5. Contains over 400 chemical compounds
Highest concentration of bioactive compounds in resin
exuded from flowers of female plants
Main psychoactive component believed to be delta-9-
THC
At least 100 other cannabinoids identified in
combusted products
delta-8-THC similar in potency but only in small
concentration
6. ∆9-tetrahydrocannabinol (THC) is the primary active
ingredient of cannabis
Secondary compounds may enhance the beneficial
effects of THC
Other cannabinoid and non-cannabinoid compounds
may reduce THC-induced anxiety, cholinergic effects
and immunosuppression
Terpenoids and flavonoids may increase cerebral
blood flow, enhance cortical activity, kill respiratory
pathogens and provide anti-inflammatory activity
8. CB1 and CB2 receptors identified
Receptors encoded by separate genes on separate
chromosomes; share 48% amino acid identity
G-protein coupled receptors that inhibit adenylyl
cyclase on activation
Decreases cyclic AMP and protein kinase A activity
Inhibition of Ca++
influx through various Ca++
channels
Stimulation of inwardly rectifying K+
channels and mitogen-
activated protein kinase cascades
9. Overall effect is suppression of
neurotransmitter release at both excitatory and
inhibitory synapses
Inhibition occurs through a retrograde
signaling mecahnism
ECs are synthesized and released from post-
synaptic neurons
Diffuse backward across the synaptic cleft and
bind to CB1 receptors on the pre-synaptic terminals
13. Modulates the pharmacokinetics of THC
Very low affinity for CB1 and CB2 receptors
Slight affinity for CB receptors as an antagonist
May modulate downstream signal transduction
Potent cytochrome P450 3A11 inhibitor thus blocking
formation of 11-OH metabolite
Pre-administration of CBD may potentiate THC
effects (PK mechanism)
Simultaneous co-administration may result in
attenuation of some THC effects (PD mechanism)
16. Beneficial effects of the non-psychotropic
cannabinoid is derived from in vitro and animal
studies
Few, if any, clinical studies of these substances
exist
In vitro and animal studies do suggest many
potential therapeutic applications
18. 18
Cannabis preparations are commonly used and recommended for seizure disorders.
A survey of parents belonging to a Facebook group that focused on the use of cannabidiol-enriched cannabis
for seizures in children with early-onset, severe forms of epilepsy found that 16/19 parent respondents
reported reduced seizure frequency in their children during treatment with cannabidiol-enriched cannabis.
Two reported complete seizure freedom, and
eight reported > 80% reduction in seizure
frequency. (Porter and Jacobson 2013)
A case report of a child with Dravet syndrome found that a high concentration CBD:THC strain of cannabis,
now known as Charlotte's Web, reduced seizure frequency from nearly 50 seizures per day to 2-3 nocturnal
convulsions per month.
This effect has persisted for almost 2 years,
and Charlotte was weaned off of other
antiepileptic drugs. (Maa and Figi 2014)
Seizures (Surveys and Case Studies)
19. 19
There have been four small trials of CBD for seizures.
Seizures (RCTs)
20. 20
Larger studies of CBD for seizures are needed.
Although robust evidence for the effectiveness of CBD for seizures is lacking,
controlled clinical trials are ongoing.
For example, Epidiolex, a liquid form of
CBD made by GW Pharmaceuticals, is being
tested in a clinical trial that plans to
enroll 150 pediatric patients age 1-18
with Dravet syndrome and other
intractable epilepsies.Cannabis can be considered for intractable seizures not
controlled with medications, or when patients are unable to
tolerate seizure medications.
