The FDA Process
and
Modern Medicine
Bertha K Madras, PhD
Professor of Psychobiology
Department of Psychiatry
Harvard Medical School
February 18, 2013
Plant products as medicines
Food and Drug Administration: approval process
Marijuana History
The FDA and Marijuana
Without FDA Process,
What are Conceivable Consequences?
Plant Products As Medicines
Composition unknown, unregulated
Treatment of symptoms, not illnesses
Poor understanding of pathology
Poor understanding of mechanisms
Quantities inconsistent, unregulated
Digitalis
Atropine
•
•
•
•
Aspirin
Highly purified and defined
Treat specific illness
Mechanism of action known
Controlled, consistent, regulated doses
Quinine
Food and Drug Administration, approval process
Scientific, regulatory, and public health agency
• In 1862: a single chemist in the Department of Agriculture:
Now: > 9,000 (25¢ of every $ spent by consumers).
• Jurisdiction: drugs, foods, additives, infant formula biotherapeutics, medical devices, radiation-emitting products,
cosmetics, animal feed.
• The staff: Chemists, pharmacologists, physicians,
microbiologists, veterinarians, pharmacists, lawyers, etc.
• What FDA does: Monitors manufacture, import, transport,
storage, sale of ~$1 trillion products annually.
• What FDA does: Investigates and inspects >16,000 facilities
FDA is the sole Federal
agency that approves
drugs as safe and
effective for intended
indications.
FDA approval process
requires: controlled research,
clinical trials to base approval
on safety, efficacy and
labeling decisions.
The Federal Food, Drug, and
Cosmetic (FD&C) Act requires:
new drugs be shown safe and
effective for their intended use
before US marketing.
To bypass the FDA drug
approval process might
expose patients to unsafe and
ineffective drug products.
LAETRILE
The FDA Ensures Drug Safety
FDA job: evaluate new drugs before they can be sold
• prevent quackery
• provide information to use medicines wisely
• ensure that drugs’ health benefits outweigh known risks
To sell a drug in the US, drug must be safe, effective
• Evidence proving drug is safe, effective
• Physicians, statisticians, chemists,
pharmacologists, other scientists review data
• Drug is approved if review establishes that a
drug's health benefits outweigh known risks
3.5 years +
• laboratory testing
1 year:
• application to FDA for
human testing
20-80 healthy volunteers
to establish safety and
profile
• 1/1000 compounds go to
human testing
PHASE I
3 years PHASE III
2.5 years
1000’s patients
Application for
approval
•multiple sites
• different populations,
doses, effectiveness
•Drug combinations
adverse reactions
< or > 100,000
pages!!!!!
2 Years PHASE II
100’s patient volunteers
determine if drug is
effective for a specific
disease state
PHASE IV
If approved, requirement
to report cases of adverse
reactions, other clinical
data to the FDA.
2.5 years
Application for
approval
< or > 100,000
pages!!!!!
• Review meeting: discuss drug and data
• New Drug Application (NDA) submission: animal, human data,
analyses, drug behavior in body, manufacturing process.
• FDA Review: decide to review (60 days); review (several years)
• Drug labeling: is information accurate (indication, dose, side
effects, proscriptions, drug interactions?
• FDA Facility inspection: Inspects facility where drug is
manufactured
• FDA Decision: approve or reject
PHASE IV:
If approved, requirement
to report cases of adverse
reactions, other clinical
data to the FDA.
•Drug manufacturer: submits required periodic
safety updates (new risks)
