Cannabis/Cannabinoids As Medicine?

Home , Appetite stimulant, Cannabicyclol

MEDICINAL MARIJUANA Cannabis/Cannabinoids as Medicine?

Jag H. Khalsa, MS, PhD Currently: Special Volunteer at NIDA/NIH Formerly Chief, Medical Consequences of Drug Abuse and Infections Branch, DTMC National Institute on Drug Abuse, NIH

2019 MDSAM Annual Meeting Clarksville, MD October 26, 2019

Thanks to many colleagues and authors for sharing/ letting me borrow material from their publications. Maryland-DC Society of Addiction Medicine’s Annual Meeting and Conference October 26, 2019 Disclosure for Jag Khalsa, MS, PhD

In compliance with COI policy

Shareholder No relevant conflicts of interest to declare Grant / Research Support No relevant conflicts of interest to declare Consultant No relevant conflicts of interest to declare Employee No relevant conflicts of interest to declare Paid Instructor No relevant conflicts of interest to declare Speaker bureau No relevant conflicts of interest to declare Other No relevant conflicts of interest to declare Types of Cannabis

Sativa generally has a higher THC to CBD ratio as compared with Indica. Components 2

• 104+ cannabinoids, each with their own--often complementary— pharmacology, e.g., THC, CBD, CBN, CBC, CBG etc., have been promoted for different medical conditions Only THC is psychoactive Multiple extracts can be blended to form new products Likely research targets: cancer, epilepsy, inflammation, metabolic disorder/diabetes, psychiatric disorders, substance abuse, etc.

• Plus non-cannabinoid active components, e.g., terpenes, flavonoids

• Can plant extracts be adequately characterized and standardized? GW have shown that they can and have been! MEDICINAL MARIJUANA

Active chemical constituents of Cannabis: Delta-9 THC (Tetrahydrocannabinol): Active psychoactive component CBD (Cannabidiol)- increases some of the effects of THC and decreases other effects of THC. CBN, an oxidative product of THC; some psychoactive properties (10% of THC) THCV (Tetrahydrocannabivarin): found primarily in strains of African and Asian cannabis; increases the speed and intensity of THC effects, but also causes the subjective experience to end. CBC (Cannabichromene), rare; is probably not psychoactive in pure form but is thought to interact with THC to enhance the subjective experience; has anti-depressive effects CBL (Cannabicyclol) is a degradative product like CBN (cannabinol). Light converts CBC to CBL. CBG (cannabigerol); non-psychoactive; anti-inflammatory; reduced IOP in glaucoma; antibiotic and antiplatelet clotting. • Cannabinoids Components of Cannabis Plant

• Cannabis plant is the unique source of cannabinoids • Cannabis used centuries ago possessed a 1:1 CBD:THC ratio

? analgesic, anti-spasmodic, Both compounds are THC anti-tremor, anti- in Sativex, unlike (tetrahydrocannabinol) inflammatory, appetite stimulant, anti-emetic other licensed cannabinoid CBD ? anti-inflammatory, analgesic, medicines (e.g. anti-convulsant, anti-psychotic, dronabinol, nabilone) (cannabidiol) anti-oxidant, neuroprotective;

does not bind to cannabinoid receptors does bind to other receptors in the body Single product reduces the negative effects of THC polypharmacology has been bred out of modern herbal cannabis! Approved Cannabinoid Pharmaceuticals  Sativex (GW) - Mouth spray; contains natural extract of the cannabis plant; THC+CBD (1:1 ratio);[20 countries but not US]

 Dronabinol / Marinol (Unimed)/Solvay; Synthetic Delta-9-THC – Approved for appetite stimulation and reducing nausea

 Nabilone / Cesamet (Valeant); Synthetic cannabinoid similar to THC. For Treatment of nausea and vomiting in patients undergoing cancer treatment. MEDICINAL MARIJUANA

Clinical Evidence MEDICINAL MARIJUANA

Anti-emetic Effects: •Nabilone (Cesamet) approved; dose: 2-6 mg/day; approximately 15 controlled studies with ~600 patients with cancer, drug was effective (superior to other known drugs such as prochlorperazine, domperidone etc.) for treating chemotherapy- associated nausea/vomiting. •Dronabinol (Marinol) (5-15 mg/m2/day) was found to be effective in 14 controlled studies involving 681 patients with cancer for treating chemotherapy- associated nausea and vomiting. However, there are significant side effects (dizziness, drowsiness, hallucinations, euphoria etc.) that have reduced their use. MEDICINAL MARIJUANA

Anti-emetic Effects (contd.):

•Smoked marijuana: Three Canadian studies, 2 by Chang et al. 1979 and 1981; and one by Levitt et al. 1984 used smoked marijuana for anti-emetic effects. • Was effective in 25% patients; of 20 study patients, 20% preferred smoked Mj, 30% preferred oral nabilone and 45% did not express any preference.

