Craig   D.
Blinderman,   MD,   MA
Director,   Adult   Palliative   Medicine   Service
Associate   Professor   of   Medicine
Columbia   University   Medical   Center
• Multiple   Sclerosis   (Canada)   http://www.youtube.com/watch?v=B8_5Ebsjk8I
• Seizures   (Colorado)   http://www.tokeofthetown.com/2013/02/powerful_video_shows_ins tant_relief_for_epileptic_cannabis_patient.php
• CP   Stutter   (Missouri)   http://sploid.gizmodo.com/watch ‐ the ‐ instant ‐ change ‐ when ‐ girl ‐ with ‐ cerebral ‐ palsy ‐ 1478892426
• Parkinson's   (Israel)   http://www.youtube.com/watch?v=rHmbNjCNRQM
• Severe   Tourette’s   (Germany)   http://www.youtube.com/watch?v=pInkduXOQac
1. Describe   the   pharmacology   of   cannabinoids
2. Name   3   indications   for   the   use   of   cannabinoids   in   palliative   care
3. Recognize   the   side   effects   and   potential   harms   of   medical   marijuana   use

• Background   of   cannabinoids
– History
– Pharmacology
• Medical   Use   in   Palliative   Care
– Cannabis
– Synthetic   cannabinoids
• Side   Effects   and   Safety   Concerns
• Legal   and   Ethical   Issues
Cannabinoids   and   Opioids:
An   Historical   Perspective
First   evidence   of   medicinal   use   in   China
3000   BC
Cannabinoids
W.B.
O’Shaughnessey’s work   popularizes   cannabis   use
1800’s
Medicinal   cannabis   use   declines
1900’s
9 ‐ THC   identified   as   main   psychoactive   agent   in
Cannabis   sativa   plant
1964
1988:   CB
1   receptor   identified.
1990:   CB
1 receptor   cloned
1992:   Anandamide   discovered,   CB2   receptor   identified
1993:   CB2   receptor   cloned
1998:   Endogenous   cannabinoid   ligands   shown   to   be   analgesic
1988 1998
500   BC
Earliest   known   reference   for   opium ‐ based   elixir
1522
Paracelsus   reference   to
“laudanum”,   opium ‐ based   elixir,   as   a   potent   painkiller
1804 1817
1804:   Morphine   extracted   from   opium   poppy   plant
1817:   Morphine   first   marketed   in   Germany   as   analgesic
1874 1900’s
Morphine
1874:
(heroin)
1900s:
analogs synthesized: oxycodone,
codeine, dihydromorphine, pethidine, oxymorphone
Diacetylmorphine
Opioids
1970 1975
1970s:   Discovery   of   opioid   receptors   –
µ (mu),  к (kappa),  δ (delta)
1975:   Discovery   of   endogenous   opioid   peptides  ‐ endorphins
Slide   courtesy   of   M.
Ware 1. Mack   A   &   Joy
2. Notcutt
J.,
W.,
2001.
2004.
• Shen   Nung ,   an   emperor   of   China   (also   the   discoverer   of   tea   and   ephedrine),   is   held   to   be   among   the   first   to   report   on   therapeutic   uses   of   cannabis in   a   medicinal   compendium   that   dates   to   2737   BCE.
• In   1839,   William   O’Shaughnessy ,   a   British   doctor   working   in   India,   published   a   paper   on   cannabis   as   an   analgesic   and   appetite   stimulant   that   also   tempered   nausea,   relaxed   muscles,   and   might   ameliorate   epileptic   seizures.
– Led   to   widespread   medical   use   of   cannabis   in   the   United
Kingdom   (E.g.
it   was   prescribed   to   Queen   Victoria   for   relief   of   menstrual   discomfort)
Groopman,   J.
NYRB ,   2014.