•MedWatch: Physicians and consumers can report
adverse events www.fda.gov/medwatch
•New risk disclosures: drug labeling changed,
public & physicians informed, drug use may be
restricted or withdrawn
Marijuana History
2727 BC
CHINA
1200 BC
INDUS VALLEY
400 AD (CE)
ISRAEL
• Pen-ts’ao Ching Pharmacopeia
• Medicinal properties of marijuana
• Psychiatric side-effects
• Marijuana is one of five sacred plants
• In tomb near Jerusalem
• Ashes of marijuana metabolite found near
skeleton of pregnant women
Adapted from Murray et al., Nat Rev Neurosci. 2007 Nov;8(11):885-95; additions by BK Madras
1928-1942
US and UK
1894
INDIA
1961
60 Nations
1976
NETHERLANDS
1980, 1992
UNITED STATES
• Recreation use of marijuana banned
• Marijuana tax prohibits marijuana use
• Marijuana removed US Pharmacopeia
• British Report of Indian Hemp Drugs Commission
• Sign Uniform Drug Convention
• Pledge to end marijuana use within 25 years
• Opium Act separates marijuana from “hard drugs”
• Sale of marijuana is tolerated
• 1980 Marinol (THC) approved for nausea in cancer
• 1992 Marinol (THC) approved for anorexia/AIDS
Adapted from Murray et al., Nat Rev Neurosci. 2007 Nov;8(11):885-95; additions by BK Madras
FDA and Marijuana
THC (Dronabinol, Marinol), is recognized as an appetite
stimulant and anti-nausea/vomiting (antiemetic) agent.
The FDA approved it for use:
- as an antiemetic for chemotherapy patients in 1985
- as an appetite stimulant for AIDS patients in 1992
Special prescription to treat chemotherapy-, or radiationrelated nausea, AIDS-related loss of appetite.
Pure compound
Chemistry, manufacturing, and composition of matter predictable
Production methods are validated
Non-clinical pharmacology and toxicology
Human pharmacokinetics and bioavailability
Clinical microbiology
Clinical data: dose response, efficacy, safety
Side effect profile
Case reports, safety updates
Pure compound, with
predictable chemistry,
manufacturing, and
composition of matter
Phyto- and synthetic cannabinoids
Phytocannabinoids: plant-derived
80 or so phytocannabinoids made by marijuana plant
Cannabis Sativa
D9-TetraHydroCannabinol or THC is highest
D9 refers to double C=C bond in 9-position of THC
OH
O
Synthetic cannabinoids: 1,000s made by chemists
Δ9-THC (Gaoni & Mechoulam, 1964)
Anandamide: arachidonoylethanolamide
2-AG: 2-arachidonoylglycerol
7 or more made in brain and in other tissues
O
H
OH
N
ANANDAMIDE
O
OH
C
O
OH
2-ARACHIDONOYL GLYCEROL (2-AG)
Is Marijuan a Pure Compound?
Marijuana Smoke and Tobacco Smoke
Chemical
TOBACCO
Pyridine
59
93
Quinoline
2.2
2.68
Toluene
169
199
Benzene
94
84
Styrene
28
44
Acrylonitrile
24
67
Isoprene
540
132
Hydroquinone
299
71
m + p-cresols
51
46
TOBACCO
MARIJUANA
naphthalene
1-methylnaphthalene
2-methylnaphthalene
acenaphthylene
acenaphthene
fluorene
phenanthrene
anthracene
fluoranthene
pyrene
benzo(a)anthracene
4908
4888
3666
711
309
1369
515
162
171
154
52
4459
4409
2917*
459*
213*
659*
476
136*
117*
82.3*
43.1*
chrysene
benzo(b)fluoranthene
61.7
21.9
56.3
16.2*
benzo(k)fluoranthene
7.45
4.54*
benzo(e)pyrene
benzo(a)pyrene
perylene
indeno(1,2,3,-cd)pyrene
19.2
25.1
10.8
10.1
12.6*
15.5*
6.10*
8.65
dibenz(a,h)anthracene
4.84
2.83*
Extreme
MARIJUANA
Chemical
tar (mg/cig)
pH
NO (μg/cig)
NOx (μg/cig)
CO (mg/cig)
nicotine
(mg/cig)
ammonia
(μg/cig)
HCN (μg/cig)
NNN
NAT
NAB
NNK
Mercury
Cadmium
Lead
Chromium
Nickel
Arsenic
Selenium
TOBACCO
MARIJUANA
80.3
5.47
151
158
41.5
5.2
103
7.73
685
693
35.3
0.002−0.007*
67
1315
320
160
125
8.26
158 ± 15
5.35
284
43.8
11.9−39.6
12.9−43.1
12.7