•The newer agents such as 5HT3 receptor antagonists are much better than cannabinoids. MEDICINAL MARIJUANA

Appetite-Stimulant Effects: • [741 patients; 5 controlled studies] Oral THC (dronobinol [Marinol]), 2.5-20 mg/day; -- • As a stimulant of appetite-(FDA-for treating AIDS-anorexia); and by Canada. • Smoked marijuana (2.5 mg, tid) was effective in stimulating appetite in 67 HIV-infected patients without affecting viral load or immune function (CD4 counts) (Abrams et al. 2003).

• (References for appetite stimulant effects: Iversen 2000; Beal et al. 1995 [139 pts]; Regelson et al. 1976 [54 pts]; Struwe et al. 1993 [12 pts]; Jatoi et al. 2002 [469 pts]; and Abrams et al. 2003 [67 pts]). MEDICINAL MARIJUANA Analgesic Effects: •14 studies [353 pts]; oral THC, sublingual spray, or iv THC, have been tested. •Oral THC at 10, 15 and 20 mg doses was effective, but with significant ADRs (e.g., drowsiness, confusion). The 5mg THC was ineffective as an analgesic. •Recent data from Ware et al. (2010) in 21 patients, a single inhalation dose of 25 mg of 9.5% THC showed positive effects on neuropathic pain. No significant effects at lower doses. •(References for analgesic effects: Noyes et al. 1975a, b [46 pts]; Raft et al. 1977 [10 pts]; Staquet et al. 1978a [10 pts]; 1978b [30 pts]; Jochimsen et al. 1978 [35 pts]; Jain et al. 1981 [56 pts]; Lindstrom et al. 1987 [10 pts; Holcroft et al. 1997 [1 pt]; Karst et al. 2003 [21pts]; Buggy et al. 2003 [40 women]; Neef et al. 2003 [12 pts]; Notcutt et al. 2004 [34 pts]; Berman et al. 2004 [48 pts]; Ware et al. 2010 [23 pts]). MEDICINAL MARIJUANA

Multiple Sclerosis: • 13 controlled studies [total 939 pts]; smoked marijuana, hashish, oral THC in capsule, oral extracts of C. sativa in oral and sublingual spray forms containing THC, cannabidiol, or a combination of the two and oral nabilone. • Two clinical trials are worthy of note: Zajicek et al. 2003 [630 pts-15 wks]; Wade et al. 2004; 160 pts). Data from most studies showed some effect on mobility and muscle spasticity compared to placebo. MEDICINAL MARIJUANA Multiple Sclerosis (contd.): •Zajicek et al: [double blind randomized placebo controlled trial]: 206 SS on oral THC in capsule, 211 SS on oral cannabis extract [2.5 mg THC+ 1.25 mg cannabidiol, + <5% other cannabinoids/capsule], and 213 SS on placebo, for 15 wks. •No objective effects on spasticity but subjective improvement in spasticity was observed; there was objective improvement in mobility and decreased hospitalizations with oral THC. ADRs were mild and tolerable. Overall, one year f/u showed positive effects on spasticity. MEDICINAL MARIJUANA Multiple Sclerosis (contd.): • Wade et al (2004) study [160 pts]; (Sativex capsules; cannabis extract [oral THC 2.5 mg + cannabidiol 2.7 mg]; total doses: 2.5-120 mg/d; 6 wks].

• Results showed significant reduction in spasticity, sleep quality and mobility with Sativex compared to placebo.

• ADRs were mild and well-tolerated. MEDICINAL MARIJUANA Multiple Sclerosis (contd.):

• Another small randomized, double-blind, parallel groups, placebo controlled study of 4 wks [n=32/group] (Rog et al. 2005) showed similar beneficial effects of Sativex [THC+CBD by oromucosal spray] on pain and sleep disturbance (spasticity).

