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The FDA Process and Modern Medicine . Bertha K Madras, PhD Professor of Psychobiology Department of Psychiatry Harvard Medical School February 18, 2013. The Food and Drug Administration (FDA). Plant products as medicines. Food and Drug Administration: approval process. - PowerPoint PPT Presentation
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The FDA Process and
Modern Medicine
Bertha K Madras, PhDProfessor of Psychobiology
Department of PsychiatryHarvard Medical School
February 18, 2013
The Food and Drug Administration (FDA)
Plant products as medicines
Food and Drug Administration: approval process
The FDA and Marijuana
Marijuana History
Without FDA Process, What are Conceivable Consequences?
Plant Products As Medicines
Plant Products as Medicines
Composition unknown, unregulated
Treatment of symptoms, not illnesses
Poor understanding of pathology
Poor understanding of mechanisms
Quantities inconsistent, unregulated
Modern MedicationsActive chemical isolated from plants
• Highly purified and defined• Treat specific illness• Mechanism of action known• Controlled, consistent, regulated doses
Digitalis
Aspirin
Atropine
Quinine
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 bio-therapeutics, 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
Food and Drug Administration, approval process
How Do Drugs Get Approved in the United States? Food and Drug Administration
FDA is the sole Federal agency that approves
drugs as safe and effective for intended
indications.
The Federal Food, Drug, and Cosmetic (FD&C) Act requires: new drugs be shown safe and effective for their intended use
before US marketing.
FDA approval process requires: controlled research, clinical trials to base approval on safety, efficacy and labeling
decisions.
To bypass the FDA drug approval process might
expose patients to unsafe and ineffective drug products.
LAETRILE
The FDA Ensures Drug Safety
• prevent quackery • provide information to use medicines wisely• ensure that drugs’ health benefits outweigh known risks
FDA job: evaluate new drugs before they can be sold
• 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
To sell a drug in the US, drug must be safe, effective
Food and Drug Administration Drug Development Process
Test Tube to New Drug Application Review: ~12 years; ~$350 Million
3.5 years + • laboratory testing• application to FDA for
human testing• 1/1000 compounds go to
human testing
1 year: PHASE I20-80 healthy volunteers to establish safety and profile
2 Years PHASE II 100’s patient volunteers determine if drug is effective for a specific disease state
3 years PHASE III 1000’s patients •multiple sites • different populations, doses, effectiveness
•Drug combinations adverse reactions
2.5 years Application for approval < or > 100,000 pages!!!!!
PHASE IVIf approved, requirement to report cases of adverse reactions, other clinical data to the FDA.
Food and Drug Administration Drug Development Process
• 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
2.5 years Application for approval < or > 100,000 pages!!!!!
PHASE IV or Monitoring PhaseEven with 12 years of discovery, not possible to predict all drug side effects
•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
PHASE IV:If approved, requirement to report cases of adverse reactions, other clinical data to the FDA.
Marijuana History
Marijuana History
Adapted from Murray et al., Nat Rev Neurosci. 2007 Nov;8(11):885-95; additions by BK Madras
•Pen-ts’ao Ching Pharmacopeia•Medicinal properties of marijuana•Psychiatric side-effects 2727 BC
CHINA
•Marijuana is one of five sacred plants1200 BCINDUS VALLEY
•In tomb near Jerusalem•Ashes of marijuana metabolite found near
skeleton of pregnant women400 AD (CE)ISRAEL
Marijuana History
Adapted from Murray et al., Nat Rev Neurosci. 2007 Nov;8(11):885-95; additions by BK Madras
•Recreation use of marijuana banned•Marijuana tax prohibits marijuana use•Marijuana removed US Pharmacopeia1928-1942
US and UK
•British Report of Indian Hemp Drugs Commission1894 INDIA
•Sign Uniform Drug Convention•Pledge to end marijuana use within 25 years1961
60 Nations
•Opium Act separates marijuana from “hard drugs”•Sale of marijuana is tolerated 1976
NETHERLANDS
•1980 Marinol (THC) approved for nausea in cancer•1992 Marinol (THC) approved for anorexia/AIDS 1980, 1992
UNITED STATES
FDA and Marijuana
Has FDA approved pure products from marijuana plant? Marinol
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 radiation-related nausea, AIDS-related loss of appetite.
