Cannabis: The Fog of Ignorance

1. Cannabis: The Fog of Ignorance
ChiefClinicalOfficer ClinicalProfessorofPsychiatry
GeorgetownUniversitySchoolof
Medicine
UniversityofMarylandSchoolof
Medicine
GeorgeKolodner, M.D.

2. Long History of Medicinal Use
• 2700 BC. First documented use (China)
• Used for millennia in India, China, Egypt,
Middle East
• Western medicine: mainstream use in 19th
and early 20th Centuries
– 1850 to 1942. Listed in U.S. Pharmacopoeia
• Fluidextracts(notrawplantforinhalation)
• Manufacturedbymajorpharmaceuticalcompanies

3. Dr. William Osler’s Opinions
• Regarding medication in general
– “One ofthe first duties ofthe physician is to
educatethe masses not to take medication.”
– “Youcannot have a drug for everymalady.”
• Regarding cannabis
– “Probably the most satisfactoryremedyfor the
treatmentof migraine headaches.”
– TextbookofMedicine,1892-1915

4. Repetitious Process
1. Concern about widespread illegaluse and
uncertainty about facts
2. Appointment of high levelgovernment
commission or scientific committee
• Conclusion:“Cannabisisnotwithoutdangers,but
penaltiesforusearedisproportionatetothethreat”
• Recommenddecriminalization
3. Opposition from law enforcement,politicians,
some physicians
4. Sweeping,confident, disrespectful assertions by
extremeson both sides
5. Stalematewith minimal or no legalchanges

5. Commissions and Committees
• 1893-4,UK:IndianHempDrugsCommission
• 1929,U.S.:PanamaCanalZoneMilitaryInvestigation
• 1939-44,U.S.:LaGuardiaReport.NYAcademyof Science
• 1968,UK:BaronessWootton
• 1970,Canada:LeDainCommission
• 1970-2,U.S.:SchaferCommission(Nixon)
• 1999,U.S.:InstituteofMedicine

6. De-Medicalization of Cannabis
(Harry Anslinger)
1937
Marijuana Tax Act
• Allowed medical use but imposed
heavy administrative burdens
• Adopted despite AMA opposition
• Declared unconstitutional in 1969
1942
Removed from U.S.
Pharmacopeia
1961
Included in UN Single
Narcotics Convention
1970
Classified as Schedule 1
Substance in Controlled Drug
Substances Act

7. DEA as an Information Source
• “ReeferMadness.” 1936 movie referred to
cannabis as “the burning weed with its roots
in hell … that leads to debauchery, murder,
suicide and the ultimate end -- hopeless
insanity.”
• Assertionsthatcannabis a “gateway drug” and
causes cognitive damage and psychosis in
adults wererecentlyremovedfrom DEA website

8. DEA Schedule I Criteria
1. High potential for abuse
2. No currently accepted use for treatment in
the United States
3. Lack of accepted safety for use under
medical supervision

9. Context of Classification
as Schedule I
"Since there is still a considerable void in our
knowledge of the plant and effects of the
active drug contained in it, our
recommendation is that marijuana be
retained within Schedule I at least until the
completion of certain studies now
underway to resolve the issue.“
Dr.RogerO.Egeberg
AssistantSecretaryofHealth
August14,1970

10. Raphael Mechoulam
• 86 y.o. Israeli chemist, still professionally
active
• Identified THC as the primary psychoactive
ingredient in cannabis
• Discovered the endocannabinoid system
• “The Scientist”: YouTube documentary
about his discoveries
– https://www.youtube.com/watch?v=csbJnBKq
wIw

11. Modern Timeline
• 1940. Cannabidiol (CBD) isolated from plant
• 1964. THC isolated from plant
• 1981. CBD anticonvulsant effect demonstrated
• 1985. Synthetic THC approved by FDA
• 1988. CB1 receptoridentified
• 1992. Endogenous anandamide (AEA)
• 1993. CB2 receptoridentified
• 1995. Endogenous 2-arachidonoyl glycerol

12. Endocannabinoid System:
Helps Regulate Multiple Systems
• Pain
• Immunity
• Inflammation
• Movement
• Bone density
• Tumor surveillance
• Appetite
• Stress
• Mood

13. Endocannabinoid Receptors
• CB1
– MostcommonreceptorinCNS
• Responsibleforpsychoactiveeffects
• Absentinbrainstemnorespiratorydepression
– Alsoinperipheralnervesandnon-neuronaltissues
• CB2
– Locatedinmacrophages
– Involvedinimmunesystemandanti-inflammatory
activity
• Exactfunctionsunknownduetoabsenceofgoodprobes
• Both inhibit synaptictransmission
• Other receptorsnot as well characterized

14. Endocannabinoid Ligands
• Anandamide(AEA)
– Partialagonist
– CNS:Stressresponse.Periphery:pain
– Metabolizedbyfattyacidamidehydrolase(FAAH)
• 2-arachidonoylgylcerol(2-AG)
– Fullagonist
– Broadlyexpressed.“Workhorse”
– Metabolizedbymono-acyl-glycerol(MAGL)
• Ligand diversification:Both acton CB1 receptor
but actdifferentiallyto modulatesystems

15. Efficacy
• High qualityevidence
– Chemotherapy-inducednauseaandvomiting
– Appetitestimulation
– Chronicpain,neuropathic(especiallyHIV/AIDS)
– Spasticityofmultiplesclerosis,spinalcordinjury
– Anticonvulsant(CBDforDravetSyndrome)
• Lowqualityevidence
– Anxiety,sleepdisorders,PTSD
• Possiblerolein addictiontreatment
– Reducecannabiswithdrawal
– CBDcounteractspsychoactiveeffectofTHC
– CB1blockerrimonabantwithdrawn2008

16. Safety
• No overdosedeaths
– AbsenceofCBreceptorsinbrainstem
• Intoxicationa problem
– Impaireddriving
• Especiallyifmixedwithalcohol
– Delayedeffect
• Addictivepotentialequalto benzodiazepines(9%)
– Lessthanalcohol(15%)
• Cognitivedeficitsresultingfromheavyusebefore
age18
• Fetaldevelopment
– Negativeeffectoncognitivefunctioninginchildren
• Associationwithpsychosis
– Causationpossible

17. Obstacles to Knowledge
• Access
– Singlesourceforresearchgrade
• UniversityofMississippifarm,contractedbyNIDA
• LowTHCconcentrationofresearchgrade
• Fall,2016:DEAwillingtoallowothersources
– 5levelsofapproval(morethananyotherdrug)
DEA–notFDA–hasfinalauthority
• Organizationalissues
– Nogovernmentagencyfocusedonbeneficialuses
• Discouragesdevelopmentof new
pharmaceuticalproducts
• Endocannabinoidsystem is not being taughtin
medicalschools

18. Summary
• Cannabis has medicinalvalue
– Benefitsandriskstendtobeexaggerated
• Influenceof law enforcementagencieshas
outweighedhealth agencies
• Politicalconsiderationshaveinterferedwith
scientificevaluationand left physicians in a
disadvantagedposition
– Bewareofselectiveuseofdatatosupport
particularpositions
• Barriers toresearch and pharmaceutical
developmentshould be lowered