• ADRs (dizziness, dry mouth, and somnolence] were mild]; cognitive effects were limited to long term memory storage. MEDICINAL MARIJUANA Spinal cord injuries:

• Only 3 studies in the literature; • (i)-5 patients, (ii) 1 patient, (iii) 4 patients; • oral THC or C. sativa extracts (THC, cannabidiol or a combination] in sublingual spray, may lead to an improvement in spasticity, muscle spasm, pain, vesicle dysfunction and sleep quality.

• (References for Spinal cord injuries: Hanigan et al. 1986 [5 pts]; Wade et al. 2003 [4 pts]; Maurer et al. 1990 [1 pt]). MEDICINAL MARIJUANA Gilles de la Tourette’s Syndrome:

•Two randomized, double-blind, placebo controlled studies (12 and 24 patients), oral THC (up to 10 mg/d for 6 wks) significantly reduced the frequency of tics. •ADRs –no serious ADRs (one patient dropped out due to anxiety and agitation).

•(References for Gilles de la Tourette’s syndrome: Muller- Vahl et al. 2002a [12 pts], 2003a [24 pts]); MEDICINAL MARIJUANA Epilepsy: • Several anecdotal observations suggest positive effects of cannabidiol on grand mal epilepsy. • One controlled RDBPC-clinical study of 15 patients inadequately controlled on conventional anti-epileptic meds; • Group 1: 8 patients; oral CBD at 200-300 mg/d, for 8-18 wks, in addition to their conventional meds; • Group 2: 7 on placebo. • Tx group: of the 8 pts, 4 remained convulsion-free for the duration; 3 showed clinical improvement. • Placebo: No change • ADRs: Drowsiness in 4 of the treated patients. • (Cunha et al. 1980) MEDICINAL MARIJUANA Epilepsy (contd.): • Tzadok et al. (2016): CBD-enriched cannabis showed reduced the frequency of seizures in 89% (66/74) of the treated children with intractable epilepsy; 7% pats reported aggravation of seizures leading to CBD withdrawal. • % Subjects Reduction in seizure activity • 18% 75-100% • 34% 50-75% • 12% 25-50% • 26% <25%

Improvement in behavior, alertness, language, communication, motor skills and sleep. MEDICINAL MARIJUANA Epilepsy (contd.): • Devinsky et al. (2016): Large 11 Center study • Open label interventional clinical trial, CBD at 2-5 mg/kg/d for 12 weeks tested in patients (1-30 yr old) with severe intractable, childhood-onset, treatment-resistant epilepsy, receiving conventional anti-epileptics. • Median monthly frequency of seizures reduction was 36.5% over 12 wk period. ADRs in 79% patients: to be completed. MEDICINAL MARIJUANA Glaucoma: • Anecdotal reports of cannabis on intraocular pressure but only two controlled studies in the literature. • Merritt et al. (1980), in a RDBPC study showed that one Mj cigarette containing 2% THC significantly reduced IOP. • In another RDBPC study, Merritt et al. (1981) showed that eye drops containing 0.01, 0.05, and 0.1% THC, significantly reduced the IOP. ADRs were significant: tachycardia, palpitations, and postural hypotension.

• (References for glaucoma: Merritt et al. 1980 [18 pts], 1981 [8 pts]) MEDICINAL MARIJUANA Parkinson Disease: • Only two controlled clinical trials have studied the effect of cannabinoids on Parkinson disease. • Both clinical trials (one of 7 and another of 19 pts) did not show any beneficial effect of oral THC (nabilone) on the disease. • (References for Parkinson Disease: Sieradzan et al. 2001 [7 pts]; Carroll et al. 2004 [19 pts]) Dystonia: Only one RDB cross-over PC- controlled study (Fox et al. 2002) of 15 patients showed no beneficial effects of oral THC (nabilone) on generalized and segmental dystonia.