• 1937:   Harry   J.
Anslinger,   a   prominent   prohibitionist,   successfully   lobbied   Congress   to   pass   the   Marihuana   Tax
Act,   making   access   to   the   plant   costly.
– Anslinger   was   the   head   of   the   Federal   Bureau   of   Narcotics   and   presented   cannabis   use   to   the   public   as   an   unalloyed   danger,   resulting   in   “reefer   madness.”
– The   AMA   opposed   the   Marihuana   Tax   Act,   fearing   that   it   would   limit   medicinal   study   and   potential   prescription   of   the   plant.
• 1942:   Marijuana   was   removed   from   the   United   States
Pharmacopeia ,   a   compendium   that   set   standards   for   medicines   and   foods.
• 1970:   Congress   enacted   the   Controlled   Substances   Act,   classifying   marijuana   along   with   heroin   as   a   Schedule   I   drug.
Groopman,   J.
NYRB ,   2014.
Today:   States   that   have   legalized   cannabis   for   medical   purposes
• Cannabis   strains   may   vary   by   morphology,   odor,   and   chemotype,   producing   plant   resin   with   varying   ratios   of   pharmacologically   active   cannabinoids,   principally   tetrahydrocannabinol   (THC)   and cannabidiol   (CBD) ,   terpenoids,   flavonoids,   and   other   molecules.
• Although   other   receptors   play   a   role,   the   majority   of   the   effects   of
THC   from   cannabis   are   mediated   through   partial   agonism   of   central   and   peripheral   cannabinoid   receptors,   CB1   and   CB2 ,   respectively.
• Activation   of   CB1   and   CB2   directly   inhibits   the   release   of   multiple   neurotransmitters   including   acetylcholine,   dopamine,   and   glutamate   while   indirectly   affecting   γ‐ aminobutyric   acid,   N ‐ methyl ‐
D ‐ aspartate,   opioid,   and   serotonin   receptors.
Russo   EB.
Br   J   Pharmacol.
2011;   163:1344 ‐ 64.
Wilson   RI,   Nicoll   RA.
Nature.
2001;   410:588 ‐ 592.
Aggarwal   SK.
Clin   J   Pain.
2013;   29(2):162 ‐ 171.
Davison   SN,   et   al.
J   Pain   Symptom   Manage.
2011;   41(4):768 ‐ 78

• Cannabinoid   receptors   (CB1,   CB2)   are   part   of   the   endocannabinoid   system   (ECS),   a   pro ‐ homeostatic   modulatory   system   composed   of   several   endogenous   ligands   (e.g.
anandamide   and   2 ‐ arachidonylglycerol)
• Physiologically,   the   ECS   been   shown   to   impact   pain   perception,   movement,   appetite,   aversive   memory   extinction,   hypothalamic ‐ pituitary ‐ adrenal   (stress)   axis   modulation,   immune   function,   mood,   inflammation,   and   others.
Russo   EB.
Br   J   Pharmacol.
2011;   163:1344 ‐ 64.
Wilson   RI,   Nicoll   RA.
Nature.
2001;   410:588 ‐ 592.
Aggarwal   SK.
Clin   J   Pain.
2013;   29(2):162 ‐ 171.
Davison   SN,   et   al.
J   Pain   Symptom   Manage.
2011;   41(4):768 ‐ 78
Cannabinoid   binding   (activation) negatively   coupled   to   adenylate   cyclase,   suppresses   neuronal   Ca 2+ conductance,   inhibits   inward   rectifying   K + conductance suppression   of   neuronal   excitability
CB1
• Periaqueductal   gray
• Rostral   ventromedial   medulla   (nucleus   raphe   magnus  ‐‐ antinociceptive   actions   of   cannabinoids   within   RVM   are   primarily due   to   presynaptic   inhibition   of   GABAergic   neurotransmission)
• Thalamus
• Dorsal   root   ganglion
• Amygdala
• Cortex
CB2
• Immune   cells,   including   microglia   – cytokine,   chemokine   modulation
• Dorsal   root   ganglion
• Brainstem
• Thalamus
• Periaqueductal   gray
• Cerebellum

