Cannabis/Cannabinoids as Medicine?...Types of Cannabis Sativa generally has a higher THC to CBD...
Transcript of Cannabis/Cannabinoids as Medicine?...Types of Cannabis Sativa generally has a higher THC to CBD...
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!
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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,
anti-tremor, anti-
inflammatory, appetite
stimulant, anti-emetic
THC(tetrahydrocannabinol)
does not bind to cannabinoid receptors
does bind to other receptors in the body
reduces the negative effects of THC
has been bred out of modern herbal cannabis!
CBD(cannabidiol)
? anti-inflammatory, analgesic,
anti-convulsant, anti-psychotic,
anti-oxidant, neuroprotective;
Both compounds are
in Sativex, unlike
other licensed
cannabinoid
medicines (e.g.
dronabinol, nabilone)
Single product
polypharmacology
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.
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Clinical Evidence
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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.
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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.
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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]).
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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]).
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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.
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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.
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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.
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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.
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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]).
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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]);
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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)
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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.
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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.
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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])
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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. )
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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.
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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
• 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. %
• 11 4 5.4 +35 – 0.3 *
• 12 4 4 0 – 0 *
• 13 4 4.2 +5 – 0 *
• 14 3 3.1 +3.3 – 0.2 *
• 15 2.75 2.8 +1.8 – 0.1 *
• 16 0.1 0.1 0 4 6.3 +57.5
• 17 – 0.1 * 7 7.9 +12.9
• 18 – 0 * 5 0.7 –86
• 19 – 0 * 5 0.9 –82
• 20 – 0.1 * 20 15.8 –21
• 21 – 0 * 7 6.4 –8.6
• 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 CannabinoidsCannabichromene (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)