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MEDICAL USE OF CANNABIS– with a
focus on Neuromuscular Disorders
• Gregory T. Carter, MD, MS
Medical Director
• Muscular Dystrophy Association
Regional Neuromuscular Center
Olympia, WA
Overview of Lecture
• the colorful history of cannabis in
America: Politics, Paranoia, and Harry
Anslinger
• Pharmacology
• Clinical Applications
• Research – from bench to bedside
Cannabis
• cannabis is one of the oldest known psychoactive
plants
• First reported use as medicine > 5000 years ago
• Introduced into Western medicine in 1840’s by
• Dr. W.B. O’Shaughnessy
• One of earliest non-food plants cultivated
– fiber for rope, seeds for oil and birdseed
– mixture of leaves, stems, tops
– 1960’s: 1-3% THC; 1990’s: up to 8-10%
The chemical makeup of cannabis
• The active ingredients in cannabis are
cannabinoids, a group of terpenophenolic
compounds The cannabinoids are
concentrated in a viscous resin that is
produced in glandular structures known as
trichomes, these are the tiny, sticky hair
like formations you see at the end of
buds.
Some of the more prominent
cannabinoids include:
• Delta-9-tetrahydrocannabinol (THC)
• Cannabidiol (CBD)
• Cannabinol (CBN)
• Tetrahydrocannabivarin (THCV)
• Cannabichromene (CBC)
• Cannabicyclol (CBL)
• Yet still another est. 80-100 other cannabinoids!
Cannabis – medical uses
• Has been used medicinally, spiritually, and
recreationally for thousands of years
• Promoted for putative analgesic, sedative,
antiinflammatory,
• antispasmodic and anticonvulsant properties
• Glaucoma (decreases intraocular pressure)
• Antiemetic (reduce nausea and vomiting)
• Enhance appetite (e.g., AIDS patients)
History of Cannabis
• Chinese cultures were growing marijuana
more than 3000 years ago.
• there are 3,000-year-old Egyptian
mummies that containing cannabis traces
• The first written account of cannabis
cultivation (ostensibly used as medical
marijuana) is found in Chinese records
dating from 28 B.C.
Examples of Flowers from Different Clones
“Bubble Gum”
“Big Bud”
“Dutch Northern Lights”
That came from
• Cannabis seeds
Preparing the flowers to use
• Wet flowers on a scale (L)
• Dried flowers ready to use (R)
Hashish
– dried resin from top of female plant
– THC usually 2-5%, but up to 15%
Hash Oil
– organic extraction
from hashish
– THC usually ~ 10-20%
up to 70%
FDA-Regulated Cannabinod-Based Medicines:
Chemicals, Extracts, Botanicals
Photo from pharmer.org
Photo from epocrates.com
Photo from nida.org
Dronabinol
(Marinol™)
Nabilone
(Cesamet™)
Cannabis Sativa L.
Extracts (Sativex™)
Photo from Russo et al. 2002
Cannabis Sativa L.
Cigarettes
Photo from Russo et al. 2002
Photo from wikipedia.org
1985
1985
2006
Approximately 460 chemical
constituents, >100
phytocannabinoids
1976
SF General Hospital Inpatient Clinical Trials Ward—Smoked Cannabis in HIV
Neuropathy, Pilot Study
A different kind of pharmacy
CANNABIS AT A PHARMACY IN THE NETHERLANDS
Meanwhile, back at the warehouse
AN INDUSTRIAL GROW HOUSE – NOTE UNIFORMITY OF
PLANTS
Here in the United States, circa 1900…
• many cannabis based medications were
produced by Eli-Lilly, Parke Davis, and
Sharp Dohme (now Merck Sharp Dohme).
• Tinctures
• Pills
• Liniments
Cannabis Tincture, circa 1910, Parke
Davis
Cannabis for neuropathic pain…in 1906
Cannabis for Neuralgia 1925
And then along came Harry…
Harry Anslinger
• Had NO formal medical training
• Our first drug czar
• Despite being “anti-drug”, he authorized a pharmacist near
the White House to supply morphine for addicted Senator
Joseph McCarthy during the communist crusades.
