Finding the Medicine in Marijuana

Alice P. Mead

GW Pharmaceuticals

Presentation to the 2012 Nevada Marijuana Summit

October 1, 2012

Myth: Who Killed Marijuana?

Marijuana was widely used as a medicine until the federal government killed it with the Marijuana Tax Act in 1937

2

Fact

Crude marijuana extracts and tinctures couldn’t compete with modern opiates and new synthetic medicines

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Modern History

In 1839, William B. O’Shaughnessy introduced European world to therapeutic properties of cannabis

There was increased medical use of oral extracts and tinctures (not smoked!) in Europe and North America

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Different Paths of Opiates and Cannabinoids

During the 1800s, the active ingredient in opium—morphine—was identified and isolated.

Other opiates and synthetic medicines rapidly followed

Opium was not smoked for medical purposes

The paths of medicinal opioid development and recreational use of smoked herbal opium became clearly distinct

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Smoked opium vs. modern opiates

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Different Paths cont.

BUT, the active ingredients in cannabis remained unknown

Lack of standardization in preparations ; high variability in clinical response

Oral cannabis products fell out of favor with the medical profession

Smoked recreational cannabis became a focus of governmental restriction and prohibition

Marijuana Tax Act of 1937 = cannabis products even less attractive as a treatment option

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Different Paths cont.

In 1964, THC identified as the primary psychoactive cannabinoid and synthesized

Still very limited follow-up scientific research interest

In 1960s, recreational use of smoked cannabis increased; some users accidentally re-discovered its therapeutic properties

The medical and recreational forms—smoked—were merged

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• Had technology been more advanced in the early 1900s, cannabinoid medicines would have developed as did opiates and there might be no “medical marijuana” controversy today.

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Research/Technology Breakthrough

In the early 1990s, two cannabinoid receptors, CB1 and CB2, were identified and cloned

Endogenous cannabinoids identified, e.g., anandamide

This clarified the mechanism of action of cannabinoids, legitimated research

Scientific interest in cannabinoids greatly increased

In 20 years, a huge body of preclinical data has developed

This is how new medications begin!

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The Importance of the FDA Process

• Provisions developed over the past 100 years to protect patient health and safety

promotes quality, safety and efficacy of medications;

supported by all major medical organizations

• The US must require all controlled substance medications to go through the FDA process in order to satisfy its international treaty obligations

• GW is a pharmaceutical company and accordingly is firmly committed to meeting all FDA requirements

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The Modern Medication Approach…

…is very important (part 1):

• Products required to meet standards of modern medicine

• Standardized by composition and dosage

• Delivered like other pharmaceutical products; not smoked;

• Clinical and preclinical studies ensure physicians have appropriate prescribing information

• Prescription only; patients obtain only through monitored health care sources, i.e., pharmacy

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The Modern Medication Approach…

…is very important (part 2):

• Reimbursed by health insurance

• Registration/inspection ensures that manufacturing process conducted in accordance with validated quality control tools

Manufacturers accountable for defective products

• Promotional activities of manufacturers limited

• Products dispensed under the supervision of licensed health care providers, e.g., physicians, pharmacists

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Justification for Products like Sativex

“Medical marijuana” does not fit into the modern medical paradigm - (part 1)

• Composition ( % of THC) of herbal cannabis varies significantly depends on strains, cultivation and storage, etc.

“laboratories” often cannot replicate results

• Modern cannabis bred to exhibit (only) high levels of THC no meaningful levels of other cannabinoids such as CBD

• Delivery systems (smoked/vaporized, baked goods, teas) do not provide a standardized dose

• Contamination with microbes, heavy metal, and pesticides a real possibility.

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Justification cont.

“Medical marijuana” does not fit into the modern medical paradigm - (part 2)

• Distribution does not take place within regulated supply chain for pharmaceuticals

“collectives” and “cooperatives”

• No collection of adverse event or efficacy data

impossible to know who is really benefiting or being harmed

• Medical advice being given by untrained and unlicensed individuals

broad efficacy claims

often no meaningful physician supervision

no labelling with risk information or instructions for use

• Patients cannot obtain health insurance coverage

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This is how it works….

• Who the “patients” are:

• How they get “medical information:

• The doctors:

The “Medical Marijuana” Manufacturing Process

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MYTHS

• The federal government is suppressing

research into cannabis

• It is impossible to take a product made from the cannabis plant through the FDA process

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Is the federal government suppressing research?

• In the past 12 years, the FDA/DEA have licensed at least 12 human studies investigating smoked/inhaled cannabis for therapeutic use;

NIDA provided the herbal cannabis for those 12 studies.