4.42−14.7
1668
<1.49*
<1.87*
0.063−2.00*
<3.72*
3.51
14.6
7.7−25.7*
11.9−39.6
<12.9
2.25−7.49*
4.42−14.7
Moir et al, A Comparison of Mainstream and Sidestream Marijuana and Tobacco Cigarette
Smoke Produced under Two Machine Smoking Conditions. Chem. Res. Toxicol., 2008, 21 (2), pp
494–502 Standard conditions employed a puff volume of 35 ml, a puff duration of 2 s, and a
puff interval of 60 s. These conditions are termed “ISO” throughout. Conditions more reflective
of marijuana smoking employed a puff volume of 70 ml, a duration of 2 s, and a 30 s interval.
These conditions are referred to as “extreme” and differ from the Health Canada “intense”
tobacco smoking conditions, which employ a puff volume of 55 ml
benzo(g,h,i)perylene
7.17
6.03
<0.071
<0.071
benzo(b)fluoranthene
19.1
17.6
benzo(j)fluoranthene
13.3
12.2
dibenz(a,h)acridine
<0.628
<0.628
dibenz(a,j)acridine
<0.519
<0.519
7H-dibenzo(c,g)carbazole
<0.278
<0.278
dibenz(a,l)pyrene
dibenz(a,e)pyrene
<0.634
<0.313
<0.634
<0.313
dibenz(a,i)pyrene
dibenz(a,h)pyrene
2.55
<0.354
<0.329*
<0.354
5-methylchrysene
Marijuana contains ~ 80 cannabinoids, 100’s
of other chemicals
Marijuana smoke has ammonia at 20-times higher levels than
tobacco smoke
Marijuana smoke has hydrogen cyanide, NO, NOx, and some
aromatic at 3–5 times higher levels than tobacco smoke
Marijuana cigarette smoke contains known carcinogens and
other chemicals implicated in respiratory diseases
Chemistry, manufacturing, and composition of matter
predictable?
Contents
vary from 0.5 % to 15 %
(3 - 30 mg)
Smoked
delivery is
10 - 50%
efficient
Peak levels within
minutes - 1 hour
Ingested
delivery is
about 6%
efficient
Peak levels felt 30 120 minutes
THC
partitioning
into cells, lipid and
albumin
Clinical data: dose
response, effective,
safe
The Gold Standard of Evidence:
Randomized, Double-blinded (and
cross-over) Multi-Center Controlled
Trials
> 36 scientific reports
Minus abstracts (or proceedings)
= 24+ publications
5 performed with patients, medical
conditions
according to ballot initiative
Neuropathic Pain:
Wilsey et al, J Pain, 2012
Wilsey et al, J. Pain, 2008
Ellis et al, Neuropsychopharm., 2009
Abrams et al, Neurlogy 2007
Spasticity:
Corey-Bloom et al, CMAJ 2012 (30
patients)
5 clinical studies
discontinued
4/5 studies used EXPERIENCED MARIJUANA USERS
• INVESTIGATOR: Donald Abrams, M.D.PROJECT TITLE:
Marijuana in Combination with Opioids for Cancer Pain
• PROJECT TYPE: Clinical Study
• STATUS: DISCONTINUED
• RESULTS:
The study experienced difficulty with recruitment of
participants, in part due to the 9-day hospitalization required
for study participation. A variety of recruitment strategies
were employed, including outreach to local oncologists,
advertisements in local print media, and presentations at
various related functions. None of these strategies were
successful and the trial was discontinued.
•
INVESTIGATOR:Mark Agius, M.D.
•
•
•
•
PROJECT TITLE: Cannabis for Spasticity/Tremor in MS: Placebo Controlled Study
PROJECT TYPE:Clinical Study
STATUS: FUNDING DISCONTINUED
RESULTS:This study sought to evaluate the safety and efficacy of smoked cannabis
in relieving the spasticity associated with multiple sclerosis (MS) as measured by a
new objective measure of spasticity.
Unfortunately, recruitment for this study proved to be difficult
for many reasons, including a prohibition on driving
throughout the 16 weeks participants were enrolled in the
study. The study was reviewed by the CMCR Scientific Review
Board and Data Safety Monitoring Board who both