Seizures
21. Open label trial in 162 pts under 30 with severe,
intractable seizures on stable Rx
Enrolled at 11 US centers 1/14-1/15 and followed for
at least 12 weeks
CBD up-titrated to max of 25 mg/kg or 50 mg/kg
daily
79% with adverse events (somnolence, ↓ appetite)
Median monthly frequency of motor seizures reduced from
30.0 to 15.8. Median reduction 35.5% (IQR 0-64.7)
Devinsky, Lancet Neurol 2016
But not randomized, blinded or placebo-controlled
22. Randomized double-blind placebo-controlled
crossover trial in 15 patients with HD
CBD 10 mg/kg/day or placebo for 6 weeks
Examined effects on chorea severity, other
symptoms, toxicity
No difference seen in symptoms or toxicity between
CBD and placebo
Consroe, Pharmacol Biochem Behav, 1991
23. Open label pilot of oral CBD in 6 pts with PD
and psychosis
Psychosis improved as did overall PD symptoms
Zuardi, J Psychopharmacol 2009
3 arm RCT in 21 pts with PD (placebo, CBD 75
mg/day, CBD 300 mg/day)
No difference in motor and general symptom scores
CBD 300 mg group had improved QOL and well-
being compared with placebo (p=0.05)
Chagas, J Psychopharmacol, 2014
24. Hypothesis that enhanced anandamide signaling
with CBD will diminish psychotic symptoms
Phase II randomized double-blind controlled trial
of CBD or amisulpride in 42 adult inpatients
Ramped up to 800 mg/day each drug for 28 days
Standardized scales to measure effects on psychoses
and extrapyramidal side effects
Significant clinical improvement seen in both groups, NS
CBD associated with less extrapyramidal sx, wt gain and lower
prolactin increase (marker of sexual dysfunction)
Leweke, Trans Psychiatry, 2012
25. Double blind placebo-controlled study of
CBD 400 or 800 mg/day in heroin users
abstinent for 7 days
CBD reduced heroin-related cue-induced
craving
CBD’s attenuation of craving lasted ~7d after
last administration
CBD’s strongest effects were on the
attenuation of anxiety induced by heroin cues
Hurd, Neurotherapeutics 2015
26. Id helix-loop-helix proteins control processes
related to tumor progression
CBD down-regulates Id-1 expression in
aggressive human breast cancer cells in vitro
McAllister et al, Breast CA 2011
Addition of CBD to colorectal cancer cell lines
led to reduced cell proliferation
In mice, treatment with CBD decreased
azoxymethane induced aberrent crypt foci,
polyps and tumor formation Aviello et al, J Molec Med 2012
27. CBD-mediated attenuation of THC-induced
effects observed when CBD:THC is > 8:1
CBD-mediated potentiation of THC-induced
effects seen when CBD:THC is ~2:1
In rats and mice!
Zuardi 2012
There is NO information in scientific or medical
literature on the effects of varying CBD:THC
ratios in the Rx of medical disorders
29. Transgenic mice expressing human sickle
hemoglobin (HbS) demonstrate increased
hyperalgesia attenuated by morphine Kohli et al Blood 2010
CP55940 is a CB1 and CB2 agonist that also
markedly attenuates hyperalgesia at a dose of 0.3
mg/kg comparable to 20 mg/kg morphine
Retrospective survey of 86 SCD pts revealed 52%
reported cannabis use decreases pain, anxiety and
depression Howard et al Br J Haematology 2005
NHLBI has funded human proof of principle trial with
vaporized 4.7% THC/5.1% CBD
30. CBD is non-psychoactive and non-psychotropic
Benefits anxiety, schizophrenia, addiction and
depression
Preferably should be termed “non-intoxicating”
Lacks reinforcement, craving and compulsive use
lowering risk of abuse
Russo, Trends in Pharmacological Sciences, 2017
31. CBD is sedating
Low to moderate doses are distinctly alerting
CBD counteracts the sedative effects of THC
Studies of CBD 600 mg po show no evidence of
sedation
CBD as Epidiolex in high doses to treat epilepsy is
sedating b/o traces of THC and terpenoids
Russo, Trends in Pharmacological Sciences, 2017
32. CBD is legal in all 50 states
Although unscheduled in most nations, CBD is a
Schedule I agent in USA
Despite this prohibition, domestic commerce in
CBD is rampant
If Epidiolex is approved in a less restricted
schedule, will not change CBD status
Russo, Trends in Pharmacological Sciences, 2017
33.
34. 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.
Friedman D, Devinsky O. Cannabinoids in the treatment of epilepsy. NEJM, 2015;
373:1048-1058
Hurd YL. Cannabidiol: Swinging the marijuana pendulum from “weed” to medication to
treat the opioid epidemic. Trends in Neuroscience, 2017; in press
Leweke FM, Piomelli D, Pahlisch F et al. Cannabidiol enhances anandamide signaling
and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry, 2012; 2:e94.
McAllister SD, Murase R, Christian RT et al. Pathways mediating the effects of
cannabidiol on the reduction of breast cancer cell proliferation, invasion, and
metastasis. Breast Cancer Res Treat, 2011; 129:37-47.
Russo EB. Cannabidiol claims and misconceptions. Trends in Pharmacological
Sciences, 2017; in press
Werner CA. Marijuana Gateway to Health: How Cannabis Protects Us from
Cancer and Alzheimer’s Disease. Dachstar Press, 2011.
Yeshurun M, Shpilberg O, Herscovici C et al. Cannabidiol for the prevention of graft-
versus-host disease after allogeneic hematopoietic cell transplantation: results of a
phase II study. Biol Blood Marrow Transplant, 2015; 21:1770-1775.