• (References for dystonia: Fox et al. 2002 [15 pts]) PTSD PTSD & Nabilone (Cesamet) – Nabilone: 72% of patients experienced cessation of nightmares or reduction in nightmare intensity; subjective improvement in sleep quality & time, reduction of daytime flashbacks and night sweats. Suggesting potential benefit of nabilone in PTSD. (Fraser, GA CNS Neurosci Ther. 2009) – Nabilone at 4.0 mg: sig improved PTSD-symptoms including insomnia, nightmares; and Global Assessment of Function, subjective improvement in chronic pain in 104 male inmates with serious mental illness. (Cameron et al. 2014) – A RDPC study of 15 patients: No beneficial effect on generalizewd segmental dystonia (Fox et al. 2002). More randomized trials are needed to confirm the efficacy of cannabis in treatment of PTSD (Wilkinson et al. ) MEDICINAL MARIJUANA EFFICACY SUMMARY: • Limited data from small clinical studies or trials show the following: • Nausea/Vomiting: Oral THC (FDA-approved nabilone or dronabinol) for treating chemotherapy-associated nausea/vomiting. • Oral THC shows some appetite stimulant activity in HIV-infected patients, but large clinical trials with oral THC or smoked marijuana are needed for FDA approval. • Neuropathic pain: Sativex approved in Canada and other countries; • For inflammation, MS, dystonia, Tourette’s syndrome, Parkinson disease, or glaucoma: • No good evidence from large clinical trial(s) that would support the use of either oral THC or smoked marijuana in clinical practice. • PTSD: Limited evidence to treat with cannabis • Well-designed RDB-placebo controlled trials are needed to obtain the FDA approval to use smoked marijuana or cannabinoids for the treatment of any of the above mentioned conditions. CBD products CBD and Your Health Cannabis Constituents

CBD Oil: Manufacture: CBD oil is extracted from flowers and leaves of the plant, C. sativa using super critical CO2 method of extraction. Manufacturers claim it to contain up to 99.9% CBD and less 0.03% THC. It is primarily being used for medicinal purposes treating a wide range of clinical conditions. Incidentally, other methods of extraction use ethanol, olive oil or even naphtha or petroleum as solvents.

Hemp Oil: Manufacture: Hemp oil is extracted (cold-pressed) from the seeds of the plant, typically from the industrial hemp plant, Cannabis sativa, and is used as protein supplement and in lotions, creams and soap. It contains very small amounts of THC. It may contain as much as 25 ppm of CBD.

Discussion follows Pharmacology of Cannabinoids • Pharmacologic actions of non-psychotropic cannabinoids (with indications of possible mechanisms of action, Izzo et al. 2009) Medicinal Value of Cannabinoids

Cannabidiol (CBD): non-psychoactive, increases some of the effects of THC and decreases other effects of THC. • Anti-inflammatory, anti-fibrotic, antioxidant, neuroprotective, antiepileptic, etc.

• Conditions for which it has been tested: • Anxiety Depression Nausea/vomiting Epilepsy Schizophrenia Alzheimer’s Parkinson’s Pain • Bipolar disorder Stroke MS ADHD • Sleep disorders Spinal cord injuries Brain Injury

• Details to follow Approved Cannabinoid Pharmaceuticals  Epidiolex (CBD; GW): For treating epilepsy (Dravet synd) in children

 Sativex (GW) - Mouth spray; contains natural extract of the cannabis plant; THC+CBD (1:1 ratio);[20 countries but not US]

 Dronabinol / Marinol (Unimed)/Solvay; Synthetic Delta-9-THC – Approved for appetite stimulation and reducing nausea  Nabilone / Cesamet (Valeant); Synthetic cannabinoid similar to THC. For Treatment of nausea and vomiting in patients undergoing cancer treatment. Cannabidiol (CBD)

CLINICAL EVIDENCE FOR CANNABIDIOL AS MEDICINE Cannabidiol (CBD) Epilepsy: • Several anecdotal observations suggest positive effects of cannabidiol on grand mal epilepsy. • One controlled RDBPC-clinical study of 15 patients inadequately controlled on conventional anti-epileptic meds; • Group 1: 8 patients; oral CBD at 200-300 mg/d, for 8-18 wks, in addition to their conventional meds; • Group 2: 7 on placebo. • Tx group: of the 8 pts, 4 remained convulsion-free for the duration; 3 showed clinical improvement. • Placebo: No change • ADRs: Drowsiness in 4 of the treated patients. • (Cunha et al. 1980) Cannabidiol (CBD) Epilepsy (contd.): Devinsky et al. (2016): Large 11 Center study (n=214); Open label interventional clinical trial, CBD at 2-5 mg/kg/d for 12 weeks tested in patients (1-30 yr old) with severe intractable, childhood-onset, treatment-resistant epilepsy, receiving conventional anti-epileptics. • Median monthly frequency of seizures reduction was 36.5% over 12 wk period. ADRs in 79% patients: Somnolence, 25%; reduced appetite, 19%; diarrhea 19%; Fatigue, 13%; convulsions, 11%; one unexpected death, status epilepticus 9%. NOTE: Of the 102 clinical trials registered in www.clinicaltrials.gov, 26 are studying the efficacy of CBD for one or more types of seizures. CURRENT: CBD [EPIDIOLEX]-approved for tx Dravet and LG- epilepsy in young children Cannabidiol (CBD) Epilepsy (contd.): • Tzadok et al. (2016): CBD-enriched cannabis reduced the frequency of seizures in 89% (66/74) of the treated children with intractable epilepsy; 7% pts reported aggravation of seizures leading to CBD withdrawal. • % Subjects Reduction in seizure activity • 18% 75-100% • 34% 50-75% • 12% 25-50% • 26% <25%