• FDA/DEA have also allowed research involving a cannabis-derived medication;

this study had over 30 research sites in the US and another 60 in 10 other countries.

DEA permitted importation of the product.

Suppressing research cont.

• Advocates claim that it is impossible to develop a cannabis-based medication in the U.S. because the DEA will not authorize a second source of cannabis besides the U. of Mississippi.

Manufacture/Cultivation in the US?

• Under international policies of past 85 years, the US imports, rather than cultivates, psychoactive herbal material; finished products are manufactured in US.

• Finished cannabis-derived product can be imported into the US for research or for commercial use without the need to cultivate cannabis in US.

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Seeking FDA approval

• Herbal material grown by clones under rigorous conditions, ideally computer controlled greenhouses, to produce standardized starting materials

The US imports, rather than cultivates, psychoactive herbal material and manufactures finished products in US

• Need to extract the components and incorporate into an appropriate delivery system;

No precedent for administering any crude herbal material in a manner that reliably achieves a reproducible dose, produces no carcinogens

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FDA approval cont.

• Sponsor must manufacture and test product in accordance with FDA “Guidance for Industry: Botanical Drug Products”

Guidance allows some leniency in early research; by Phase 3 /NDA, all NCE standards must be met

Blinded, placebo-controlled large clinical studies must examine specific medical condition in specific population

Sponsor must conduct abuse liability testing and prepare risk management plan/REMS

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MYTH

• Cannabis obtained from dispensaries is much cheaper than what would be produced by pharmaceutical companies

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FACTS

• The average patient usage is 1.8-3 grams per day, but there is quite a range. Patients who vaporize cannabis or incorporate it into baked goods use much more

• The average price is $11-15 per gram (28 grams in an ounce), but the range of costs is wide. Prices of up to $50 per gram have been recorded;$35 is not unusual.

• An average daily use of 2.2 grams times $11 per gram equals $726 per 30-day month

• The range (at 2.2 grams/day) in price is $726-$2,310 per month

• If a patient uses more than 2.2 grams, as many do, the monthly cost is huge!

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There is more to cannabis than THC!

• Over 60 cannabinoids in total, each with their own--often complementary—pharmacology, e.g., CBDV, THCV, CBG, CBN, CBC, etc., for different medical conditions

Only THC is psychoactive

Multiple extracts can be blended to form new products

Likely research targets: oncology, epilepsy, inflammation, metabolic disorder/diabetes, psychiatric disorders, substance abuse, etc.

• There are also other non-cannabinoid active components, e.g., terpenes, flavonoids

• Real issue is whether plant extracts can be adequately characterized and standardized

GW have shown that they can and have been!

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More than THC cont.

• Cannabis used centuries ago would have involved a 1:1 CBD:THC ratio

• THC (tetrahydrocannabinol): is analgesic, anti-spasmodic, anti-tremor, anti-inflammatory, appetite stimulant, anti-emetic

• CBD (cannabidiol): does not bind with strong affinity to CB1 cannabinoid receptor, but does bind to other receptors in the body;

is anti-inflammatory, analgesic, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective;

reduces the negative effects of THC

has been bred out of modern herbal cannabis!

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Research Takes Time!

• Improved technology and discovery of endocannabinoid receptor system means that we are only at the early stages of developing modern medications, i.e., numerous preclinical studies, gradually moving into clinical trials, etc.

• At some point soon, will be same distinction as there is with smoked opium (recreational use only) and modern opiate medications

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GW’s Cannabinoid Pipeline

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International Clinical Research

30 clinical trials involving over 3500 patients in 12 countries

Canada

Colombia

South Africa

Finland

UK

India

Spain

France

Germany

Poland

Italy

Czech Rep

Belgium

Chile

Argentina Australia

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Advisors and Collaborators:

• Prof Roger Pertwee • Prof Vincenzo Di Marzo • Prof Raphael Mechoulam • Prof Mike Cawthorne • Prof Jimmy Bell • Prof Clive Page • Prof Tamas Biro • Prof Dave Kendall • Prof Yasmin Hurd • Prof Daniela Parolaro • Prof Ruth Ross • Prof Mauro Maccarone • Pro Fernadez-Ruiz • Dr Ben Whalley • Dr Marilyn Huestis • Dr Manuel Guzman • Dr Guillermo Velasco • Dr Cristina Sanchez • Dr Pepe Martinez-Orgado • Dr Angelo Izzo • Dr Alistair Nunn • Dr Saoirse O’Sullivan • Dr Sabatino Maione • Dr Barbara Costa

Etc….