FDA and Marijuana: CriteriaPure 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 cannabinoidsPhytocannabinoids: plant-derived
80 or so phytocannabinoids made by marijuana plant Cannabis Sativa
D9-TetraHydroCannabinol or THC is highest
OH
O
Synthetic cannabinoids: 1,000s made by chemists
D9 refers to double C=C bond in 9-position of THC
Δ9-THC (Gaoni & Mechoulam, 1964)
Endocannabinoids produced by brain, other organs
NOH
HO
ANANDAMIDE
C
O
O
OH
OH
2-ARACHIDONOYL GLYCEROL (2-AG)
Anandamide: arachidonoylethanolamide 2-AG: 2-arachidonoylglycerol
7 or more made in brain and in other tissues
Is Marijuan a Pure Compound?Marijuana Smoke and Tobacco Smoke
Extreme
Chemical TOBACCO MARIJUANAtar (mg/cig) 80.3 103pH 5.47 7.73NO (μg/cig) 151 685NOx (μg/cig) 158 693CO (mg/cig) 41.5 35.3nicotine (mg/cig)
5.2 0.002−0.007*
ammonia (μg/cig)
67 1315
HCN (μg/cig) 320 1668NNN 160 <1.49*NAT 125 <1.87*NAB 8.26 0.063−2.00*NNK 158 ± 15 <3.72*Mercury 5.35 3.51Cadmium 284 14.6 Lead 43.8 7.7−25.7*Chromium 11.9−39.6 11.9−39.6Nickel 12.9−43.1 <12.9Arsenic 12.7 2.25−7.49*Selenium 4.42−14.7 4.42−14.7
Chemical TOBACCO MARIJUANAnaphthalene 4908 44591-methylnaphthalene 4888 44092-methylnaphthalene 3666 2917*acenaphthylene 711 459*acenaphthene 309 213*fluorene 1369 659*phenanthrene 515 476anthracene 162 136*fluoranthene 171 117*pyrene 154 82.3*benzo(a)anthracene 52 43.1*chrysene 61.7 56.3benzo(b)fluoranthene 21.9 16.2*benzo(k)fluoranthene 7.45 4.54*benzo(e)pyrene 19.2 12.6*benzo(a)pyrene 25.1 15.5*perylene 10.8 6.10*indeno(1,2,3,-cd)pyrene 10.1 8.65dibenz(a,h)anthracene 4.84 2.83*benzo(g,h,i)perylene 7.17 6.035-methylchrysene <0.071 <0.071benzo(b)fluoranthene 19.1 17.6benzo(j)fluoranthene 13.3 12.2dibenz(a,h)acridine <0.628 <0.628dibenz(a,j)acridine <0.519 <0.5197H-dibenzo(c,g)carbazole <0.278 <0.278dibenz(a,l)pyrene <0.634 <0.634dibenz(a,e)pyrene <0.313 <0.313dibenz(a,i)pyrene 2.55 <0.329*dibenz(a,h)pyrene <0.354 <0.354
Chemical TOBACCO MARIJUANA
Pyridine 59 93
Quinoline 2.2 2.68
Toluene 169 199
Benzene 94 84
Styrene 28 44
Acrylonitrile 24 67
Isoprene 540 132Hydroquinone 299 71
m + p-cresols 51 46
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
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
Is marijuana smoke “cleaner” than tobacco smoke?
Contents vary from 0.5 % to 15 % (3 - 30 mg)
Smokeddelivery 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
Chemistry, manufacturing, and composition of matter predictable?
Clinical data: dose response, effective,
safe
The Gold Standard of Evidence: Randomized, Double-blinded (and
cross-over) Multi-Center Controlled Trials
Center for Medicinal Cannabis Research (California)
> 36 scientific reportsMinus abstracts (or proceedings)
= 24+ publications
5 performed with patients, medical conditions
according to ballot initiative
5 clinical studies discontinued
4/5 studies used EXPERIENCED MARIJUANA USERS
Neuropathic Pain: Wilsey et al, J Pain, 2012Wilsey et al, J. Pain, 2008Ellis et al, Neuropsychopharm., 2009 Abrams et al, Neurlogy 2007
Spasticity: Corey-Bloom et al, CMAJ 2012 (30 patients)
Center for Medicinal Cannabis Research
• 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.
Center for Medicinal Cannabis Research
• 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.
Center for Medicinal Cannabis Research
• 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.
Center for Medicinal Cannabis Research
• 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.
Center for Medicinal Cannabis Research
• 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.
Clinical Trials: otherCondition 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.)
States with Marijuana Approval as MedicineCACHEXIAANOREXIA
CANCER CHRONIC PAIN
EPILEPSY SEIZURES GLAUCOMA HIV-AIDS/Hep C
MULTIPLE SCLEROSIS
SPASTICITY OR CROHN’S
NAUSEA MIGRAINE ORALZHEIMER’
AK1998 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes CA 1996 Yes Yes Yes Yes Yes Yes Yes
CO 2000 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes HI 2000 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 2010Yes Yes Yes Yes Yes Yes Yes Yes Yes/ALS Yes
Dose: How Much Can Public Possess?