• CB1   receptors   are   found   in   the   dorsal   vagal   complex
(medullary   nucleus   solitarius,   area   postrema,   dorsal   motor   nucleus   of   the   vagus).
• CB1   receptor   agonists   reduce   in   intestinal   5 ‐ HT   release,   suggesting   enterochromaffin   cells   express   functional   CB1   receptors.
• Cannabinoid   inhibition   of   5 ‐ HT3   receptor   activity   in   this   region—increased   GABAergic   activity
• Receptor ‐ independent   pathways   too
Sharkey KA, et al. European Journal of Pharmacology . 2014;722:134-146.
Martin BR and Wiley JL. Mechanism of Action of Cannabinoids: How It May Lead to Treatment of Cachexia, Emesis, and
Pain. Journal of Supportive Oncology. 2004;2(4):305-316.
Pacher P, Batkai S, Kunos G. The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacological
Reviews . 2006;58(3):389-462.
1.
Cannabinoids   induce   cancer   cell   death
2.
Cannabinoids   inhibit   angiogenesis,   invasion   and   metastasis
Velasco   G,   et   al.
The   use   of   cannabinoids   as   anticancer   agents.
Prog   Neuro ‐
Psychopharmacol   Biol   Psychiatry   (2015)   http://dx.doi.org/10.1016/j.pnpbp.2015.05.010
• 95 ‐ 99%   THC   is   plasma   protein   bound   (lipoproteins)
• Metabolism   via   hydroxylation,   oxidation,   and   conjugation   (CYP2C9 and
CYP3A)
– First ‐ pass   metabolism   with   oral   admin.
(11 ‐ OH ‐ THC)
• Rapidly   cleared   from   plasma   (70%   tissues   /   30%   metabolized)
• Elimination   over   several   days   (adipose)
• THC   is   excreted   via   both   hepatic   and   renal   mechanisms.
• No   specific   studies   have   been   done   with   cannabis ‐ based   medicines   in   patients   with   significant   hepatic   or   renal   impairment,   but   it   can   be   expected   that   effects   would   be   more   exaggerated   or   prolonged   in   these   settings.
• Breastmilk   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)
MEDICAL   CANNABIS

• Over   the   last   several   decades   cannabis   and   cannabinoid   therapeutics   have   been   studied   in   over   100   controlled   clinical   trials   of   varying   size   and   quality,   investigating   a   wide   range   of   conditions.
• As   with   the   evidence   for   most   pharmacologic   symptom   interventions,   there   are   a   lack   of   comparative   data   between   cannabis   and   other   commonly   used   treatments.
Hazekamp   A,   Grotenhermen   F:   Review   on   clinical   studies   with   cannabis   and   cannabinoids   2005–2009.
Cannabinoids   2010;5:1–21
Hill   KP   et   al.
JAMA 2015;313(24):2474 ‐ 2483) Slide   courtesy   of   Sunil   Aggarwal,   MD
• Total:   24,023  ‐‐ 2.3
publications/day   for   last   20   years
• 2013   projected:   280   in   first   38   days Æ 2689.
• For   cancer   pain ,   a   multicenter   RCT,   involving
360   patients,   investigated   oral   cannabis   to   treat   breakthrough   cancer   pain   in   subjects   who   were   started   on   a   long ‐ acting   opioid.
• It   showed   analgesic   efficacy   in   the   low   and   medium   dose   ranges,   which   were   also   well ‐ tolerated.
Portenoy   RK,   et   al.
Nabiximols   for   opioid ‐ treated   cancer   patients   with   poorly ‐ controlled   chronic   pain:   a   randomized,   placebo ‐ controlled,   graded ‐ dose   trial.
J   Pain.
2012;
13(5):438 ‐ 449.
• Two   RCTs   of   inhaled   cannabis   for   painful   HIV   sensory   neuropathy   involving   89   subjects   in   total   showed   significant   analgesic   efficacy,with   a   combined   NNT   of   3.38,   superior   to   all   other   medications   similarly   tested   for   this   indication.
Abrams   DI,   et   al.:   Cannabis   in   painful   HIV ‐ associated   sensory   neuropathy.
Neurology   2007;
68:515–521.
Ellis   RJ,   et   al.:   Smoked   medicinal   cannabis   for   neuropathic   pain in   HIV:   A   randomized,   crossover   clinical   trial.
Neuropsychopharmacology   2009;34:672–680.
Phillip   TJ,   et   al.:   Pharmacological   treatment   of   painful   HIV ‐ associated   sensory   neuropathy:   A   systematic   review   and   meta ‐ analysis   of   randomised   controlled   trials.
PLoS   One   2010;5:e14433.