Improvement in behavior, alertness, language, communication, motor skills and sleep. Cannabidiol (CBD) Alzheimer’s and Parkinson’s Diseases: • Alzheimer’s disease: • CBD prevented development of amyloid plaques suggesting it could treat AD (Libro et al. 2016). • In-vivo evidence supported its use in AD (Watt and Karl, 2017). But a lot more clinical research is needed to support its use in treating AD (Mannucci et al. 2017).

• Parkinson’s Disease: • In a double blind randomized clinical trial, CBD at 75 mg/d or 300 mg/d was ineffective in controlling motor effects but improved the quality of life (reducing REM- sleep disturbances) of 7 patients (Chagas et al. 2014). Cannabidiol (CBD) Alzheimer’s and Parkinson’s Diseases (contd): • Parkinson’s Disease: • • In a pilot study with 6 PD patients (4 men and 2 women) with diagnosis of psychosis, CBD at 150 mg/d for 4 wks, in addition to their usual therapy, significantly decreased the total scores of Unified Parkinson’s dis rating scale, with no adverse effects. Suggesting that CBD may be effective, safe and well-tolerated for treating psychosis in PD (Zuardi et al. 2009). Cannabidiol (CBD)

Movement disorders/Multiple Sclerosis: • CBD (CBD+THC) was effective in patients (n=52 from 6 sites) with MS with resistant spasticity (Lus et al. 2018)). • CBD improved mobility in pts with MS (Rudroff et al. 2018).

• CBD + THC (Sativex) was effective in treating MS without adversely impairing driving performance (Celius et al. 2018). • In a clinical trial (n=349), pts with moderate to severe MS and who were resistant to other drugs, CBD+THC (Sativex) improved their spasticity-related symptoms (Vermersch and Trojano, 2016). Cannabidiol (CBD) Trauma/Injuries/Stroke: •For its neuroprotective effects (Schiavon et al. 2014), CBD showed positive effects in the rat model of spinal cord injury (Kwiatkoski et al. 2012). •There are no human studies, but could be developed to treat spinal cord and brain injuries. •Similarly, studies in rats (Pazos et al. 2012) and mice (Hayakawa et al. 2007) that showed CBD protected against brain damage in stroke. •But there are no data from studies in humans to support its use in treating stroke in humans. Cannabidiol (CBD) Anxiet/Depressive Disorders: • CBD appears to be a promising drug to treat: • Anxiety, opiate use disorders, panic disorder, generalized anxiety disorder, PTSD, social anxiety disorder. • Several anecdotal reports support the benefits of CBD in treating anxiety. • CBD acts on serotonin pathways, and endocannabinoid system (anandamide); thus could treat depression and bipolar disorder. But there are no good clinical studies to suggest that CBD is effective in treating depression as yet. Cannabidiol (CBD) Sleep disorders: • In animal models, CBD was effective in promoting wakefulness via triggering increased levels of dopamine (Murillo-Rodriguez et al. 2006).

• In one case report, CBD improved the quality and quantity of sleep in a 10-year old patient with PTSD, likely due to its anti-anxiety-relieving benefits (Shannon et al. 2016). Cannabidiol (CBD) Schizophrenia: • Preclinical and clinical studies show that CBD could treat schizophrenia and related symptoms like hallucinations and delusions, via increasing the naturally occurring endocannabinoids, anandamide. • In patients with schizophrenia, CBD at 600 mg/d was well tolerated with no worsening of mood, suicidality or movement side effects, but it was ineffective in treating cognitive impairment and other neuropsych complications of schizophrenia (Boggs et al. 2018). • Extensive review of the literature by Khoury et al. (2017) and Osborne at al. (2017) suggest that clinical evidence to treat SC with CBD is unconvincing. Cannabidiol (CBD) Schizophrenia (contd): • In a study of 18 regular cannabis users, CBD at 200 mg/d over a 10-week period, reduced the neuroanotmical damage in the hippocampus without causing any adverse effects; suggesting the neuroprotective role of CBD against brain structural harm caused by chronic cannabis use (Beale et al. 2018).