recommended discontinuation for lack of feasibility. No
preliminary analyses of safety or efficacy were possible.
• INVESTIGATOR: Dennis Israelski, M.D.
• PROJECT TITLE: MMJ for HIV-associated DSPN: Adherence & Compliance
Sub-Study
• PROJECT TYPE: Clinical Study, Sub-Study
• STATUS: DISCONTINUED
• RESULTS: Recruitment for this sub-study stemmed from the parent study.
Methods for recruitment included: dear doctor letters, flyers, and postings
on San Mateo Medical Center and Center Watch clinical trials websites. A
series of focus groups were organized to get community input regarding
the study.
• Changes were made to the study as a result of the focus
groups with the intent of improving recruitment, but no such
improvement occurred. In total, only three patients were
recruited into the sub-study, and thus did not provide
enough data for analyzable results.
• INVESTIGATOR: Suzanne Dibble, DNSc, RN
• PROJECT TITLE: Treating Chemotherapy-Induced Delayed Nausea with
Cannabinoids
• PROJECT TYPE:Clinical Study
• STATUS: DISCONTINUED
Unfortunately, recruitment proved more difficult than
anticipated and the study was discontinued. In total, 172
people were screened, but only 6 completed the study. Most
people who could not participate in the study lacked a
"moderate amount of nausea." This may be in large part due
to recent advances in anti-nausea drug treatments. As the
target for enrollment was 81 patients, the 6 who completed
were not sufficient to produce analyzable results.
• INVESTIGATOR: Mark Wallace, M.D.
• PROJECT TITLE: Analgesic Efficacy of Smoked Cannabis in Refractory
Cancer Pain
• PROJECT TYPE:Clinical Study
• STATUS: DISCONTINUED
• RESULTS: Recruitment for this study was difficult. Typical methods for
recruitment, including posters, newspaper advertisements, and
community referral were unsuccessful. Very few cancer pain patients were
being seen in the UCSD Pain Clinic during this recruitment period. Local
hospice agencies were willing to refer potential subjects, however, these
subjects were often already smoking cannabis for pain control. To avoid
potential complications from off-study cannabis use, these participants
were not recruited. Only one subject was enrolled in the study, and was
withdrawn for non-compliance with study procedures. No unexpected or
unusual adverse events were noted in this subject.
Condition
Results
Primary dystonia
Nabilone (n=15): no improvement
Tourette’s
THC (n=36): reduced tics
Psychosis/schizophrenia
CB1 antagonist (n=481): no improvement
Obesity
Rimonabant (n>5,500) weight reduction (nausea, anxiety, diarrhea, depression)
Parkinson’s disease
CB1 antagonist (n=24): no improvement
Nabilone (n=7): - not psychoactive - reduces dyskinesia (Sieradzan KA, et al.,
Neurology. 2001 Dec 11;57(11):2108-11.) Cannabinoids reduce levodopa-induced
dyskinesia in Parkinson's disease: a pilot study.
Alzheimer’s Disease
Dronabinol (n=6): reduced agitation
(Walther S, Mahlberg R, Eichmann U, Kunz D. Delta-9-tetrahydrocannabinol for
nighttime agitation in severe dementia. Psychopharmacology (Berl). 2006
May;185(4):524-8.)
Traumatic brain injury
Dexanabinol: (n=861) no improvement
(Maas AI et al., Pharmos TBI investigators. Efficacy and safety of dexanabinol in
severe traumatic brain injury: results of a phase III randomised, placebo-controlled,
clinical trial. Lancet Neurol. 2006 Jan;5(1):38-45.)
CACHEXIA
ANOREXIA
CANCER
CHRONIC
PAIN
EPILEPSY
SEIZURES
GLAUCOMA
HIVAIDS/Hep C
MULTIPLE
SCLEROSIS
SPASTICITY
OR
CROHN’S
NAUSEA
MIGRAINE
OR
ALZHEIMER’