International Academic Network

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Challenges of Developing Cannabinoid Medication: Quality and Manufacturing Demands

Terminology & Quality Standards

Botanical Raw Material (BRM)

Botanical Drug Substance (BDS)

Botanical Drug Product (BDP)

Stage 1

Stage 2

Stage 3

GAP (Good Agricultural

Practice)

GMP (Good Manufacturing

Practice)

Note: Above terms are all taken from FDA botanical guidelines

Plants grown, harvested, dried and leaves and flowers removed

BRM milled and treated to produce concentrated extract

BDS used with ethanol and propylene glycol to produce oro-mucosal spray

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Tightly Controlled Indoor Environment

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BRM: Control of Starting Materials

• Uniform Genetics

• Precise Propagation Timings

• Tightly Controlled Temperature

• Near Uniform Light Intensity

• Automated Irrigation

• Automated Irrigation

• Bespoke Growth Medium

• Tightly Controlled Plant Nutrition

• ‘Organic’ Pest/Disease Prevention

• Attention to detail by trained staff

Controlled genetics and standardized environment to

produce consistent starting material

uniform mature crop

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Growing on a Commercial Scale

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GMP Extraction and Manufacture

Storage of BRM under appropriate conditions

Selection of batch of stored BRM for extraction

Controlled decarboxylation of BRM

Primary Extraction of BRM under controlled conditions

Secondary Extract – Botanical Drug Substance (BDS)

QC & Release BDS (contains: THC + CBD)

Further processing of Primary Extract under controlled conditions

Apply BDS specification

QC sampling / Release

QC / In process control

Apply macro / micro appearance

BRM → BDS BDS → BDP

Selection of batch of stored BDS for formulation

Dissolve BDS in Solvent 1

Dissolved BDS in vehicle

Filter & fill final bulk Solution – Botanical Drug Product (BDP)

QC & Release BDP (contains: THC + CBD)

Mix final bulk solution

Apply BDP specification

QC sampling / Release

Add Solvent 2

Add Flavouring

QC / In process control

Storage of BDS under

appropriate conditions

(cold room)

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Supercritical CO2 Extraction

• Low temperature (30° Celsius)

• Retains cannabinoids • Retains most terpenoids • Retains little pigment or

chlorophyll • Waxy ballast removed by

“winterization” (chilling in ethanol solution)

• Ready for liquid dose forms

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BDS: Highly Characterised and Complex

Analysis to determine the extract standardisation:

• Principal Cannabinoids

THC, CBD

• Minor Cannabinoids

CBC, CBG, CBN, THCV, CBDV,

THCA, CBDA, CBO, CBE, CBCV, CBL

• Terpenoids

• Carotenoids

• Fatty Acids

• Sterols

• Vitamins

• Triglycerides

• Waxes

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CBD Content Between Batches

Extract Characterisation

Batch Reproducibility

Chromatographic image of multiple batches of a THC BDS over laid

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Sativex® (USAN: nabiximols)

• Each ml contains: 38-44 mg and 35-42 mg of two extracts from Cannabis sativa L. corresponding to 27 mg delta-9-tetrahydrocannabinol and 25 mg cannabidiol

• Excipients: Ethanol anhydrous Propylene glycol Peppermint oil (0.05%)

• Pharmaceutical form: Oromucosal solution in spray container

• Extraction solvent: Liquid carbon dioxide

• Each 100 microlitre spray contains: 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD) contains up to 0.04 g alcohol self titration

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Sativex® is not Cannabis

“Medical Marijuana” Cannabis Based Medicine – Sativex®

Product Development Clinical Evaluation Raw Material Production

None None Grown in uncontrolled, unregulated conditions resulting in variability Herbal cannabis is predominantly grown for high potency of THC only

World class academic / scientific research programme Regulated pre-clinical and clinical evaluation to prove Efficacy, Safety and Quality Consistent materials due to highly controlled growing conditions, growing medium and documentation. Sativex® is made from an extract of cannabis plants containing a ratio of 1:1 THC and CBD as well as other active cannabinoids. Plants are bred specifically to consistent cannabinoid profile and potency

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Sativex® is not Cannabis

Medical Marijuana Cannabis Based Medicine – Sativex®

Manufacturing Process

Process is not registered or regulated in any way Dried material packaged in basic packaging materials

Manufactured to Good Manufacturing Practices (GMP) in regulated facilities to processes that are registered with the competent authorities and inspected regularly Results in a quality, consistent and safe product made to the highest pharmaceutical industry standards