• Thus CBD might be a useful adjunct in the treatment of cannabis dependence and a range of clinical disorders characterized by hippocampal pathology (schizophrenia, Alzheimer’s disease and major depressive disorders). Cannabidiol (CBD)

Anti-emetic Effects: Proposed use for nausea is relatively recent. Preclinical research in animals suggests that CBD may stop nausea and vomiting in humans. CBD may be particularly helpful in treating nausea in patients that are not getting relief from prescribed anti-nausea drugs (prochlorperazine). But there are no clinical studies to support its use for treating nausea/vomiting in humans.

Appetite Stimulant Effects: No clinical studies to support its use as appetite stimulant. Cannabidiol (CBD) Inflammation and Pain (analgesic effect): •Preclinical research suggests CBD could be used to treat: •Colitis, inflammatory bowel disease (IBD), Crohn’s disease. •But CBD at 10 mg/d, po, was ineffective in treating Crohn’s disease in a small number of patients (Naftali et al. 2017). •For chronic neuropathic pain, CBD at 40 mg/d for one week was ineffective in patients with chronic neuropathic pain (Ben, 2006).

• CBD could treat cancer pain (Darkovska et al. 2018). But potential benefits could outweigh its potential harm (Mucke et al. 2018). •Currently, there are no good clinical studies to support its use to treat cancer pain. Cannabidiol (CBD) CBD for treating substance use disorders:

•Tobacco: •In one study of 24 tobacco smokers, CBD for one week resulted in subjects smoking 40% less cigarettes than placebo (Morgan et al. 2013).

•In another study, a single oral dose of 800 mg CBD reduced the salience and pleasantness of cigarette cues; but did not decrease tobacco craving or withdrawal or subjectivity related side effects. • Cannabidiol (CBD) CBD for treating substance use disorders: •CUD: •In one RDB-placebo controlled trial, CBD+THC (Sativax) plus MET/CBT, reduced cannabis use and craving, but not withdrawal symptoms in chronic cannabis smokers (Trigo et al. 2018). •In another study, cannabis users reported reduced euphoria when smoking cannabis. There were no impairment of cognition or psych function; were fewer depressive and psychotic-like symptoms, improved attentional switching, verbal learning and memory (Slowij et al. 2018). •Additional trials are recommended. MEDICINAL MARIJUANA EFFICACY SUMMARY: • Data from clinical studies and trials show the following: • • CBD in combination with THC can treat neuropathic pain.

• MS-related neuropathic pain: Sativex approved in 25 countries. • CBD can treat seizures/epilepsy. Based on excellent and convincing data from clinical trials, the FDA has for the first time approved CBD (Epidiolex [GW]) for the treatment of a specific type of epilepsy in children (Dravet syndrome). Cannabidiol (CBD) EFFICACY SUMMARY (contd.):

• No good evidence from large clinical trial(s) that would support the use of CBD as medicine for the treatment of a wide range of clinical conditions as claimed in the lay literature.

• Well-designed RDB-placebo controlled trials are needed to obtain the FDA approval to use CBD or other cannabinoids for the treatment of any of the discussed conditions. CBD sample variability

• Table 1. Analysis of Dutch cannabis oil samples obtained from actual patients, comparing the claimed cannabinoid content on the product label with lab results measured in the study. • Sample ID CBD(A) THC(A) • label, % measured, % deviation, rel. % label, % measured, % deviation, rel. % • 1 27 2.3 –91.5 17 0.1 –99.4 • 2 25 0 –100 35 4.6 –86.9 • 3 12 0.2 –98.3 – 0 * • 4 10.9 2.8 –74.3 – 0.1 * • 5 10 2.2 –78 10 4 –60 • 6 8 0.6 –92.5 4 0.2 –95 • 7 8 0.6 –92.5 4 0.1 –97.5 • 8 6 0.2 –96.7 5 0.1 –98 • 9 5 0 –100 40 3.4 –91.5 • 10 4 4.7 +17.50 – 0.2 * • • CBD, cannabidiol; THC, tetrahydrocannabinol; CBD(A), total sum of CBD plus CBD-acid; THC(A), total sum of THC plus THC-acid. * Not applicable because no label claim was made. • [Hazekamp A. The trouble with CBD oil, Med Cannabis Cannabinoids, 2018; 1:65-72; partial data shown] CBD sample variability