AK1998
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
CA 1996
Yes
Yes
Yes


Yes
Yes

Yes
CO 2000
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

HI
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

ME 1999

Yes

Yes
Yes
Yes

Yes
Yes
Yes

MT
2004
Yes

Yes
Yes
Yes


Yes
Yes
Yes

NV
2004
Yes
Yes
Yes

Yes
Yes
Yes

Yes
Yes

NM 2007

Yes

Yes

Yes
Yes
Yes
Yes


OR 1998
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
RI 2006
Yes
Yes
Yes
Yes
Yes
Yes
Yes/HepC
Yes
Yes
Yes
Yes
VT 2004
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

Yes

WA 1998
Yes
Yes
Yes
Yes

Yes
Yes/HepC
Yes
Yes
Yes

MI 2008
Yes
Yes
Yes
Yes
Yes
Yes
Yes/HepC
Yes
Yes/ALS
Yes
Yes
NJ 2010
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes/ALS
Yes
2000
Yes
Yes
Alaska
1 oz
6 immature
3 mature
California
8 oz
12 immature
6 mature or more
Colorado
2 oz
6 plants
Hawaii
1 oz
7 plants
3 mature
Maine
1.25 oz
6 plants
3 mature
Montana
1 oz
6 plants
New Mexico
Adequate supply
3 months uninterrupted
supply
Nevada
1 oz
7 plants
3 mature
Oregon
24 oz
18 seedlings
6 mature
Rhode Island
2.5 oz
or
Vermont
3 oz
Washington
60 day supply
Michigan
2.5 oz
New Jersey
2 oz
12 plants
7 plants
12 plants
Side effect
profile
CB1 receptors
BRAIN
Heart
Testis
Uterus
Prostate
Vascular tissue
Immune cells
CB2 receptors
brain
Hematopoietic
cells
IMMUNE CELLS
Adrenal
Ileum
Jejunum
Marijuana distributes to many
regions (CB1) of Human Brain
Red, yellow regions have high concentrations of CB1 cannabinoid receptor
Left: PET image to probe CB1
Center: MRI to define brain anatomy
Right: MRI, PET combined
GE Terry et al., Quantitation of cannabinoid CB1 receptors in healthy human brain using positron
emission tomography and an inverse agonist radioligand. Neuroimage 48 362, 2009
THC produces euphoria
THC produces perceptual changes
THC produces depersonalization, derealization, distorted sensory perceptions, altered body perception, feelings of
unreality, and extreme slowing of time in both healthy individuals and patients with schizophrenia . Subjects were
reported as being ‘‘spaced out,’’ looking ‘‘separated or detached,’’ and as if they said or did ‘‘something bizarre,’’ or
if they needed redirection.
Source: D'Souza DC. Cannabinoids and psychosis. Int Rev Neurobiol. 2007;78:289-326.
Maximum Score
12
11
- Placebo
10
- THC 2.5 mg
9
# Correct Words Recalled
8
- THC 5 mg/kg
7
6
5
4
3
2
1
Minimum Score
Immediate recall
Trail #1
Immediate recall
Trail #2
Immediate recall
Trail #3
Delayed Free
Recall
Delayed Cued
Recall
Delayed Recognition
Recall
D’Souza, 2005
Long Term Marijuana Use Affects Cognitive Function
Performance of frontal-executive tests lower in heavy
marijuana users
(Pope and Yurgelun-Todd (1996)
Performance on neurocognitive tests - attention, memory, and
executive function - worse in heavy MJ smokers
(Solowij et al. 2002, Fletcher et al., 1996; McHale and Hunt,2008)
Cognitive deficits in heavy marijuana users
after 28-day abstinence
(Porter, & Frampton, 2007; et al., 2002)
MJ use impairs memory, attention, inhibitory control, executive
function, decision making; effects can persist beyond acute
intoxication for days, weeks, or longer, with long-term heavy MJ use
(Solowij & Pesa, 2010).
Odds ratio
3.5
3
2.5
2
1.5
1
0.5
0
NO RISK
Adapted from Nat Rev Neurosci. 2007 Nov;8(11):885-95. Cannabis, the mind and society: the hash realities. Murray RM, Morrison PD,
Henquet C, Di Forti M. McGrath et al, Association Between Cannabis use and Psychosis-related outcomes using sibling pair analysis in a
cohort of young adults. Arch Gen Psychiatry 2010: 67: 440-447
Changes in brain
structure, activity, gene
expression
Negative long-term
educational, career
achievements
Impaired learning,
cognitive, executive
function
Compromised
measures of
reproduction
Higher Risk for
Adolescents
Pathology in lung,
compromised
cardiovascular function
Addiction 9-10%, and
higher prevalence with
early onset
Impaired school,
work, social life
Increased risk of
psychosis,
schizophrenia, other
