Finding the Medicine in
Marijuana
Alice P. Mead
GW Pharmaceuticals
Presentation to the 2012 Nevada Marijuana Summit
Octobe...
Myth: Who Killed Marijuana?
 Marijuana was widely used as a medicine
until the federal government killed it with
the Mari...
Fact
 Crude marijuana extracts and tinctures
couldn’t compete with modern opiates and
new synthetic medicines
3
Modern History
 In 1839, William B. O’Shaughnessy
introduced European world to
therapeutic properties of cannabis
 There...
Different Paths of Opiates and Cannabinoids
 During the 1800s, the active ingredient in opium—
morphine—was identified an...
Smoked opium vs. modern opiates
6
Different Paths cont.
 BUT, the active ingredients in cannabis remained unknown
 Lack of standardization in preparations...
Different Paths cont.
 In 1964, THC identified as the primary psychoactive
cannabinoid and synthesized
 Still very limit...
• Had technology been more advanced in the early
1900s, cannabinoid medicines would have
developed as did opiates and ther...
Research/Technology Breakthrough
 In the early 1990s, two cannabinoid receptors, CB1 and
CB2, were identified and cloned
...
The Importance of the FDA Process
• Provisions developed over the past 100 years to
protect patient health and safety
prom...
The Modern Medication Approach…
…is very important (part 1):
• Products required to meet standards of modern medicine
• St...
The Modern Medication Approach…
…is very important (part 2):
• Reimbursed by health insurance
• Registration/inspection en...
Justification for Products like Sativex
“Medical marijuana” does not fit into the modern
medical paradigm - (part 1)
• Com...
Justification cont.
“Medical marijuana” does not fit into the modern
medical paradigm - (part 2)
• Distribution does not t...
This is how it works….
• Who the “patients” are:
• How they get “medical information:
• The doctors:
The “Medical Marijuana” Manufacturing
Process
17
MYTHS
• The federal government is suppressing
research into cannabis
• It is impossible to take a product made from
the ca...
Is the federal government suppressing
research?
• In the past 12 years, the FDA/DEA have licensed at least 12 human
studie...
Suppressing research cont.
• Advocates claim that it is impossible to develop a cannabis-based
medication in the U.S. beca...
Manufacture/Cultivation in the US?
• Under international policies of past 85 years, the US
imports, rather than cultivates...
Seeking FDA approval
• Herbal material grown by clones under rigorous conditions,
ideally computer controlled greenhouses,...
FDA approval cont.
• Sponsor must manufacture and test product in accordance
with FDA “Guidance for Industry: Botanical Dr...
MYTH
• Cannabis obtained from dispensaries is much
cheaper than what would be produced by
pharmaceutical companies
24
FACTS
• The average patient usage is 1.8-3 grams per day, but there is quite
a range. Patients who vaporize cannabis or in...
There is more to cannabis than THC!
• Over 60 cannabinoids in total, each with their own--often
complementary—pharmacology...
More than THC cont.
• Cannabis used centuries ago would have involved a
1:1 CBD:THC ratio
• THC (tetrahydrocannabinol):
is...
Research Takes Time!
• Improved technology and discovery of
endocannabinoid receptor system means that we
are only at the ...
GW’s Cannabinoid Pipeline
29
International Clinical Research
30 clinical trials involving over 3500 patients in 12 countries
Canada
Colombia
South Afri...
Advisors and Collaborators:
• Prof Roger Pertwee
• Prof Vincenzo Di Marzo
• Prof Raphael Mechoulam
• Prof Mike Cawthorne
•...
Challenges ofDeveloping Cannabinoid
Medication: Quality andManufacturing
Demands
Terminology & Quality Standards
Botanical Raw Material
(BRM)
Botanical Drug Substance
(BDS)
Botanical Drug Product
(BDP)
S...
Tightly Controlled Indoor Environment
34
BRM: Control of Starting Materials
• Uniform Genetics
• Precise Propagation Timings
• Tightly Controlled Temperature
• Nea...
Growing on a Commercial Scale
36
GMP Extraction and Manufacture
Storage of BRM under appropriate conditions
Selection of batch of stored BRM for
extraction...
Supercritical CO2 Extraction
• Low temperature (30°
Celsius)
• Retains cannabinoids
• Retains most terpenoids
• Retains li...
BDS: Highly Characterised and Complex
Analysis to determine the
extract standardisation:
• Principal Cannabinoids
THC, CBD...
Batch Reproducibility
Chromatographic image of multiple batches of a THC BDS over laid
40
Sativex® (USAN: nabiximols)
• Each ml contains:
38-44 mg and 35-42 mg of two extracts
from Cannabis sativa L. correspondin...
Sativex® is not Cannabis
“Medical Marijuana” Cannabis Based Medicine – Sativex®
Product
Development
Clinical
Evaluation
Ra...
Sativex® is not Cannabis
Medical Marijuana Cannabis Based Medicine – Sativex®
Manufacturing
Process
Process is not
registe...
Safe for the Patient to Use
“Medical Marijuana” Cannabis Based Medicine – Sativex®
Delivery system
Supervision by
Patient’...
Sativex® GMP Manufacturing Process
Uniform plants grown in
controlled conditions
Fully automated
GMP manufacturing
Highly ...
Taking the Difficult Pathway
Why not just make a pure, synthetic medicine?
• Pharmaceutical companies believed for some ti...
A New Paradigm For Drug Development
• Old development model is failing: Increasing support within the
industry for a diffe...
