Transcript The Medical Use of Marijuana

Medical Uses of Marijuana
John Woytowicz, MD
University of New England School of Pharmacy
UNE Pharmacy Convention
April 2. 2016
Portland ME
Objectives
To review the Maine statue on marijuana
To understand the endocannabinoid system and
the effects of THC and CBD
To review the evidence based literature on the
clinical use of medical marijuana
To develop an integrative medicine approach in
the clinical application of medial marijuana
State Statutes
 23 states: AK, AZ ,CA, CO, CT, DE, FL, HI, IL,
ME, MD, MA, MI, MN, NV, NH, NJ, NM, OR, RI,
VT, WA, and DC. CA-1996, ME-1999/2010
 Seven states accept out-of-state certification
cards AZ, DE, ME, MI, NV, NH, RI
 OR and MN accept out-of-state applications.
States that allow CBD products
 Legislation allowing for low-THC, CBD-rich marijuana
oil has been approved for limited use in 14 states.
 AL, FL, GA, IO, KY, MI, MO, NC, OK, SC, TN, UT, VA, WI,
WY, ID, NY
Indications for CBD products
 Indications: pediatric seizure disorders like Dravet’s
and Lennox-Gastaut syndromes, Parkinson’s disease,
Alzheimer’s dementia, PTSD, Cancer, MS, ALS
Medical indications
specified in state statutes
Seizure disorder including epilepsy, intractable skeletal
muscular spasticity, glaucoma, severe or chronic pain,
severe nausea or vomiting, cachexia, or wasting syndrome
resulting from AIDS/HIV or cancer, Amyotrophic lateral
sclerosis (Lou Gehrig’s disease, Multiple sclerosis, terminal
cancer, muscular dystrophy, inflammatory bowel disease
(e.g. Crohn’s or ulcerative colitis), intractable muscle
spasm, Hepatitis C, agitation from Alzheimer’s disease,
Nail-Patella Syndrome, chronic or debilitating pain
syndrome, intractable nausea, peripheral neuropathy,
PTSD in NM, DE and ME (2013)
Hospice in NM and ME (use in free standing hospice units)
On-line resources
www.procon.org Use for a comparison of medical
marijuana statues across the nation.
www.maine.gov/dhhs/dlrs/mmm/index./html Use to
locate the forms to certify a patient for the use of
medical marijuana and to obtain details about the
Maine statute.
Certification guidelines
 Most states will or have established a
review/oversight board usually comprised of
physicians, health care clinicians, and the public to
review new indications and special cases.
 Pediatrics: most states limit its use on a case by case
basis.
 NPs allowed to certify patients in some states, in ME
as of 2013
Medical Indications Established
in ME 1999
 Persistent nausea, vomiting, wasting syndrome of loss of
appetite as a result of: AIDS, chemo and radiation therapy
to treat cancer
 Heightened intraocular pressure as a result of glaucoma
 Seizures associated with a chronic, debilitating disease.
e.g. epilepsy
 Persistent muscle spasms associated with chronic
debilitating disease. e.g. multiple sclerosis
Referendum Nov. 2009
 Establishment of a dispensary for patients to purchase
marijuana, 8 in Maine
 Establishment of a bona-fide physician-patient relationship
 Broader medical indications:
- Crohn’s disease
- Hepatitis C
- Agitation from Alzheimer’s dementia
- ALS, Nail-Patella syndrome
- Intractable pain of greater than 6 months duration
that has not responded to ordinary medical or surgical
measures
So What Are The Most Common
Requests Before 2009
 Prior to 2009 muscle spasms…multiple sclerosis and
injuries; and nausea, vomiting, cachexia from cancer often
in the setting of chemotherapy
 One request each for elevated IOP in glaucoma and
Alzheimer’s dementia, and several for seizure disorders
Requests Since Nov. 2009
 Chronic pain; usually trauma/injury to head, neck
and back, fibromyalgia, chronic headaches, advanced
arthritis
 Crohn’s disease and other gastrointestinal disorders with
persistent nausea, cachexia, anorexia often in the setting
of cancer and chemotherapy, ulcerative colitis
 Muscle spasm/spasticity due to numerous neurological
conditions: e.g. MS, Freidrich’s ataxia, dystonia,
Parkinson’s disease
Historical perspective
 Cannabis sativa sees to have been diffused from the
Himalayan foothills in Central Asia
 Bound to faith and mysticism in India, both in the Hindu
and Islamic traditions
 Cannabis flowers and seeds have been found at excavation sites
as early as 2000 BC
 Earliest written reference to cannabis in India in the Arthavaveda
in 1500 BC
Historical medical references
 3rd-8th cent BC recommended for phlegm, catarrh
and diarrhea
 Aphrodisiac and pain
 The fumes of burning hemp for anesthesia
(Ref: Cannibis in India: ancient lore and moderns medicine. Ethan Russo. 2005)
Reintroduction in the West
 Seminal work by sir William B O’Shaughnessy in 1839 that
was published in 1842 reviewed classical Sanskrit and
Unani sources provided a description of cannabis sources
 Cholera, rheumatic diseases, delirium tremens, infantile
convulsions.