• Three   RCTs   of   inhaled   cannabis   for   chronic,   intractable   neuropathic   pain   due   to   multiple   etiologies,   involving   100   subjects   in   total,   all   showed   efficacy   for   smoked   and   vaporized   cannabis.
Wilsey   B,   et   al.:   A   randomized,   placebo ‐ controlled   cross ‐ over   trial   of   cannabis   cigarettes   in   neuropathic   pain.
J   Pain   2008;9:506–521.
Ware   MA,   et   al.:   Smoked   cannabis   for   chronic   neuropathic   pain:   A randomized   controlled   trial.
CMAJ   2010;182:   E694–E701.
Wilsey   B,   et   al.:   Low ‐ dose   vaporized   cannabis   significantly   improves   neuropathic   pain. J   Pain
2013;14:136–148.
• Three   RCTs,   involving   43   subjects   in   total,   investigating   inhaled   cannabis   for   nausea   and   vomiting   secondary   to   active   cancer   chemotherapy,   demonstrated   inhaled   cannabis   to   be   an   efficacious   antiemetic.
Chang   AE,   et   al.
Ann   Intern   Med   1979;91:819–824.
Chang   AE,   et   al.
Cancer   1981;47:   1746–1751.
Levitt   M,   et   al.
Proc   Am   Soc   Clin   Oncol   1984;3:91(abstr   C ‐ 354).
• Three   RCTs   of   inhaled   cannabis   involving   107   subjects   in   total   congruently   showed   efficacy   for   appetite   stimulation   and   weight   gain   in   patients   with   AIDS   wasting   syndromes.
• No   studies   have   reported   a   benefit   in   cancer   patients.
Abrams   DI,   et   al.:   Short ‐ term   effects   of   cannabinoids   in   patients   with   HIV ‐ 1   infection.
Ann   Intern
Med   2003;139:258–266.
Haney   M,   et   al.:   Dronabinol   and   marijuana   in   HIV+   marijuana   smokers:   Acute   effects   on   caloric   intake   and   mood.
Psychopharmacology   2005;181:170–178.
Haney   M,   et   al.:   Dronabinol   and   marijuana   in   HIV ‐ positive   marijuana   smokers.
J   Acquir   Immune   Defic
Syndr   2007;45:   545–554.
Spasticity   (both   objective   and   subjectively   assessed),   spasm   frequency,   insomnia,   pain,   and   impaired   mobility—were   shown   to   be   significantly   improved   in   a   630   subject   multicenter   RCT   over   a   12 ‐ month   period.
Zajicek   J,   et   al.:   Cannabinoids   in   multiple   sclerosis   (CAMS)   study:   Safety   and   efficacy   data   for   12   months   follow   up.
J   Neurol   Neurosurg   Psychiatry   2005;76:1664–1669.

