. If You Live in a State with Legal Cannabis Dispensing

This cartridge contains 302 mg of CBD, 25 mg of THC This bottle contains 400 mg of CBD, No THC

MAXIMUM Recommended dose 5 mg/kg PO Mangini M. Cannabis Therapeutics: Advising Patients on Safe and Effective Use. Presented at: 2018 Psych Congress; October 25, 2018; Orlando, Fl. Bennet P. Dab Dosage Guide: How to Dose Cannabis Oils and Concentrates. www.leafly.com/news/cannabis-101/dabbing- cannabis-oil-concentrates-dosage. Accessed June 25, 2019. Leafly.com Leafly.com Can the endocannabinoid system be stimulated without cannabis?

High Omega-3/Omega-6 Diet Curcumin (important in 2-AG and AEA synthesis) (may increase Nerve Red Clover and Soy Growth Factor through

CB1 receptors) (contain Biochannin A – an FAAH inhibitor)

Cacao Reduced Alcohol Wellness: (may inhibit FAAH enzyme) (short-term increases in AEA, but chronic use leads exercise, BMI, to CB1 downregulation) meditation (increased AEA, 2-AG) Bosch-Bouju C, et al. In: Meccariello R, et al (Eds). Cannabinoids in Health and Disease. IntechOpen; 2016. www.intechopen.com/books/cannabinoids-in-health-and-disease/dietary-omega-6-omega-3-and-endocannabinoids-implications-for-brain-health- and-diseases. Accessed July 17, 2019. di Tomaso E, et al. Nature. 1996;382(6593):677-678. Hassanzadeh P, et al. Neurochem Res. 2012;37(5):1112- 1120. McPartland JM, et al. PLoS One. 2014;9(3):e89566. Thors L, et al. Br J Pharmacol. 2010;160(3):549-50. Many More Studies are Needed • What are the benefits of lower dose CBD?

• What is the of THC with CBD?

• Will CBD work as a rapidly effective antidepressant in humans?

• What are the risks of long-term CBD use? Could endocannabinoid homeostasis be disrupted?

• Now that Epidiolex® is available as a prescription drug, will psychiatry begin using it in an off-label manner to attempt to replicate antipsychotic and anxiolytic clinical studies? CBD Needs Clarified Regulations and Labeling

• Is this a medicine, supplement, or a food product? – If a medicine, then FDA must approve through New Drug Application – If a supplement, laws would need to change, as because it contains an FDA approved drug – If a food product, laws would need to change, as because it contains an FDA approved drug

• An end to federal prohibition of cannabis? – What happens when most, if not all states have relaxed laws, or outright legalized cannabis, but the federal government has not? US Food and Drug Administration. FDA Regulation of Cannabis and Cannabis-Derived Products: Questions and Answers. www.fda.gov/news- events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-questions-and-answers. Accessed June 25, 2019. Take-Home Points

• CBD is a non-intoxicating, but psychoactive cannabinoid with multiple mechanisms of action that potentially lend well to multiple indications in psychiatry

• Higher doses of CBD have been studied in clinical trials and found to have benefit in studies of social anxiety and as an adjunctive treatment to antipsychotics in the treatment of schizophrenia

• It remains to be seen how CBD will be utilized in psychiatry now that a prescription form of the drug has entered the market