 Miraculous recoveries in a series of tetanus victims noting
anti-convulsant and anti-spasmodic effects…..”although
no cure was forthcoming, the patient was visibly relieved
of distress, and able to take some sustenance through his
suffering”.
History in the US
 Classified in 1851 as a legitimate medical compound in the
US Pharmacopeia and Dispensary, then it was removed in
1942
 Criminalized in 1937 against the advice of AMA and
pharmaceutical industry.
 Banned in the absence of scientific evidence and
associated with the “reefer madness campaign”
 Illegal under the federal Controlled Substance Act of 1970
(P.L.91-513;21 U.S.C. 801 et seq)
 Regulated with zero-tolerance by the Drug Enforcement
Agency (DEA) where it is classified as a Schedule 1 drug.
Endo-cannabinoid (EC)
Physiology
 400 different chemicals in typical marijuana
plant/bud including THC (9
tetrahydrocannabinol) and CBD (cannabidiol)
 Endocannabinoid (EC) receptors (Rc) are
found on cell membranes and related to Gproteins. All are lipophilic. Discovered in the
1990s.
Summary: 2 Types of EC Receptors
 CB1: mainly expressed in the brain/CNS. But also
found in the lung, liver, kidneys and peripheral
nerves.
 CB2: mainly expressed in the immune system and
hematopoietic cells, and found in smaller amounts
as CB1
 Perhaps non-CB1/non-CB2 expressed in the brain
 No CB Rc’s are found in the brainstem or heart
EC-Rc are activated by
3 groups of ligands
 The endocannabinoids, anandamide and 2arachidonoylglycerol, are found in mammalian
species
 THC and CBD in plant species
 Synthetic forms: dronabinol (Marinol, schedule
3), whole plant extract nabiximol (Sativex:THC &
CBD), nabilone (Cesamet, schedule 2)
Anandamide and 2arachidonylglycerol
 Naturally occurring substances of the eicosanoid
family which are long-chain fatty acids
 Released from neurons via a neurotransmitter
receptor-dependent action
 Pro-inflammatory agents can release them from
immune cells.
Endocannabinoid Physiology
 Far-reaching modulatory effects throughout
body with high density receptors in central
and autonomic nervous system in areas that
regulate motor activity, short-term memory,
cognition, affect, appetite, anti-nausea,
sedation, pain, immune function, and
inflammation.
Therapeutic Activity of
Endocannabinoids
 Sensorimotor and motivational aspects of
behavior
 Regulation of fertilized egg implantation
 Hypotensive and bradycardic effects
 Cognition an drug dependence
 Sleep-wakefulness cycle, memory formation,
locomotor activity, and pain perception
 Modulation of immune response
 Control of pain
Phytocannabinoid: THC
 Inhibits release of GABA and glutamate by binding to CB1
Receptors found on pre-synaptic neurons which
mediates feelings of euphoria, an altered sense of time,
analgesia, increased appetite, and impaired memory.
 The primary psychoactive compound in cannabis
 CB1 RC on widely distributed in the peripheral and central
nervous systems. Sympathetic preganglionic adrenergic
neurons can cause hypotension and bradycardia.