• CBD, cannabidiol; THC, tetrahydrocannabinol; CBD(A), total sum of CBD plus CBD-acid; THC(A), total sum of THC plus THC-acid. * Not applicable because no label claim was made. [Hazekamp A. The trouble with CBD oil, Med Cannabis Cannabinoids, 2018; 1:65-72] Medicinal Value of Cannabinoids Cannabichromene (CBC): rare, probably not psychoactive in pure form, thought to interact with THC to enhance the subjective experience; has anti-depressive effects Seems to act via non-CB1 receptor; Anti-inflammatory: Reduces inflammation-induced hypermotility in mice; Anti-fibrotic in mouse and human skin sebocytes, thus potential to treat dry skin conditions Reduces the formation of cardioprotective epoxides, thus protective against cannabis-induced cardiac complications

No human data. More clinical studies needed.

Cannabivarin (CBV): Since its discovery in 1971, no animal or human studies have been conducted.

Cannabinol (CBN): By product of THC metabolism; not much is known about its pharmacology or any pre-clinical or clinical observations Medicinal Value of Cannabinoids Cannabigerol (CBG): non-psychoactive; neuroprotective, anti-inflammatory, anti-oxidant – Neuroprotective: Animal studies positive for testing for MS

– Anti-inflammatory: Colitis, IBD, and dry skin conditions- acne and psoriasis

– Inhibited growth of colon, breast and human oral epithelial cancer cells

– Reduced intraocular pressure in the rat and cat but not in monkey – Elicited hyperphagia and increased the frequency of food intake, thus could treat eating disorders including cachexia Medicinal Value of Cannabinoids

Cannabidivarin (CBDV): Isolated in 2005 from C. sativa; occurs in high concentrations in cannabis from India, Hashish from Pakistan and in small concentrations in Mexican varieties; non-psychoactive

– For its antiepileptic action, it may act independent of CB1 receptors, modulation of neuronal excitability and neuroinflammation and expression of epilepsy genes in the hippocampus, neocortex and prefrontal cortex (Amada et al. 2013).

– A case report of a patient successfully treated with CBDC. – Anti-inflammatory (dry skin conditions) [Olah et al. 2016] Medicinal Value of Cannabinoids delta-9-Tetrahydro-Cannabivarin (THCV): found primarily in strains of African and Asian cannabis; increases the speed and intensity of THC effects, but also causes the subjective experience to end.

– Antipsychotic, Anti-convulsant, Anti-inflammatory, Immunomodulatory properties – Pre-Clinical and clinical studies---suggest potential to treat:

– Epilepsy, MS, schizophrenia symptoms, neuropathy, inflammatory conditions like pain, cancer, diabetic complications, obesity, CV dysfunction, nephropathy, bladder dysfunction, and dry skin conditions like acne and psoriasis

– Marker of Cannabis use MEDICINAL MARIJUANA References

Beale C, Broyd SJ, Chye Y et al. Prolonged Cannabidiol Treatment Effects on Hippocampal Subfield Volumes in Current Cannabis Users. Cannabis Cannabinoid Res 2018;3:94-107. Ben AM. Cannabinoids in medicine: A review of their therapeutic potential. J. Ethnopharmacol. 2006; 105:1-25. Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurotherapeutics 2015;12:825-836. Boggs DL, Surti T, Gupta A et al. The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial. Psychopharmacology (Berl) 2018;235:1923-1932. Celius EG, Vila C. The influence of THC:CBD oromucosal spray on driving ability in patients with multiple sclerosis-related spasticity. Brain Behav 2018;8:e00962. Chagas MH, Zuardi AW, Tumas V et al. Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial. J Psychopharmacol 2014;28:1088-1098. Devinsky O, Marsh E, Friedman D et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol 2016;15:270-278. Devinsky O, Patel AD, Cross JH et al. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N Engl J Med 2018;378:1888-1897. Devinsky O, Patel AD, Thiele EA et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology 2018;90:e1204-e1211. Giacoppo S, Pollastro F, Grassi G, Bramanti P, Mazzon E. Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis. Fitoterapia 2017;116:77-84. Hayakawa K, Mishima K, Nozako M et al. Repeated treatment with cannabidiol but not Delta9- tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. Neuropharmacology 2007;52:1079-1087. Hazekamp A. The trouble with cannabidiol oil. Med Cannabis Cannabinoids, 2018; 1:65-72. Khoury JM, Neves MCLD, Roque MAV et al. Is there a role for cannabidiol in psychiatry? World J Biol Psychiatry 2017;1-16. MEDICINAL MARIJUANA