• Openly prosecuted doctors for over-prescribing, sending
some to prison Single-handedly created “Reefer Madness”
• Anslinger was privately funded by William Randolph Hearst
who wanted to eliminate hemp as an industrial competitor
• This also allowed Anslinger, an avowed racists, to rid the
southwest of Hispanics
•
Thanks to one man…
• cannabis was criminalized in the United
States by 1942
• against the advice of the AMA
• And just for entertainment value, we had…
• REEFER MADNESS
The laws started to change…
•
Every government-appointed commission investigating marijuana's
medical potential has issued favorable findings.
•
This include
•
1) The Nixon appointed Shafer Commission in 1972
•
2) the U.S. Institute of Medicine in 1982
•
3) the Australian National Task Force on Cannabis in 1994
•
4) the U.S. National Institutes of Health Workshop on Medical Marijuana in
1997
•
Institute of Medicine affirmed: "Scientific data indicate the potential
therapeutic value of cannabinoid drugs ... for pain relief, control of nausea
and vomiting, and appetite stimulation. ... Except for the harms
associated with smoking, the adverse effects of marijuana use are within
the range tolerated for other medications.“
•
Predictably, federal authorities ignored the IOM's recommendations
More history
• the Drug Enforcement Agency (DEA) did finally held public
hearings on the issue before an administrative law judge.
Two years later, Judge Francis Young ruled that "Marijuana
has been accepted as capable of relieving distress of great
numbers of very ill people, and doing so with safety under
medical supervision. It would be unreasonable, arbitrary
and capricious for DEA to continue to stand between those
sufferers and the benefits of this substance in light of the
evidence in this record." Young recommended, "The
Administrator transfer marijuana from Schedule I to
Schedule II, to make it available as a legal medicine."
• DEA Administrator John Lawn rejected Young's
determination, effectively continuing the federal ban on the
medical use of marijuana by patients.
Fifteen states and counting
• Since 1996, voters in fifteen states -- Alaska,
Arizona, California, Colorado, Hawaii, Maine,
Michigan, Montana, Nevada, New Jersey, New
Mexico, Oregon, Rhode Island, Vermont and
Washington -- and the District of Columbia have
adopted initiatives exempting patients who use
marijuana under a physician's supervision from
state criminal penalties.
• Yet states may not authorize medical marijuana
clinical trials without federal approval. All
medical marijuana research must meet NIDA
approval and receive funding from the National
Institutes of Health (NIH).
CLINICAL PHARMACOLOGY OF
CANNABIS
• 95-99% plasma protein bound
• hydroxylation, oxidation, and conjugation for rapidly
clearance from plasma
• First-pass metabolism with oral admin. (11-OH-THC)
• Elimination over several days (adipose)
• Breast milk distribution
• Pregnancy Category C
• Excretion: days to weeks 20-35% found in urine
• 65-80% found in feces
• 5% as unchanged drug (when given PO)
• Works via RECEPTOR BASED MECHANISMS
Cannabinoid Receptors
AEA also an endovanalloid at
TRPV1 (with 5-20-fold lower
affinity cf with CB1); also
PPARy
Key ECS Elements
The CB1 Receptor
Activation
negatively
coupled to
adenylate
cyclase,
suppresses
neuronal Ca2+
conductance,
inhibits inward
rectifying K+
conductance
suppression of
neuronal
excitability
Difference Between Classical
and Retrograde Neurotransmission
Physiological Effects of Endocannabinoids
Common Misconceptions
• No evidence-based studies demonstrating
that chronic cannabis use can cause or
exacerbate schizophrenia
• Smoking cannabis is not associated with
an increased risk of developing COPD or
lung Ca
– In fact, protective effects of cannabis smoking
seen in two large retrospective, populationbased case-control studies
Clinically Useful Drug Interactions
• When THC co-administered with CBD, as can
occur with the usage of some strains of
herbal cannabinoid medicines and certain
cannabinoid-based extractions
– anxiogenic, dysphoric, and possibly short-term
memory interrupting effects of THC are mitigated
• Evidence suggests cannabinoid drugs can
enhance the analgesic activity of coadministered opioids
– Opioid dose reductions
Neuropathic Pain
• 3-8% prevalence in industrialized countries
• Due to direct damage to or abnormal functioning of
the nervous system
• 2/2 infections, diabetes, trauma, stroke, etc.