Characteristics of cannabis species
 THC: 20 x strength of aspirin

2 x strength of hydrocortisone

neither COX-1 or COX-2

increases beta-endorphin levels

regulates substance P and enkephalin mRNA
levels in basil ganglia

enhances opioid anti-nociception, blocks
opiate withdrawal and prevents development of
opiate tolerance
Phytocannabinoid:CBD
 A non-psychoactive compound, an
endogenous neurotransmitter of serotonin, 5HT1A receptor agonist, that has inhibitory
effects on the limbic system (emotions)
 Interacts with CB2 receptors found primarily
on cells of the immune system, but also found
in the gut, brain, and vascular endothelium
Cannabidiol (CBD)
 Neuroprotective
 Through vanilloid activity-capsaicin like effect
 Increases uptake of anandimide and decreases its
breakdown
 Antioxidant
 Nonsedating
 Anti-convulsant/anxiety/emetic
 Decreases IOP and anorexia
 Blocks 17-OH of THC (degradation)
 Cytotoxic to cancer cells
CBD & THC activity
 CBD: reduces mitochondrial superoxide activity,
iNOS, NFkappa B activation and transdermal
migration of monocytes.
 CBD counteracts undesireable effects of THC
( sedation, psychotropic effects, tachycardia)
(Burstein SH, etal. Cannabinoids, endocannabinoids and related agents in inflammation.
AAPS Journal. Vol 11, no 1, March 2009.109-119)
More on Cannabidiol
 Decreases TNF-alpha
 No COX-1 or COX -2 activity
 Decreases hepatic encephalopathy
 Influences adenosine receptors to modulate
pain and inflammation
 Anti-prion
 Anti-MRSA(antiseptic)
Other constituents in cannabis species
 D-limonene (lemon): anxiolytic,
antidepressant, immune modulator, increases
apoptpsis in breast CA, antifungal
 P-myrene (hops): blocks PGE-3 (antiinflammatory) and naloxone, muscle
relaxation, potentiates barbiturates, blocks
hepatic carcinogenesis by aflatoxin
Other constituents
 Alpha-pinene (pine needles):
antiinflammatory, bronchodilator,
Acetylcholinesteras inhibitor, anti-MRSA
 D-linalool (lavender): local anesthetic,
anxiolytic, anticonvulsant, anti-leshminasis,
reverses doxirubacin resistance, reduces pain,
modulates glutamate and GABA
More constituents
 B-caryophllene (black pepper): blocks PGE-1
(antiinflammaotry), equal to phenylbutazone,
gastroprotective, CB2 agonist
 Nerolidol: transdermal absorption, antifungal/malarial/leshminiasis
 Caryophellene oxide (lemon balm): anti-fungal,
decreases platelet aggregation
 Phytol (tea): prevents vit A teratogenesis,
sedating,increases GABA
 Squalene: decreases cholesterol synthesis,
bacterialcidal, antioxidant and anti-inflammatory
FLAVANOID content
 Apigenin (chamomile): anxiolytic and
antiinflammatory by decreases TNK-alpha activity
 Cannflavin A: decreases PGE-2
 B-sitosterol: topical anti-inflammatory and
increases 5-alpha reductase
 Alpha tocopherol: antioxidant
Physiology of EC RC’s
 CB1: antiemetics and appetite
stimulants…..agonists like tetrahydrocannabinol
(THC) and nabilone. Suppressions of muscle
spasms/spasticity in MS and spinal cord injury.
Relief of chronic pain, lowering intraocular
pressure and preventing bronchospasm.
 CB1 antagonists might suppress appetite and play
a role in the management of schizophrenia or
disorders of cognition and memory
Phamacokinetics
 Inhaled THC causes maximum plasma levels
within minutes, psychotropic effects begins
within seconds. Maximum levels after 15-30
minutes before tapering down over 2-3 hours
in most people.
 Oral ingestion have a longer active duration of
4-12 hours.
Available forms of
medical marijuana
 Dried herb used to smoke or vaporize
 Edibles: cookies, candy, butter or ghee
 Young green tips of plant: fresh or dried used in cooking
to make spaghetti sauce, for instance, or steep as a tea.
 Liquid extracts: “glycerine” based contain both active
THC and CBD or “alcohol” or “tincture” contains only
active CBD
 Topical salves
Management of Chronic Pain
 Cannabinoids act synergistically with opioids and
act as opioid sparing agents allowing for lower
doses and fewer side effects form chronic opioid
therapy. (Elikottil J, etal J Opioid Manag. 2009 Nov-Dec;5(6): 341-57)
Synergy with opiate use
 Medical cannabis use was associated with a 64%
decrease in opioid use (n=118), decreased number and
side effects of medications, and improved quality of
life (45%).