Kwiatkoski M, Guimaraes FS, Del-Bel E. Cannabidiol-treated rats exhibited higher motor score after cryogenic spinal cord injury. Neurotox Res 2012;21:271-280. Libro R, Diomede F, Scionti D et al. Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci 2016;18. Mannucci C, Navarra M, Calapai F et al. Neurological Aspects of Medical Use of Cannabidiol. CNS Neurol Disord Drug Targets 2017;16:541-553. Morgan CJ, Das RK, Joye A, Curran HV, Kamboj SK. Cannabidiol reduces cigarette consumption in tobacco smokers: preliminary findings. Addict Behav 2013;38:2433-2436. Mucke M, Phillips T, Radbruch L, Petzke F, Hauser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2018;3:CD012182. Murillo-Rodriguez E, Millan-Aldaco D, Palomero-Rivero M, Mechoulam R, Drucker-Colin R. Cannabidiol, a constituent of Cannabis sativa, modulates sleep in rats. FEBS Lett 2006;580:4337-4345. Naftali T, Mechulam R, Marii A et al. Low-Dose Cannabidiol Is Safe but Not Effective in the Treatment for Crohn's Disease, a Randomized Controlled Trial. Dig Dis Sci 2017;62:1615-1620. Osborne AL, Solowij N, Weston-Green K. A systematic review of the effect of cannabidiol on cognitive function: Relevance to schizophrenia. Neurosci Biobehav Rev 2017;72:310-324. Pazos MR, Cinquina V, Gomez A et al. Cannabidiol administration after hypoxia-ischemia to newborn rats reduces long-term brain injury and restores neurobehavioral function. Neuropharmacology 2012;63:776-783. Rudroff T, Sosnoff J. Cannabidiol to Improve Mobility in People with Multiple Sclerosis. Front Neurol 2018;9:183. Schiavon AP, Soares LM, Bonato JM, Milani H, Guimaraes FS, Weffort de Oliveira RM. Protective effects of cannabidiol against hippocampal cell death and cognitive impairment induced by bilateral common carotid artery occlusion in mice. Neurotox Res 2014;26:307-316. Shannon S, Opila-Lehman J. Effectiveness of Cannabidiol Oil for Pediatric Anxiety and Insomnia as Part of Posttraumatic Stress Disorder: A Case Report. Perm J 2016;20:108-111. Solowij N, Broyd SJ, Beale C et al. Therapeutic Effects of Prolonged Cannabidiol Treatment on Psychological Symptoms and Cognitive Function in Regular Cannabis Users: A Pragmatic Open-Label Clinical Trial. Cannabis Cannabinoid Res 2018;3:21-34. Cannabidiol (CBD)

Trigo JM, Soliman A, Quilty LC et al. Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: A pilot randomized clinical trial. PLoS One 2018;13:e0190768. Vermersch P, Trojano M. Tetrahydrocannabinol:Cannabidiol Oromucosal Spray for Multiple Sclerosis-Related Resistant Spasticity in Daily Practice. Eur Neurol 2016;76:216-226. Watt G, Karl T. In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer's Disease. Front Pharmacol 2017;8:20. Zuardi A, Crippa J, Dursun S et al. Cannabidiol was ineffective for manic episode of bipolar affective disorder. J Psychopharmacol 2010;24:135-137. Zuardi AW, Crippa JA, Hallak JE et al. Cannabidiol for the treatment of psychosis in Parkinson's disease. J Psychopharmacol 2009;23:979-983. CONTACT

Jag H. KHALSA, MS, PhD

Special Volunteer, NIDA/NIH Retired October 2017 after 30 years as: Chief, Medical Consequences of Drug Abuse and Infections Branch, DTMC, National Institute on Drug Abuse, NIH E-mail: [email protected]

Personal e-mail: [email protected] 24924 McNair Place ALDIE, VA 20105 Telephone: 703-475-6727 (cell)