• Exact   dosages   depend   on   individual   patient   need   and   tolerance   of   side   effects.
No   evidence   based   guidelines   on   dosing   have   been   developed.
• Cannabis   preparations   include:
– resin ‐ containing   herbal   flowers,   which   can   be   heated   and   delivered   to   the   lungs   via   inhalation   of   smoke   or   vapor,
– cannabis ‐ based   extracts,   which   include   oral,   oromucosal,   rectal,   and   topically   delivered   preparations   in   the   form   of   concentrates,   suppositories,   edibles,   and   salves .
Aggarwal   S,   Blinderman   CD.
Fast   Facts   #279   JPM,   2014
FDA ‐ Regulated   Cannabinoid ‐ Based   Medicines:
Chemicals,   Extracts,   Botanicals
Photo   from   epocrates.com
Dronabinol
(Marinol™)
Nabilone
(Cesamet™ )
Photo   from   nida.org
Cannabis   Sativa   L.
Extracts (Sativex™)
Photo   from   Russo   et   al.
2002
Cannabis   Sativa   L.
Cigarettes
1985 1985
Photo   from   wikipedia.org
2006
Photo   from   Russo   et   al.
2002
Approximately   460   chemical   constituents,   >100   phytocannabinoids
1976
From: Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical
Review
JAMA. 2015;313(24):2474-2483. doi:10.1001/jama.2015.6199
Date of download: 6/29/2015
Copyright © 2015 American Medical
Association. All rights reserved.
• Cannabinoids   are   lipophilic   and   have   nearly   immediate   onset   of   action   when   smoked   or   vaporized.
• Vaporization   has   the   advantage   of   rapid   onset   of   effect   and   easy   dose   titration.
– Patients   can   be   advised   to   pause   briefly   between   inhalations   to   ascertain   effectiveness   of   the   medicine   and   to   stop   when   maximum effect   is   achieved.
• Oral   ingestion   of   cannabis   products   has   a   delayed   onset   of   action   compared   to   inhalation   and   titration   is   more   difficult.
• Maximum   cannabinoid   blood   levels   are   reached   up   to   six   hours   post   oral   ingestion,   with   a   half ‐ life   of   20   to   30   hours.
Aggarwal   S,   Blinderman   CD.
Fast   Facts   #279   JPM,   2014

SYNTHETIC   CANNABINOIDS   (DRONABINOL   AND   NABILONE)
• Dronabinol   and   nabilone   are   FDA   approved   for   the   treatment   of   nausea   and   vomiting   associated   with   cancer   chemotherapy   in   patients   who   have   failed   to   respond   to   conventional   antiemetics.
• There   are   no   published   studies   comparing   dronabinol   and   nabilone   to   newer   antiemetic   agents.
Arnold   RM,   Wilner   LS.
Fast   Facts   #93   Cannabinoids   In   The   Treatment   Of
Symptoms   In   Cancer   And   Aids
• Only   dronabinol   is   FDA   approved   for   the   treatment   of   anorexia   associated   with   weight   loss   in   patients   with   HIV/AIDS.
– Early   studies   of   dronabinol   in   this   population   showed   promising   increases   in   caloric   intake   and   stabilization   or   gains   in   weight.
– However,   later   analysis   showed   that   the   effect   sometimes   represented   accumulation   of   water   or   fat   instead   of   the   preferred   lean   body   mass.
• Neither   dronabinol   or   nabilone   are   indicated   for   cancer   associated   anorexia.
Arnold   RM,   Wilner   LS.
Fast   Facts   #93   Cannabinoids   In   The   Treatment   of
Symptoms   In   Cancer   and   AIDs.
• Dronabinol   (Marinol)
– Chemotherapy   induced   N/V:   5mg/m 2 PO   1 ‐ 3   hours   before   and   Q2 ‐ 4   hr   after   chemo;   may   be   increased   in   2.5mg/m 2 increments   to   15mg/m 2 ;   not   to   exceed   4 ‐ 6   doses/day
– Appetite   stimulation:   2.5mg
PO   Q12hr,   may   be   increased   to   20mg/day
• Nabilone   (Cesamet)
– Chemotherapy   induced   N/V:   1 ‐ 2mg   PO   Q8 ‐ 12h