 Cross-sectional retrospective survey of 244
medical cannabis patients with chronic pain.
Patrons at a medical cannabis dispensary in
MI. ( Boehnke KF, etal. J Pain. 2016 Mar 18. pii: S1526-5900(16)00567-8)
Different Types of Pain
 Various forms of medicinal cannabis have
provided mostly positive response for
patients with different types of pain:
neuropathic, chronic, post-operative, that
related to fibromylagia, rheumatoid arthritis,
multiple sclerosis and cancer.
(Borgelt, LM, etal. The Pharmacologic and Clinical Effects of Medical
Cannabis. Pharmacotherapy. vol 33, no 2, 2013195-209)
Opioid and Cannabinoid Intereactions
 Recent studies indicate that opioid and cannabinoid
antinocioception may have additive or even
synergistic antinocioceptive effects
 Clinically this may enhance analgesic effects with
lower doses and consequently fewer undesirable
side effects.
(Desroches J, Beaulieu P. Curr Drug Targets 2010 Apr;11(4):462-73)
Synergy Between Cannibis
and Opioids
 The combination of THC in low, non-psychoactive
doses with opioids has a synergistic effect and
reduces the opioid tolerance effects.
(Karst M, Wippermann S. Expert Opin Investig Drugs. 2009 Feb: 18(2):125-33)
Synergistic interactions between cannabinoid and
opioid receptors show potential reduction in drugseeking behavior and opiate sparing effects.
( Leung L. J Am Board Fam Med. 2011 Jul-Aug;24(4):452-62)
Multiple Sclerosis
 Interesting group of studies. Most studies show
variable results from medical marijuana when
measured against the Ashworth scale used to
assess muscle spasm
 Remarkably, most studies note that patients report
improved function in ADLs, control of pain related
to muscle spasm, and improved sleep
(Vaney C, etal. Mult Scler. 2004 Aug;(10):417-24)
CBD reduces inflammation in viral
model of Multiple Sclerosis
 Modifies the deleterious effects of inflammation
in TMEV-demyelinating disease.
 Decreases the transmigration of leukocytes by
downregulating the expression of vascular cell
adhesion molecules, chemokines and
proinflammatory cytokines (IL-1beta and
attenuates activation of microglia.
(Mecha M, etal. Cannibidiol provides long-lasting protection against deleterious
effects of inflammation in a viral model of MS. Neurobiol Dis 2013 Jul 11:59C:141-150)
Cytoprotection mediated through
endocannabinoid recepetors.




Immune cells mainly have CB2, and less CB1
Expression of CB1 and CB2 altered by inflammation.
Decreased production of pro-inflammatory cytokines
Suppression of mitogen-induced cell proliferation,
migration, Antigen presentation and trafficking into
inflamed tissues are regulated via CB2
 Suppression of auto-reactive T cells controlled by CB2
 Neuro-protective action on neurons controlled by CB1
 MS cannabinoid-mediated neuroprotection may be more
important than immunosuppression in chronic stages of
MS. ( Delago E, etal and Kozela E, etal)
Cannabis spp effects
on inflammation
 Cannabidiol (CBD) decreases the level of IL-6 and
increases IL-10, pro-inflammatory and antiinflammatory cytokines, respectively.
 CBD and THC did/did not effect levels of TNFalpha or IFN—gamma
(Kozela E, etal Cannabinodis decrease the Th17 inflammatory autoimmune
phenotype 2013 Jul 28) (DeLago E, etal. Cannabinoids ameliorate disease
progression in a multiple sclerosis model in mice, acting preferentially through CB1
receptor mediated anti-inflammatory effects. Neuropharmacology, 2012, 62(7),
2299-308)
 THC and CBD decrease pro-inflammatory
cytokines IL-1beta, Il-6, IFN-beta in microglial cells.