• Often refractory to existing treatments
• Currently available treatments: gabapentin and other
anticonvulsants, NMDA receptor antagonists –
limited by their SE
• NP medicine market forecast: expected to double to
$5.2 bil by 2018
Cannabinoid Suppression of Neuropathic Pain –
Basic Science
• Cannabinoids have been shown to suppress
neuropathic nociception in at least 9 different
animal models of surgically-induced traumatic
nerve or nervous system injury1
– Chronic constriction injury: infraorbital nerve, saphenous
nerve
– Partial nerve ligation: sciatic, saphenous
– Spinal nerve ligation: L5
– Spared nerve injury
– Spinal cord injury
– Tibial nerve injury
– Streptozotocin-induced diabetic neuropathy
1Rahn
EJ and Hohmann AG. Cananbinoids as Pharmacotherapies for Neuropathic Pain:
From the Bench to the Bedside. Neurotherapeutics 2009. 7:4, 713-737.
Cannabinoid Suppression of Neuropathic Pain –
Basic Science
• In CCI of infraorbital nerve model, CB1 receptor upregulation was
observed in both the ipsalateral and contralateral superficial layer
of the trigeminal caudal nucleus (I>C)
• CB2 receptor immunoreactivity is increased in the ipsilateral
dorsal horn after L5 spinal nerve transection
• Saphenous partial nerve ligation increased u-opioid, CB1, and CB2
receptor protein levels in ipsalateral/contralateral hind paw skin,
DRG, and ipsalatera/contralateral L-cord (1-7 days post-surgery)
• Tibial nerve injury upregulation of CB1 receptor mRNA in the
contralateral thalamus, 1 day post-surgery
• SCI model—mechanical allodynia was reduced with chronic
administration of WIN (mixed CB agonist) with no decrease in
effectiveness, unlike morphine
1Rahn
EJ and Hohmann AG. Cananbinoids as Pharmacotherapies for Neuropathic Pain:
From the Bench to the Bedside. Neurotherapeutics 2009. 7:4, 713-737.
Cannabinoid Suppression of Pain
• Analgesia: different mechanism than opiates, some synergy
though.
• Spasticity: likely GABA mediated
• Appetite enhancement: hippocampal?
• Anti-emetic: cerebellar?
• Elevated levels of the CB1 receptor - like the
• opioids are found in areas of the brain that
• modulate nocioceptive processing
• CB1 and CB2 agonists have peripheral analgesic actions
• CBs may also exert anti-inflammatory effects
• Analgesic effects not blocked by opioid antagonists
Results: Neurology RCT
Abrams et al Neurology 2007
EBM One Clinical trials
• Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly
ME, Rowbotham MC, Petersen KL. Cannabis in painful HIVassociated sensory neuropathy: a randomized placebo-controlled
trial. Neurology 2007; 68(7):515-21.
• Ellis RJ, Toperoff W, Vaida F, van den Brande G, Gonzales J,
Gouaux B, Bentley H, Atkinson JH. Smoked medicinal cannabis for
neuropathic pain in HIV: a randomized, crossover clinical trial.
Neuropsychopharmacology 2009;34(3):672-80.
• Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled
trial of cannabis-based medicine in central pain in multiple
sclerosis. Neurology 2005; 65(6):812-9.
Cochrane reviews
• Phillips TJ, Cherry CL, Cox S, Marshall SJ, Rice AS.
Pharmacological treatment of painful HIV-associated
sensory neuropathy: a systematic review and metaanalysis of randomised controlled trials. PLoS One 2010;
28;5(12):e14433.
• Martín-Sánchez E, Furukawa TA, Taylor J, Martin JL.
Systematic review and meta-analysis of cannabis treatment
for chronic pain. Pain Med 2009; 10(8):1353-68.
