the fda process and modern medicine

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.

http://www.fda.gov/medwatch

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.


• 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.

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



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

the fda process and modern medicine

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