CBD, but not THC, decreases NF-kappaB
(Kozela E, etal. Cannabinoids THC and CBD differentially inhibit lipopolysaccahride-activated NK-kappaB and interferon-beta proinflammatory
pathaways in microglial cells. J Biol Chem.2010 Jan 15;285(3):1616026)
 Other studies show that THC and CBD decrease
cytokines TNF-alpha, Il-1beta, Il-2, Il-6, Il-12 and
IFN-gamma. (Delago E,etal)
Treatment of Spasticity
 Randomized, placebo-controlled trials, as well as longer-term openlabel extensions, show a clear cut improvement in spasticity in
patients refractory to other therapies, with a good tolerability and
safety profile
(Oreja-Guevara C. Treatment of spasticity in multiple sclerosis: a new
perspective regarding the use of cannabinoids. Rev Neurol. 2012 Oct
1;55(7): 4210430. )
 300 pts who were previously refractory to treatment showed clear
improvement in sleep quality, bladder function control and mobility
(Flachenecker P. Expert Rev Neurother 2013 Feb;13 (3suppl 1): 15-19)
Modifying Disability from MS
CB1 And CB2 stimulation may have a NEUROPROTECTIVE potential in addition to the antiinflammatory as the endocannabinoid system controls
the level of neuro-degeneration that occurs as a result of
the inflammatory insults. Thus, cannabinoids not only
offer symptoms control but may slow the
neurodegenerative disease progression leading to the
accumulation of disability.
( Baker D, etal. The endocannabinoid sytem and multiple
sclerosis. Curr Pharm Des 2008;14(23):2326-36)
Buccal mucosal THC:CBD
 In the UK a 2 year study showed no evidence
of driving impairment, no increase in falls, or
other adverse events including psychiatric and
nervous system events among users of buccal
mucosal spray of THC:CBD
( Garcia-Merino A Expert Rev Neurother. 2013 Feb; Feb 13 (Suppl 1):9-13.)
Multiple Sclerosis
 Data from 300 patients showed that Sativex
provided relief of MS-related spasticity in the
majority of patients who were preciously
resistant to treatment.
 Clear improvements in associated symptoms of
sleep quality, bladder function control and
mobility.
(Flachenecker P. Expert Rev Neurother.2013 Feb;13 (3 Suppl 1):15-9)
Multiple Sclerosis
 In the UK a 2 year study showed no evidence
of driving impairment, no increase in falls, or
other adverse events including psychiatric and
nervous system events among users of buccal
moucosal spray of THC/CBD
(Garcia-Merino A. Expert Rev Neurother. 2013 Feb; Feb 13 (3 Suppl 1):9-13)
MS: Neuropathic Pain
 Sativex: Phase I-III studies in 2000 subjects
demonstrate marked improvement in sleep
parameters in patients with wide variety of
pain conditions including MS, peripheral
neuropathic pain, intractable cancer pain, and
RA with acceptable adverse event profile.
Sativex is an inhaled form of marijuana
marketed in Canada and Europe.
(Russo EB, etal Chem Biodivers. 2007 Aug;4(8) 1729-43)
Neuropathic Pain
 Clinical studies largely affirm that neuropathic
pain patients derive benefits from cannabinoid
treatment using subjective ( i.e. rating scales) and
objective (i.e. stimulus-evoked) measures of pain.
 Studies included marijuana, synthetic delta(9)THC (e.g. Marinol) and cannabidiol (e.g. Sativex
or Cannador: THC and CBD)
(Rahn EJ, Hohmann AG. Neurotherapeutics. 2009 Oct;6(4)713-37)
Neuropathic Pain
 In one study, neuropathic pain reduction from smoked
cannabis found to be modest compared with gabapentin
and pregabalin
(0.7 reduction on a 10-cm scale compared to 1.2 and 1.3 respectively)
 Dose-response relationship ( i.e. higher THC content) and
other variables factor into effective dose (individual
tolerance, dosage form used, frequency of dosing, adverse
effects). (Ware MA, etal Smoked cannabis for chronic
neuropathic pain, a randomized controlled trial.
(CMAJ 2010;182: E694-71)
Neurodegenerative Disorders
 Further study of the endocannabinoid system
especially by antagonists of the CB1 receptors
or inhibition of EC metabolism may play
significant role for treatment in
neurodegenerative disorders like Alzheimer’s
disease, Parkinson’s disease, Huntington’s
disease and multiple sclerosis.
(Basavarajappa BS etal Mini Rev Med Chen. 2009 Apr;9(4):448-62)
Neuroinflammatory and
Neurodegenertive Disorders
 CB2 Rc’s are found in glial cells and microglia which
become activiated and overexpressed in disorders like
Alzheimer’s, MS, ALS, Parkinson. Disease and Huntington
chorea.