• Campbell FA, Tramèr MR, Carroll D, Reynolds DJ, Moore
RA, McQuay HJ. Are cannabinoids an effective and safe
treatment option in the management of pain? A qualitative
systematic review. BMJ 2001; 323(7303):13-6.
Cochrane reviews
• Smith PF. The safety of cannabinoids for the
treatment of multiple sclerosis. Expert Opin Drug
Saf. 2005 May;4(3):443-56.
• Mills RJ, Yap L, Young CA. Treatment for ataxia in
multiple sclerosis. Cochrane Database Syst Rev
2007; Jan 24;(1):CD005029.
• Machado Rocha FC, Stéfano SC, De Cássia Haiek
R, Rosa Oliveira LM, Da Silveira DX. Therapeutic
use of Cannabis sativa on chemotherapy-induced
nausea and vomiting among cancer patients:
systematic review and meta-analysis. Eur J
Cancer Care 2008;17(5):431-43.
Other Neuropathic Indications
• spasticity and pain associated with multiple
sclerosis, amyotrophic lateral sclerosis, or spinal
cord injury;
• physical or verbal tics caused by Tourette's
syndrome.
• Refractory seizure disorder
• Nerve pain, nausea and loss of appetite resulting
from chemotherapy, radiotherapy or HIV
combination therapy
So how does this all work in clinic?
• Methods of Use
• Pros and Cons of inhalation versus
ingestion
• How to educate patients in usage and
dosage
Vaporization of cannabis – safe
alternative to smoking
• examples
How do vaporizers work?
• When cannabinoids are heated to between
285 °F (140 °C) and 392 °F (200 °C) they
literally boil and vaporize.
• Studies show that vaporization is most
effective at around 338 °F (170 °C)
• a vaporization temperature over 392 °F
(200 °C) will burn the cannabis, creating
unwanted smoke.
–Serum levels after inhalation
Injection
THC Administration
Smoking
Blood levels
100
100
1
1
0
17.2
1
2
3
4
0
Time (hr)
1
2
3
4
Absorption
– slow absorption with oral
THC Administration
Oral
17.4
0
120
240
Time (min)
360
100
Blood levels
Rated “high”
Intravenous (5 mg)
Smoking (19 mg)
Oral (20 mg)
1
0
17.2
1
2
3
4
Time (hr)
5
6
• rapid initial drop due to redistribution to
fats
• slower metabolism in liver
• metabolites may persist for a week
Primary metabolic product of 9-THC
(11-OH-9-THC) is more potent than 9-THC
Delay between peak plasma levels and peak effect
With so many choices…how do I
pick the RIGHT medicine??
• Sativa?
• Indica?
• Genetic clones?
• Hashish?
• Oils?
And how do I use it?
• Vaporize?
• Ingestion?
• Transdermal?
Start by understanding the differential
effects of major cannabinoids
• Cannabis strains with high levels of both THC and CBD will
create a strong energetic high. This is typical of Cannabis
Sativa (or Sativex!!)
• low levels of THC and high levels of CBD will be more of a
body, sleepy feeling. This is typical of Cannabis Indica
• Tetrahydrocannabivarin (THCV) is found primarily in strains
from African and Asian cannabis.
• THCV intensifies THC effects
• Cannabis with a potent smell (aka “skunk”) indicates a high
level of THCV.
• Some cannabinoids, including Cannabichromene (CBC) and
Cannabicyclol (CBL) are not psychoactive but may enhance
the effects of THC.
KNOW THE SIDE EFFECTS
–
–
–
–
–
–
–
disinhibition, relaxation, drowsiness
feeling of well being, exhileration, euphoria
sensory - perceptual changes
recent memory impairment
balance/stability impaired
decreased muscle strength, small tremor
poor on complex motor tasks (e.g., driving)
Blurred vision?