psychiatric symptoms
Crean RD, Crane NA, Mason BJ. An evidence based review of acute and long-term effects of cannabis use on
executive cognitive functions. J Addict Med. 2011 Mar;5(1):1-8; many other sources
Marijuana and the Developing
Adolescent Brain
Adolescent Marijuana Use Escalating
Any Illicit drug - past 30 days % increase in illicit drug use
Grade 12 from 2007
20%
15.1%
15%
10%
8.7%
6.4%
5%
1.8%
0%
2008
2009
2010
2011
Monitoring the Future, 2011
Marijuana’s Effects are Greater in
Adolescents Than Adults
Brain
changes
Learning
deficits,
future
Addiction
Psychosis
Other
effects
Short-term
memory
impaired
Learning
impaired
Attention
span
impaired
even after 6
weeks of
abstinence
Adolescents
who use
marijuana
are 10 times
more likely
to use
cocaine
compared
with peers
who never
smoked
marijuana
Arseneault et al., 2002; van Os et al, 2002; Zammit et al., 2002; Henquet et al., 2005;
Stefanis et al., 2004; Rubino and Parolaro, 2008; Konings et al., 2008; Andreasson et al., 1987;
Moore et al, 2007; McGrath J, et al. Arch Gen Psychiatry. 2010 May;67(5):440-7. Association between
cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults
The Prevalence Of Addiction to Marijuana or Alcohol is 5-6
Times Higher if Teenagers Start Using at Age 15 or Less
% Abuse
Dependence
Age at first use and abuse/dependence as adult
20.00%
18.00%
16.00%
14.00%
12.00%
10.00%
8.00%
6.00%
4.00%
2.00%
0.00%
< 15 years
18 + yeears
Marijuana
Alcohol
2010 National Survey Drug Use and Health, NSDUH Sept 2011
Dosage forms (smoke, vapor; baked; teas; dose standardized; Pure compound - NO
Chemistry, manufacturing , and control of composition - NO
Quality control; Production methods are validated - NO
Non-clinical pharmacology and toxicology – SOME, BUT INADEQUATE
Human pharmacokinetics and bioavailability – NOT SYSTEMATIC
Clinical microbiology - NO
Clinical data: dose response, efficacy, safety - INADEQUATE
Side effect profile - NO
Case reports, safety updates -NO
•
Marijuana is in schedule I of the Controlled Substances Act (CSA), the most restrictive schedule.
•
The Drug Enforcement Administration (DEA) continues to support that placement and FDA concurred
because marijuana met the three criteria for placement in Schedule I under 21 U.S.C. 812(b)(1)
•
1. Marijuana has a high potential for abuse, and no currently accepted medical use in treatment (US).
•
2. Lacks accepted safety for use under medical supervision. 3. There is sound evidence that smoked
marijuana is harmful.
•
A past evaluation by HHS agencies, FDA, SAMHSA and NIDA, concluded that no sound scientific
studies supported medical use of marijuana for treatment in the United States
•
No animal or human data supported the safety or efficacy of marijuana for general medical use.
•
There are alternative FDA-approved medications in existence for treatment of many of the proposed
uses of smoked marijuana
•
A growing number of states have passed voter referenda (or legislative actions) making smoked
marijuana available for a variety of medical conditions upon a doctor's recommendation.
•
These measures are inconsistent with efforts to ensure that medications undergo the rigorous
scientific scrutiny of the FDA approval process are proven safe, effective with FD&C Act standards.
•
FDA, the federal agency responsible for reviewing the safety and efficacy of drugs, DEA the federal
agency charged with enforcing the CSA, the Office of National Drug Control Policy, the federal
coordinator of drug control policy, do not support the use of smoked marijuana for medical purposes.
Who was included/excluded from study and why?
How many people dropped out from the study and why?
Are only experienced marijuana users in the study?
What is their substance abuse history?
Are subjects taking other pain-killers or medicines for the condition?
How many subjects in each group? I,II,III?
Is marijuana smoke being tested or a pure cannabinoid (e.g , marinol, cannabidiol), or an
antagonist? Or an FAAH inhibitor? Source and purity?