 The neuromodulatory effects en ECs at CB1 RCs by
endogenous cannabinoids counteract the neurochemical
imbalances arising during these disorders.
 Delta-9-THC modulates the effects at these RCs thus,
having a positive influence on the deleterious effects of
the degenerative disorders.
(Bisogno T, Di Marzo V.CNS Neurol Disord Drug Target. 2010 Jul 16)
Overall Benefit in MS
 Cannibis may slow the neurodegenerative
process
 Boost the immune
 Reduce spasm and spasticity
 Improve urinary incontinence
Spinal Cord Injuries
 Oral THC or Cannabis extracts containing THC,
CBD or both administered in sublingual spray
may lead to improvement in spasticity, muscle
spasms, pain, vesical dysfunction, and sleep
quality.
(Amar, BM. Jour of Ethnoplarmacology 105(2006) 1-25. Elseiver)
Tourette’s Syndrome
 2 RDBPC studies, and one with crossover shows
that oral THC reduced tics compared with
placebo with no major undesirable side effects.
 THC did not impair neuropsychological
performance over 6-week study period as well as
5-6 weeks after withdrawal
(Amar, MB. Journal of Ethonopharmacology. 2006)
Parkinson’s Disease
 RDBPC, crossover study evaluated the
antiparkinson effect of nabilone and the effect of
levodopa-induced dyskinesia.
 Results: while oral nabilone had no
antiparkinsonian action it significantly reduced
total levodopa-induced dyskinesia compared with
placebo.
(Amar, MB. Journal of Ethnopharmacology. 2006)
Cannabinoids and The Gut
 EC-Rc’s are involved in the regulation of food intake,
nausea and emesis, gastric secretions and
gastroprotection, GI motility, ion transport, visceral
sensation, intestinal inflammation and cell
proliferation in the gut.
(Izzo AA, Sharkey KA. Pharmacol Ther. 2010 Apr:126(1):21-38. Epub 2010 Feb 1)
Crohn’s Disease
 The endocannabinoid system influences the GI
tract through the CB1 receptors located in the
enteric nervous system and in sensory terminals
of vagal and spinal neurons and regulate
neurotransmitter release, CB2 receptors are
mainly distributed in the immune system. The EC
system conveys protection to the GI tract
through regulation of inflammation, and gastric
and enteric secretion.
(Massa F etal J Endocrinol Invest. 2006;29(3 suppl):47-57)
Cannabis as a Steroid Sparing Alternative
 21 patients (mean age 41+/- 14 yrs, 13 men who did not
respond to therapy with steroids, immunomodulators,
anti-TNK alpha agent) assigned randomly to 2 groups
cannibis, BID, cigarettes with 115 mg delta9-THC and
placebo containing cannibis flowers from which THC was
extracted. Disease activity and laboratory tests were
assessed during 8 weeks of treatment and then Q 2 weeks.
(Naftali T, etal. Cannabis induces a clinical response in patients with Crohn’s
disease: A prospective placebo-controlled study. Clin Gastroenterol Hepatol. 2013
May 4, s1543-3565(13)00604-6)
Results
 Complete remission 5/11 in cannabis group &
1/10 in placebo group. (P=.43)
 Clinical response 10/11 in cannabis group &
4/10 in placebo group (P=.028)
 3 patients from cannabis group weaned from
steroid dependency
 Cannabis group: improved appetite and sleep,
no serious side effects.
Overall
 Although the primary endpoint of the study
(induction of remission) was not achieved, a
short course (8 weeks) of THC-rich cannabis
produce significant clinical, steroid free benefits
to 10 to 11 patients with active Crohn’s disease
compared with placebo, without side effects.
Chemotherapy-Induced Nausea
and Vomiting
 Cannabinoids are more effective than placebo and
comparable to antiemetics like prochlorperazine
and ondansetron.
(Cotter J. Oncol Nurs Forum. 2009 May 1;36(3):345-352)
Which Anti-Emetic is Best?
 A review of anti-emetic efficacy of cannabinoids in
cancer patients receiving chemotherapy.
 30 studies
 The superiority of the anti-emetic efficacy of
cannabinoids compared with conventional drugs
was demonstrated through meta-analysis.
(Machado Rocha FC, et al. Eur J Cancer Care(Engl). 2008 Sep;17(5):431-43.