MEDICAL   CANNABIS   AND   CANNABINOIDS
Safety:
• Occasional   and   low   cumulative   marijuana   use   was   not   associated   with   adverse   effects   on   pulmonary   function   (Pletcher   MJ,   et   al.
JAMA   2012)
• Medical   cannabis   laws   (from   1999 ‐ 2010)   are   associated   with   significantly   lower   opioid   overdose   mortality   rates.
(Bachhuber   MA,   et   al.
2014)
• Unlike   opioid   overdose,   marijuana   toxicity   is   not   fatal.
Concerns:
• Marijuana   adverse   effects—acute   and   chronic   (Volkow   ND,   et   al.
NEJM ,   2014)
• Increased   risk   of   MVA’s   with   acute   marijuana   impairment   (Hartman
RL,   Huestis   MA.
Clin   Chem ,   2013)
• Preliminary   research   points   to   an   association   between   marijuana   use   and   MI,   stroke,   and   PVD   (Thomas   G,et   al..
Am   J   Cardiol .
2014)
Adverse   Effects   of   Short ‐ Term   Use   and   Long ‐
Term   or   Heavy   Use   of   Marijuana.
Effects   of   short ‐ term   use
• Impaired   short   term   memory
• Impaired   motor   coordination,   interfering   with   driving   skills   and   risk   of   injuries
• Altered   judgment,   increasing   risk   of   sexual   behaviors,   transmission   of   STDs
• High   doses:   paranoia   and   psychosis
Effects   of   long ‐ term   or   heavy   use
• Addiction
– ~9%   of   users   overall,   17%   of   those   who   begin   use   in   adolescence,   and
25 ‐ 50%   of   daily   users
• Altered   brain   development
• Poor   educational   outcome,   increased   likelihood   of   dropping   out   of   school
• Cognitive   impairment
• Diminished   life   satisfaction   and   achievement
• Symptoms   of   chronic   bronchitis
• Increased   risk   of   chronic   psychosis   disorders   in   persons   with   predisposition
Volkow   ND   et   al.
N   Engl   J   Med   2014;370:2219 ‐ 2227.
Level   of   Confidence   in   the   Evidence   for   Adverse   Effects   of   Marijuana   on   Health   and
Well ‐ Being.
Volkow   ND   et   al.
N   Engl   J   Med   2014;370:2219 ‐ 2227.

Increases   over   Time   in   the   Potency   of   Tetrahydrocannabinol   (THC) in   Marijuana   and   the
Number   of   Emergency   Department   Visits   Involving   Marijuana,   Cocaine,   or   Heroin.
Volkow   ND   et   al.
N   Engl   J   Med   2014;370:2219 ‐ 2227.
Clusters   of   Cases   of
Adverse   Health   Effects   or
Severe   Toxic   Effects   and
Deaths   Associated   with
Synthetic   Cannabinoid
(SC)   Product   Use.
Trecki   J   et   al.
N   Engl   J   Med
2015;373:103 ‐ 107.

Integrating   medical   marijuana   in   clinical   practice
• Federal   law   vs   state   law
– Annas,   G.
NEJM ,   2014
• Protection   to   discuss   marijuana   as   part   of   doctor ‐ patient   confidentiality
– Protected   under   federal   law   even   in   states   where   it   is   illegal   to   prescribe
• Conflict   of   interest
– Should   physicians   who   serve   as   “scientific   advisors” to   marijuana   growers/suppliers   be   allowed   to   prescribe?
• Cannabinoids   act   on   unique   G ‐ protein   receptors   (CB1   and
CB2)   found   in   the   CNS,   immune   system,   and   elsewhere   in   the   body.
• High   quality   studies   have   demonstrated   that   cannabinoids   can   be   of   benefit   in   patients   with   cancer   pain,   neuropathic   pain,   anorexia,   nausea/vomiting,   and   spasticity.
• There   are   no   evidence ‐ based   dosing   guidelines   for   inhaled   or   ingested   cannabis.
• Side   effects   (short   and   long   term)   may   be   significant   and   should   be   reviewed   with   patients   in   whom   cannabinoids   are   being   considered.
Questions?