Are side effects documented (e.g. cognitive impairment) by direct testing or by self-reports?
How are outcomes measured? Objectively or self-report?
Without FDA Process,
What are Conceivable Consequences?
Will Other Drugs be Approved by Ballot
Box and Unscrupulous Campaigns?
 Is this the start of an erosion of, and a method to
circumvent our drug approval process with “Ballot Box
Medicines”?
 Will others (billionaires) with a “pet drug” use
advertising to convince us to approve?
 Will political pressure shift stringent FDA criteria?
 Will Congress overrule the FDA approval process?
What Effect can this Process Conceivably Have
on Practice of Medicine?
Widespread use of unregulated , possibly psychoactive drugs, with
unclear purity, potency, quality, dose and abuse liablity
Unregulated medical Indications for their use
Medical practice, increasingly evidence-based, will need to address drugs with
no scholarly presence in medical training
Physicians who recommend marijuana now are not required to extract medical history, give detailed
medical exam, discuss long term treatment or alternatives, effects or follow-up, provide informed
consent, consult with other physicians, keep records that support marijuana use instead of
approved alternatives, maintain a good faith relationship with patient, not a “pill mill”, identify
substance abusers, addicted.
Marijuana Production: Dispensaries had no product liability, no product
regulation , no chain of custody, no accountability.
What Effect can this Process Conceivably Have
on Practice of Medicine?
• Cannabinoids may have therapeutic potential (delivered
in controlled doses by non-toxic delivery systems), but
smoked marijuana has no future as a medicine
• Smoking as a medicine delivery system: Marijuana can
compromise a 50 years campaign to end smoking
• Marijuana has high abuse liability: No regulation on
prescribing practices compared with opioids, others.
• FDA approval process: is compromised and challenged by
people unqualified to make drug approval decisions.
•
Cerdá et al., Drug and Alcohol
Dependence 120 (2012) 22– 27.
•
National Epidemiologic Survey on Alcohol and
Related Conditions (NESARC) (n = 34,653) and
NSDUH (~68,000).
•
Residents of states with medical marijuana laws had
higher odds of marijuana use (OR:1.92) and
marijuana abuse/dependence (OR: 1.81) than
residents of states without such laws.
•
Marijuana abuse/dependence was not more
prevalent among marijuana users in these states
(OR: 1.03), suggesting that the higher risk for
marijuana abuse/dependence in these states was
accounted for by higher rates of use.
•
States that legalized medical marijuana had higher
rates of marijuana use.
•
Is association causal, or an underlying common
cause (eg, community norms supportive of medical
marijuana and marijuana use legalization?
8
7
6
%
5
4
No MMJ
Yes MMJ
3
2
1
0
Marijuana
abuse/dependence
marijuana use
Death Rate of People with Marijuana Use Disorder is ~ 4
Times Higher than General Population
1= no added risk
(adapted from: Callaghan RC, Cunningham JK, Verdichevski M, Sykes, J, Jaffer SR, Kish SJ. (2012) All-cause mortality among individuals with
disorders related to the use of methamphetamine: A comparative cohort study. Drug Alcohol Depend. doi:10.1016/j.drugalcdep.2012.03.004)
Not FDAapproved for a
specific medical
condition
Composed of
hundreds of
chemicals, with
unregulated
amounts
Ingested by
smoking
Exempt from
quality control
standards
Not regulated by
dose, dosing
frequency, and
side effect profile
of long term use
Not subject to
product liability
regulations
Provided at
unknown
strengths of THC
Self-prescribed
and selfadministered by
the patient
Future of Cannabinoid Medications:
Non-psychoactive cannabinoids
CBD: cannabidiol
CBN: cannabinol
CBC: cannabichromene
CBG: cannabigerol
CBDA: cannabidiolic acid
THCV: tetrahydrocannabivarin
THCA: tetrahydrocannabinolic acid
Izzo et al., Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009 Oct;30(10):515-27.