Epub 208 Jul 8)
Hepatitis C - The Controversy
 Regular cannabis smoking is an independent
predictor of both fibrosis and steatosis in the
Hepatitis C infected patient
(Mallat A. J Hepatol. 2008 Apr;48(4):657-65)
 Patients with anorexia and nausea undergoing
Hep C treatment faired better with cannabis
therapy than controls
(Costinuik CT, etal. Can J Gastroenterol.2998 Apr;22(4):376-80)
Hepatitis C
 Activation of hepatic cannabinoid CB2 Rc limits
progression of experimental liver fibrosis
 During the chronic course of Hepatitis C, daily
cannabis use increases fibrosis progression
 CB1 Rc antagonists inhibited progression of
fibrosis in three models of chronic liver injury
(Teixeira-Clerc F, etal. CB! Cannabinoid receptor
antagonism: a new strategy for the treatment of
liver fibrosis.
(Nat Med 2006 Jun;12(6)”671-6)
Other inflammatory conditions
 Atherosclerosis: cardiac & cerebral, THC
 Cancer: prostate, breast and bone
 Asthma: THC
 Arthritis: CBD via suppression of TNKalpha+
Areas of Controversy




Hepatitis C
Glaucoma
Alzheimer’s dementia
Drug addiction, e.g. alcohol and opiates, and harm
reduction
 Behavioral Health
 Effects on cognitive development
Glaucoma
 Recent review by the American Society of
Glaucoma indicated that marijuana does lower
IOP for 3-4 hours, effect is short lasting requiring
frequent use every 3-4 hours. Therefore, the ASG
does not recommend it for the treatment of
glaucoma due to its short duration of
effectiveness.
(Jampel H. J Glaucoma. 2010 Feb; 19(2):75-6)
Alzheimer’s Dementia
 Cochrane review: no evidence that
cannabinoids are effective for improvement of
disturbed behavior in dementia
(Krishnan S, Cochrane Database Syst Rev. 2009 Apr 15;(2):CD007204)
Alzheimer’s Dementia:
The Role of Inflammation
 Unfortunately, this was not the indication chosen
for the medical
 use of marijuana:
 THC competitively inhibits the enzyme
acetylcholinesterase (AChE) as well as prevents
AChE-induced amyloid beta-peptide aggregation
(Eubanks LM,etal.Mol Pharm.2006 Nov-Dec;3(6):773-7)
A Note of Caution
 As efficacy and tolerability is not completely
understood it is important that cannabinoids not
be considered as the first-line therapies for which
there are other choices.
(Turcotte D, etal Expert Opin Pharmacother. 2010 Jan;11(1):17-31)
Is this still true today?
Side Effects
 Dry mouth (xerostomia), large doses may
exacerbate vomiting. Tachycardia, hypo or
hypertension, syncope, palpitations,
vasodilatation.
 May affect motor coordination, reaction time,
and visual perceptions.
 May exacerbate panic disorders, hallucinations,
flashbacks, depression, and other emotional
disturbances.
 Chronic use may cause laryngitis, bronchitis,
sexual dysfunction, abnormal menstruation.
Interactions with Herbs
and Supplements
 Sedation may occur with concomitant use of 5HTP, calamus, California poppy, catnip, hops,
Jamaican dogwood, scullcap, valerian, yerba
mansa, among others.
Interactions with Drugs
 Competes with barbiturate metabolism and may
increase drug levels.
 Might exacerbate CNS depressants.
 One case of hypomania reported with disulfiram
and fluoxetine.
 May increase the metabolism of theophylline.
 Using more than 2 oz a week, may increase INR.
Mental Health Co-Morbidities
 Medical literature shows significant support for its use
with anxiety, agoraphobia, social anxiety disorders
depression, and PTSD
 The literature creates some doubt rather than solid
support for DSM diagnoses especially ADHD, bipolar,
psychosis, and schizophrenia
 Increasing body of evidence in “harm reduction”
literature that cannabis can help with alcohol abuse, and
opiate addiction and withdrawal.
 Once again a multidisciplinary or integrative approach is
most effective.