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Safe for the Patient to Use

“Medical Marijuana” Cannabis Based Medicine – Sativex®

Delivery system Supervision by Patient’s Treating Physician Security of Supply

Smoked, inhaled or consumed orally “Recommending” physician may not be involved in patient’s care; treating MD may not be aware of patient’s use Medical advice given by untrained personnel. Limited control on provision to patients. Easily diverted to non-medical use; no reliable records kept None

Novel delivery system, oromucosal spray Approved medicine is prescribed by registered physician with access to full product information to make an informed decision Patient Leaflet supplied with every pack National controls on prescribing and safety monitoring Secure distribution route from manufacture to patient. Packaging designed to protect the product from contamination, adulteration, diversion and counterfeiting 44

Sativex® GMP Manufacturing Process

Uniform plants grown in controlled conditions

Fully automated GMP manufacturing

Highly controlled drying conditions

Fully automated GMP labelling & packing

GMP packaging, includes product information, tamper evidence and

anti-counterfeit features

Highly controlled Extraction process

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Taking the Difficult Pathway

Why not just make a pure, synthetic medicine?

• Pharmaceutical companies believed for some time that medications should comprise a single chemical that would bind potently to a single receptor or other target

• The industry has been met with limited success as well as many failures as a result of highly potent/specific compound development

THC agonist– therapeutic doses often unachievable due to psychoactivity

Market withdrawal of rimonibant instigated a wave of terminated programmes

Peripheral restriction associated with side effects

Modulation of endocannabinoid concentrations inefficacious

• Very difficult to develop ECS modulators, yet we continue - why?

Endocannabinoids are altered and participating in most pathological conditions

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A New Paradigm For Drug Development

• Old development model is failing: Increasing support within the industry for a different approach, where in a molecule works on multiple targets or multiple molecules work in synergy together

e.g., new Gilead 4-in-1 AIDS drug

• “Multi-target” concept should be

revisited Without need for high potency

• Extracts are developed as a single pharmaceutical entity (single active)

Not considered combination products

• Compounds from same plant often interact/synergize with each other

Not just additive effect on targets

3 µM 1 µM 0.3 µM 0.1 µM

potent & selective

chemical space for target X

chemical space for target Z

chemical space for target Y

Target area of current drug

discovery

desirable area for multi-target approach

poly- pharm.

in vitro potency

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Central Nervous System/safety issues

Cannabinoid Therapeutic Window

Objective: • To provide and maintain therapeutic blood and tissue levels

of key cannabinoid components without incurring unacceptable side effects

Challenges: • Inter-subject pharmacokinetic variability • Minimise Side Effects (psychoactivity) caused by rapid rate of

rise of plasma levels in inhaled route • Limitations of oral route • Poor aqueous solubility

Predictable maintenance of acceptable risk / benefit 49

MYTHS

• In order that patients can titrate their doses, cannabis must be inhaled (smoked or vaporized);

• Vaporization addresses all the problems with smoking.

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FACT

• WRONG!

• Inhalation is not the best delivery system, at least for patients with chronic conditions

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Therapeutic Window - Solutions

• Cannabinoid ratios widen window CBD may counter some of the side effects CBD delays and reduces intensity of intoxication

• Route and method of delivery (DDS) Mucosal route far less variable than Oral (GI) Mucosal absorption decreases first pass metabolism

• Rate of absorption controlled and matches rate of redistribution in to lipid compartment

• Formulation and dosage form

Oromucosal spray

• Self-titration Predictability

Predictable maintenance within therapeutic window 52

Dose-normalised comparison of THC Levels from Smoked Cannabis (33.8mg THC) with nabiximols (Sativex) (12.5 sprays containing 33.8mg THC)

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0

20

40

60

80

100

120

140

160

180

0 60 120 180 240 300 360

TH

C p

lasm

a level

(ng

/ml)

Time (minutes)

SmokedCannabis(33.8mg THC)

Sativex (Dosenormailsed to33.8mg THC)

Intoxication

• Sativex rarely produces intoxication outside of early-on dose titration

• After titration, Sativex intoxication scores are in single digits out of 100 on Visual Analogue Scales, with no significant difference from placebo

• Mild psychoactive effects noted in patients have not been labelled as desirable

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0

10

20

30

40

50

60

70

80

90

100

BL 6 10 18 26 34 42 50 58 66 74 82

VA

S In

toxi

cati

on

Sco

re

(0-1

00

mm

)