Performance decrement (s)
Psychomotor performance-dose dependent decline
1.0
Simple
response time
Response time
(divided attention)
0.6
0.2
2
6
12
Time (hr)
2
6
12
17.5
Effects on behavior
–
–
–
–
–
pseudohallucinations
synesthesias
impaired judgement, reaction time
pronounced motor impairment
increasingly disorganized thoughts, confusion,
paranoia, agitation
Not lethal even at very high doses
DOSING: Start LOW and go SLOW
• Adverse effects: mainly seen in new users
• Euphoria versus paranoia
• Short term memory impairment
• Balance, incoordination
• These are reversible, short lived effects (3-4
hours max)
• Serious adverse effects NOT seen in chronic users
Components of pain that may respond
to cannabis
• Cramping (anti-spasticity)
• Neuropathic: allodynia, hyperpathia
• Mechanical: Dull, aching (antiinflammatory)
Pros/Cons/Risks/Benefits
• Good analgesia
• High dosing ceiling vs minimal toxicity
• Risk for psychological addiction not an
issue
• Minimal physical dependence
• Not many drug-drug interactions
Pros/Cons/Risks/Benefits
• Some tolerance may develop in heavy,
long term users may need higher doses
• Patient/family will have to purchase or
grow it
• Dronabinol is NOT as effective –
Dronabinol (Marinol)
• Dronabinol is 100% THC, the most psychoactive ingredient in
cannabis. Natural cannabis is 20% THC or less
• The physiological effect of THC is modulated when the other
cannabinoid forms are present. Dronabinol is associated with too
many psychoactive effects.
• DEA classifies dronabinol as schedule III
• FDA approved dronabinol for treatment of nausea and vomiting
associated with chemotherapy and anorexia associated with
weight loss in patients with HIV/AIDS
• Dronabinol is not an appropriate substitute for natural cannabis.
• Dronabinol is very expensive
• Sativex is much better but not available in US (50% THC, 50%
cannabadiol in a sublingual spray)
Metz, L., and S. Page. 2003. Oral cannabinoids for spasticity in
multiple sclerosis: will attitude continue to limit use? Lancet 362
(9395):1513.
“ We now have as much evidence
to support the use of the oral
cannabinoids for spasticity in
ambulatory people with multiple
sclerosis as we do for many
standard therapies for spasticity,
including baclofen.”
Sativex Oromucosal Extract
•
1:1 combination from two clonal cannabis
cultivars yielding a high THC extract
(Tetranabinex®) and a high CBD extract
(Nabidiolex®).
•
a botanical drug substance (BDS) of defined
composition with controlled reproducibility
batch to batch.
•
THC and CBD comprise some 70% (w/w) of
the total BDS, with minor cannabinoids (5 –
6%), terpenoids (6 – 7%, most GRAS), sterols
(6%), triglycerides, alkanes, squalene,
tocopherol, carotenoids and other minor
components (also GRAS).
•
each 100 μL pump-action spray provides
2.7mg of THC and 2.5mg of CBD, the minor
components, plus ethanol: propylene glycol
excipients, and 0.05% peppermint as
flavouring.
•
Intermediate onset: 15-40 minutes
•
Allows dose titration
•
Reduces first pass metabolism
•
Acceptable to patients
Primary Endpoint
NRS Spasticity Score: Change from Baseline
Mean change in Spasticity Score
(ITT)
Mean &from
95% C.I.Baseline
by week
0
-0.2
-0.4
-0.6
-0.8
p=0.048*
p=0.048*
-1
-1.2
-1.4
-1.6
GW-1000-02
-1.8
Placebo
-2
0
1
2
3
Week
4
5
Week66/End
of Treatment
Collin C, Davies P, Mutiboko IK, Ratcliffe S. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol. 2007. 14(3):290-6.
7
*Anova
Sativex – better than marinol BUT…
• Sativex produced a statistically significant
improvement in spasticity
– Improvement gained over and above concomitant
anti-spasticity medication
– Improvements gained without decrease in muscle
strength
• Sativex was well tolerated
– Few withdrawals due to adverse events
• Extension data
– sustained and continuing improvement in spasticity
– Patients did not develop tolerance to Sativex over
28 weeks
Conclusions of National Clinical Advisory
Board of the National Multiple Sclerosis
Society
• Key recommendations for research priorities include:
• Better study outcome measures need to be developed.
