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 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
 ∆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
 Cannabidiol CBD
 Cannabinol CBN
 Cannabichromene CBC
 Cannabigerol CBG
 Delta-8-THC ∆8
-THC
 Tetrahydrocannabivirin THCV
 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
 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
CB1 receptor
Pre-synaptic terminal
Post-synaptic
terminal
Neurotransmitter
vesicles
FAAH
AA
ETA
MAGL
AA
Glycerol
Neurotransmitter
receptor
Neurotransmitter
receptor
PLD
NAPE
DAG
THC
Dronabinol
Nabilone
THC
Dronabinol
Nabilone
Ca2+
- K+
Ca2+
K+
+
CB1 receptor
2-AG
2-AG
2-AG
1
1
2
2
3
3
4
4
5
5
6
6
Health Canada 2016
HEALTH CANADA
Suppression of Neurotransmitter Release
Friedman and Devinsky, NEJM 2015
 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)
CBD ALONE DOES NOT COMPLEX
WITH THE RECEPTORS
Deutsch, SUNY @ Stony Brook
 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
 Anti-inflammatory
 Analgesic
 Anti-nausea
 Anti-emetic
 Anti-psychotic
 Anti-ischemic
 Anxiolytic
 Anti-epileptiform
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
There have been four small trials of CBD for seizures.
Seizures (RCTs)
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
 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
 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
 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
 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
 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
 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
 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
From Hemprove:
Marijuana
Gateway to Health,
2011
 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
 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
 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
 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
 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.

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THC and CBD Features comparison - Hemprove

  • 2.
  • 3.
  • 4.
  • 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
  • 7.  Cannabidiol CBD  Cannabinol CBN  Cannabichromene CBC  Cannabigerol CBG  Delta-8-THC ∆8 -THC  Tetrahydrocannabivirin THCV
  • 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
  • 11. HEALTH CANADA Suppression of Neurotransmitter Release
  • 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)
  • 14. CBD ALONE DOES NOT COMPLEX WITH THE RECEPTORS
  • 15. Deutsch, SUNY @ Stony Brook
  • 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
  • 17.  Anti-inflammatory  Analgesic  Anti-nausea  Anti-emetic  Anti-psychotic  Anti-ischemic  Anxiolytic  Anti-epileptiform
  • 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.