Study Week Number

Sativex

Placebo

Placebo to Sativex

Placebo

Crossover

to THC:CBD

Intoxication

Wade DT et al. Mult Scler. 2007 55

Cognitive Assessments

• Short-term cognitive impairment predicts long-term cognitive impairment

• Cognitive impairment may predict functional outcomes i.e. retaining good cognitive performance is good for function

• Many medications may cause cognitive impairment

Three Tests Performed: 1. Sternberg Test (Short-Term Memory)

No significant effect of Sativex at any dose level

Marinol significantly different from placebo at 40 mg dose (p=0.01)

2. Divided Attention (Simultaneous performance of different tasks) No negative impact of Sativex on divided attention

High dose Marinol significantly greater times logged than placebo

3. Choice Reaction Time (Measures accuracy of responses) No significant effect of Sativex or Marinol on any of the parameters assessed

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Unlike Marinol, at single doses of 4 sprays, 8 sprays and 16 sprays, Sativex does not produce short-term cognitive impairment

No Tolerance or Dose Escalation

• Tolerance a common problem with use of opioids

• In over 1500 patient-years of experience, no dose escalation or tolerance has been observed

Long term extension studies in MS and peripheral neuropathic pain show stable/decreased doses after months/years of administration

Patient registry data confirms

• Sudden withdrawal of medication in MS patients taking it for over one year produced a gradual re-emergence of symptoms in 7-10 days, but no withdrawal syndrome or side effects requiring treatment.

• No signals of abuse or diversion in 7 yrs of prescription use

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0

4

8

12

16

20

24

18 26 34 42 50 58 66 74

Spra

ys p

er

Da

y

Study Week

Median

n=80

n=80

1 year

Tolerance – Sativex Sprays Per Day

Dosing Remains Stable in Long-Term

Wade DT et al. Mult Scler. 2007 58

Vaporization: safety issues

• Vaporization does not remove all toxic byproducts and resolve safety issues:

• Vaporizers vary significantly in quality and features, none FDA approved;

• If temperature can be set up to 200-230°C, toxic combustion products will be produced;

• Even at lower temperatures, some tars produced, and delivery of cannabinoids becomes very inefficient;

• Uncertain whether all microbes destroyed;

• Content of vapor determined by underlying quality/contamination of herbal material;

• More ammonia may be inhaled because no loss in side stream smoke.

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Other Regulatory Issues

Controlled Substances Act

• DEA must register (license) clinical and preclinical research sites and importer/manufacturer using a Schedule I product

this can, and has been done before - prior Phase IIb study involved 30+ research sites and an importer

• After FDA approves New Drug Application (NDA), product can be moved out of Schedule I

FDA approval constitutes “currently acceptable medical use in the US” for that product, a necessary criterion for Schedules II and III.

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Would Cannabis be Rescheduled?

• If a cannabis-derived product were FDA approved, cannabis itself would not be moved to Schedule II

• Opium and coca leaves are in Schedule II but there were modern medications derived from them on the market when CSA enacted

• Differential scheduling is currently in place for cannabinoids and other substances:

Marinol (Schedule III) vs. THC (Schedule I)

Xyrem (Schedule III) vs. GHB (Schedule I)

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What Would Rescheduling of Herbal Cannabis Achieve?

• FDA does not approval bulk substances/ active ingredients for direct prescriptive use

• Even if “cannabis” itself were moved to Schedule II, a specific cannabis or cannabis-based product would need FDA approval to be available by prescription

• But: would be huge symbolic victory for cannabis advocates;

further fuel state initiatives—allowing physicians to prescribe under state law?

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The Disadvantages of Giving Herbal Cannabis a “free pass”

• By creating an exception for cannabis, we are preventing the development of quality, safety and efficacy data that would allow it to become broadly accepted as a true medication

• The vast majority of patients want a product that is standardized by composition and dose and about which their physicians can offer meaningful advice

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What Do Modern Cannabis-Derived or Cannabinoid Products Get Us?

• Process governed by science

• Patients will have legitimate prescriptions and health care insurance coverage

• Products distributed and dispensed through monitored drug supply channels

• Data from controlled clinical studies available to physicians

• Products standardized by composition and dose

• Medication administered in appropriate dosage form

• Manufacturers accountable for quality

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What is Coming in the Future?

• Many more products comprising different cannabinoids and/or cannabinoid ratios, perhaps both botanically- and synthetically-derived

• It takes time! Improved technology and discovery of endocannabinoid receptor system means that we are only at the early stages of developing a range of modern medications, i.e., numerous preclinical studies, gradually moving into clinical trials, etc.

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