• A consensus is needed on standards for trial design to test
the efficacy of cannabinoids for symptomatic management.
• Because inhaled smoked cannabis has more favorable
pharmacokinetics than administrationvia oral or other
routes, research should focus on the development of an
inhaled mode of administration that gives results as close
to smoked cannabis as possible.
• Longer-term side effect data need to be obtained.
• There are sufficient data available to suggest that
cannabinoids may have neuroprotective effects that studies
in this area should be aggressively pursued.
Cannabis and amyotrophic lateral
sclerosis
•
Significant advances have increased our understanding of the molecular mechanisms of amyotrophic
lateral sclerosis (ALS), yet this has not translated into any greatly effective therapies. It appears that
a number of abnormal physiological processes occur simultaneously in this devastating disease.
Ideally, a multidrug regimen, including glutamate antagonists, antioxidants, a centrally acting antiinflammatory agent, microglial cell modulators (including tumor necrosis factor alpha [TNF-alpha]
inhibitors), an antiapoptotic agent, 1 or more neurotrophic growth factors, and a mitochondrial
function-enhancing agent would be required to comprehensively address the known pathophysiology
of ALS. Remarkably, cannabis appears to have activity in all of those areas. Preclinical data indicate
that cannabis has powerful antioxidative, anti-inflammatory, and neuroprotective effects. In the
G93A-SOD1 ALS mouse, this has translated to prolonged neuronal cell survival, delayed onset, and
slower progression of the disease. Cannabis also has properties applicable to symptom management
of ALS, including analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite
stimulation, and sleep induction. With respect to the treatment of ALS, from both a disease
modifying and symptom management viewpoint, clinical trials with cannabis are the next logical step.
Based on the currently available scientific data, it is reasonable to think that cannabis might
significantly slow the progression of ALS, potentially extending life expectancy and substantially
reducing the overall burden of the disease.
•
Carter GT, Abood ME, Aggarwal SK, Weiss MD. Cannabis and amyotrophic lateral sclerosis: hypothetical and
practical applications, and a call for clinical trials. Am J Hosp Palliat Care 2010;27(5):347-56.
Conclusions/Comments
• Preclinical data indicate that cannabis has powerful
antioxidative, anti-inflammatory, and neuroprotective
effects.
• Cannabis is also useful in management of pain, particularly
neuropathic pain, spasticity, seizures, tics, siallorhea,
bronchospasm,cachexia and wasting, and insomnia.
• Based on available scientific data,cannabis may slow
progression of ALS and other neurodenerative disorders
• Vaporization is a safe, effective alternative to smoking
• Cannabis is remarkably safe, few drug interactions
Comments
• Sativex is better than Marinol but not as good as
natural cannabis
• Cannabis plant is indiginous to North America, is
relatively easy to grow, dry out, and use as
medicine, following a tradition that has existed
for thousands of years.
• This could be done for pennies
• Risk to society? Not much
What about the war on drugs?
• Five years after the Portugese government decriminalized
the use and possession of heroin, cocaine, marijuana, LSD
and other illicit street drugs, the number of deaths from
street drug overdoses dropped almost 50% and the number
of new HIV cases caused by using dirty needles to inject
heroin, cocaine and other illegal substances plummeted
from nearly 1,400 in 2000 to about 400 in 2006
• Instead of going to prison, addicts go to treatment centers
• Under the Portuguese plan, penalties for people caught
dealing and trafficking drugs are unchanged; dealers are
still jailed and subjected to fines depending on the crime.
• “No problem can be solved from the same level of
consciousness that created it” Albert Einstein
If you choose to recommend
cannabis…
• FOLLOW THE LAW
• Counsel the patient and family
• Patient should use high quality cannabis to
improve efficacy: high CBD, CBN, lower
THC – do not need to be high to get pain
relief
• Use a delivery route that maximizes
benefits and minimizes side effects
How to prescribe medical cannabis
Primum Non Nocere:
Thanks…
• Q&A
• Contact info: [email protected]