Incidence of Schizophrenia
in Adolescents
 Growing concern that “synaptic pruning” is influenced by
endocannabinoids (Freund TF, etal. Role of endogenous cannabinoids in
sympatic signaling. Physiol Rev 2003:83:1017-66)
 Cannabis interferes with adolescent neurodevelopment
especially of the hippocampus and the cerebellum
(AshtariM, etal. Medical temporal structures and memory function in
adolescents with heavy cannabis use.. J Psychiatri Res 2011;45:1055-66)
 Continuous use of cannabis in schizophrenics is
associated with more severe psychosis. (Foti DJ, etal Cannabis
Use and the course of schizophrenia: 10-year follow-up study. Am J Psychiatry
2010; 167: 987-63)
Cannabidiol: a potential
treatment of psychosis
 CBD appears to have pharmacological profiles
similar to that of atypical anti-psychotics ( Zuardi
AW, etal. Curr Oharm Des.2012;18(32):5131-40)
 CBD may counter the effects of THC that can
cause symptoms of schizophrenia. (Manseau MW, etal.
Neurotherapeutics. 2015 Oct;12(4):816-24)
Precautions
 Doses above the psychotropic threshold causes
enhanced well-being and relaxation with an
intensification of ordinary sensory experiences in
most people.
 Side effects include dizziness, somnolence,
altered mental status, and dry mouth. Regular
use may lead to dependency in a small number of
people as well as a mild withdrawal syndrome.
Other risks….
 In 9-10% of users it becomes addictive and
interferes with interpersonal and occupational
advancement
 Psychosis may occur in 2.2 % in users compared
with non-users 0.8%
 Among teenagers, along with a decrease in the
age of first use, may induce persistent alterations
in brain structure and function.
Synthetic marijuana
 K2 and Spice: made by dissolving toxic
fluorinated synthetic cannabinoids in a
solvent that are then applied to various dried
plant materials and inhaled. Acute kidney
injury is common.
Beware….
 Second only to alcohol, cannabinoids are the
most commonly detected drug in intoxicated
drivers.
 Odds ratio of 2.66 suggests that marijuana
use is associated with a significant increased
risk of MVAs
Comments on the use of marijuana in
pregnancy and early childhood
 Growth from birth to early adolescence: prenatal exposure to
MJ does not significantly affect any growth measure at birth,
except smaller head circumference was observed at all ages only
reaching statistical significance among early adolescents born to
heavy marijuana users.
 The negative association between growth measures at birth and
prenatal cigarette exposure was overcome, sooner in males than
females, within the first few years, and by the age of six, the
children of heavy smokers were heavier than control subjects.
(Fried PA, etal. Growth from birth to early adolescence in offspring prenatally exposed to
cigarettes and marijuana. Neurotoxicol Teratol. 1999 Sep-Oct;21(5): 513-25)
The effect of marijuana on
early motor development
 While little is known about the adverse effects of
postnatal cannabis exposure through breastfeeding
due to a lack of studies in lactating women some
studies conclude that it could cause motor
development of the child at one year of age.
(Garry A, etal Cannabis and Breastfeeding. J Toxicol. 2009; 2009:596149/ Epub 2009 Apr 29)
Marijuana and SIDS
 No association between maternal recreational
drug use and SIDS.
 Paternal use during the periods of conception
and pregnancy and postnatally were significantly
associated with SIDS.
(Klonoff-Cohen H, etal. Maternal and paternal recreatinal drug and sudden
infant death syndrome. Arch Pediatr Adolesc Med. 2001 Jul;155(7):765-70)
Effects of prenatal marijuana
exposure on delinquent behaviors
 PME significantly predicted child depressive
symptoms and attention problems at age 10, after
controlling for other covariants. Child depressive
symptoms and attention problems at age 10
significantly predicted delinquency at age 14.
(Day NL, etal. Neurotoxicol Teratol. 2011 Jan-Feb:33(1): 129-136)
Assessment
 Diet (anti-inflammatory e.g. Mediterranean Diet, low acidity, more
alkaline….restrict refined carbs, caffeine, red meat and alcohol). Use a 24
hour recall.
 Lifestyle modification: exercise, stress reduction…meditation, yoga, taichi, breathing.
 Supplements: Consider Omega-3 FAs (2000 mg daily) and vitamin D3 (
goal >50) boost with 50,000 IU weekly for 8 weeks, then 2000 IU daily.
 Integrative medicine: acupuncture, OMT, energy healing, herbal
medicine, many choices of healing arts.
 Re-evaluate all therapies and remain open to new options.
 Education about management of most disabling symptom(s)