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 12 plants
Vermont 3 oz 7 plants
Washington 60 day supply
Michigan 2.5 oz 12 plants
New Jersey 2 oz
Side effect profile
What Does Marijuana (THC) Target in Brain, Blood Cells, Tissues ?
CB1 receptors CB2 receptors
BRAINHeartTestisUterusProstateVascular tissueImmune cells
brainHematopoietic cells IMMUNE CELLS
AdrenalIleumJejunum
Marijuana Targets Brain, Blood Cells, Tissues
Marijuana distributes to many regions (CB1) of Human Brain
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
Red, yellow regions have high concentrations of CB1 cannabinoid receptorLeft: PET image to probe CB1
Center: MRI to define brain anatomyRight: MRI, PET combined
Marijuana Affects Many Brain Regions
Smoked, Intravenous THCProduce “High” And Perceptual Changes
Source: D'Souza DC. Cannabinoids and psychosis. Int Rev Neurobiol. 2007;78:289-326.
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.
Smoked THC Impairs Verbal Memory
Immediate recall Trail #1
Immediate recall Trail #2
Immediate recall Trail #3
Delayed Free Recall
Delayed Cued Recall
Delayed RecognitionRecall
# C
orre
ct W
ords
Rec
alle
d
Maximum Score
Minimum Score
1
2
3
4
5
6
7
8
9
10
11
12
D’Souza, 2005
- Placebo
- THC 2.5 mg
- THC 5 mg/kg
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).
Marijuana use is associated with increased risk for psychosis, hallucinations, delusions
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
United Kingd
om
Germany
New Zealand
Israel
Sweden
United St
ates
Netherlands
Netherlands
New Zealand
00.5
11.5
22.5
33.5
Odds ratio
NO RISK
Long term Marijuana Use is Associated With
Changes in brain structure, activity, gene
expression
Impaired learning, cognitive, executive
function
Higher Risk for Adolescents
Pathology in lung, compromised
cardiovascular function
Compromised measures of reproduction
Negative long-term educational, career
achievements
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
Monitoring the Future, 2011
2008 2009 2010 20110%
5%
10%
15%
20%
1.8%
6.4%8.7%
15.1%
Any Illicit drug - past 30 days % increase in illicit drug use Grade 12 from 2007
Marijuana’s Effects are Greater in Adolescents Than Adults
Brain changes
Learning deficits, future
Addiction Psychosis Other effects
Regular Marijuana Use by Adolescents…(20-30 Days/Month)
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
Marijuana Alcohol0.00%2.00%4.00%6.00%8.00%
10.00%12.00%14.00%16.00%18.00%20.00%
< 15 years18 + yeears
% A
buse
Depe
nden
ce
2010 National Survey Drug Use and Health, NSDUH Sept 2011
Age at first use and abuse/dependence as adult
Does Marijuana Fulfill FDA Criteria?
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
FDA Statement on Marijuana For Medical Purposes
• 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.
When Presented With A Clinical Trial “Proving” Marijuana is Effective, What Should you Ask?
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.
Medical Marijuana Laws In 50 StatesState Legalization of Medical Marijuana associated with:
Higher Prevalence of Marijuana Use, and Marijuana Use Disorders
• 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?
Marijuana abuse/dependence
marijuana use0
1
2
3
4
5
6
7
8
No MMJYes MMJ%
Death Rate of People with Marijuana Use Disorder is ~ 4 Times Higher than General Population
(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 )
1= no added risk
It Is Poor Public Policy to Enable Marijuana Use as a Smoked Product For a Medical Condition, if it is:
Not FDA-approved for a
specific medical condition
Ingested by smoking
Composed of hundreds of
chemicals, with unregulated
amounts
Not subject to product liability
regulations
Exempt from quality control
standards
Not regulated by dose, dosing
frequency, and side effect profile of long term use
Provided at unknown
strengths of THC
Self-prescribed and self-
administered by the patient
Future of Cannabinoid Medications:Non-psychoactive cannabinoids
Izzo et al., Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009 Oct;30(10):515-27.
CBD: cannabidiolCBN: cannabinolCBC: cannabichromeneCBG: cannabigerolCBDA: cannabidiolic acidTHCV: tetrahydrocannabivarinTHCA: tetrahydrocannabinolic acid