CentralNervousSystem/safetyissues
Cannabinoid Therapeutic Window
Objective:
• To provide and maintain therapeutic blood and tissue levels
of key cannabinoid...
MYTHS
• In order that patients can titrate
their doses, cannabis must be
inhaled (smoked or vaporized);
• Vaporization add...
FACT
• WRONG!
• Inhalation is not the best delivery system, at least for
patients with chronic conditions
51
Therapeutic Window - Solutions
• Cannabinoid ratios widen window
CBD may counter some of the side effects
CBD delays and r...
Dose-normalised comparison of THC Levels from
Smoked Cannabis (33.8mg THC) with nabiximols
(Sativex) (12.5 sprays containi...
Intoxication
• Sativex rarely produces intoxication outside of early-
on dose titration
• After titration, Sativex intoxic...
0
10
20
30
40
50
60
70
80
90
100
BL 6 10 18 26 34 42 50 58 66 74 82
VASIntoxicationScore
(0-100mm)
Study Week Number
Sativ...
Cognitive Assessments
• Short-term cognitive impairment predicts long-term cognitive impairment
• Cognitive impairment may...
No Tolerance or Dose Escalation
• Tolerance a common problem with use of opioids
• In over 1500 patient-years of experienc...
0
4
8
12
16
20
24
18 26 34 42 50 58 66 74
SpraysperDay
Study Week
Median
n=80
n=80
1 year
Tolerance – Sativex Sprays Per D...
Vaporization: safety issues
• Vaporization does not remove all toxic byproducts and resolve
safety issues:
• Vaporizers va...
Other Regulatory Issues
Controlled Substances Act
• DEA must register (license) clinical and preclinical
research sites and importer/manufacturer ...
Would Cannabis be Rescheduled?
• If a cannabis-derived product were FDA approved,
cannabis itself would not be moved to Sc...
What Would Rescheduling of Herbal Cannabis
Achieve?
• FDA does not approval bulk substances/ active
ingredients for direct...
The Disadvantages of Giving Herbal Cannabis a
“free pass”
• By creating an exception for cannabis, we are
preventing the d...
What Do Modern Cannabis-Derived or
Cannabinoid Products Get Us?
• Process governed by science
• Patients will have legitim...
What is Coming in the Future?
• Many more products comprising different
cannabinoids and/or cannabinoid ratios, perhaps
bo...
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  1. 1. Finding the Medicine in Marijuana Alice P. Mead GW Pharmaceuticals Presentation to the 2012 Nevada Marijuana Summit October 1, 2012
  2. 2. 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
  3. 3. Fact  Crude marijuana extracts and tinctures couldn’t compete with modern opiates and new synthetic medicines 3
  4. 4. 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 4
  5. 5. 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 5
  6. 6. Smoked opium vs. modern opiates 6
  7. 7. 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 7
  8. 8. 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 8
  9. 9. • 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. 9
  10. 10. 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! 10
  11. 11. 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 11
  12. 12. 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 12
  13. 13. 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 13
  14. 14. 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. 14
  15. 15. 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 15
  16. 16. This is how it works…. • Who the “patients” are: • How they get “medical information: • The doctors:
  17. 17. The “Medical Marijuana” Manufacturing Process 17
  18. 18. 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 18
  19. 19. 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.
  20. 20. 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.
  21. 21. 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. 21
  22. 22. 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 22
  23. 23. 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 23
  24. 24. MYTH • Cannabis obtained from dispensaries is much cheaper than what would be produced by pharmaceutical companies 24
  25. 25. 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! 25
  26. 26. 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! 26
  27. 27. 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! 27
  28. 28. 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 28
  29. 29. GW’s Cannabinoid Pipeline 29
  30. 30. 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 30
  31. 31. 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 31
  32. 32. Challenges ofDeveloping Cannabinoid Medication: Quality andManufacturing Demands
  33. 33. 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 33
  34. 34. Tightly Controlled Indoor Environment 34
  35. 35. 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 35
  36. 36. Growing on a Commercial Scale 36
  37. 37. 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) 37
  38. 38. 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 38
  39. 39. 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 39 CBD Content Between Batches Extract Characterisation
  40. 40. Batch Reproducibility Chromatographic image of multiple batches of a THC BDS over laid 40
  41. 41. 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 41
  42. 42. 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 42
  43. 43. 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 43
  44. 44. 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
  45. 45. 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 45
  46. 46. 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 46
  47. 47. 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 47
  48. 48. CentralNervousSystem/safetyissues
  49. 49. 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
  50. 50. MYTHS • In order that patients can titrate their doses, cannabis must be inhaled (smoked or vaporized); • Vaporization addresses all the problems with smoking. 50
  51. 51. FACT • WRONG! • Inhalation is not the best delivery system, at least for patients with chronic conditions 51
  52. 52. 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
  53. 53. Dose-normalised comparison of THC Levels from Smoked Cannabis (33.8mg THC) with nabiximols (Sativex) (12.5 sprays containing 33.8mg THC) 53 0 20 40 60 80 100 120 140 160 180 0 60 120 180 240 300 360 THCplasmalevel(ng/ml) Time (minutes) Smoked Cannabis (33.8mg THC) Sativex (Dose normailsed to 33.8mg THC)
  54. 54. 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 54
  55. 55. 0 10 20 30 40 50 60 70 80 90 100 BL 6 10 18 26 34 42 50 58 66 74 82 VASIntoxicationScore (0-100mm) Study Week Number Sativex Placebo Placebo to Sativex Placebo Crossover to THC:CBD Intoxication Wade DT et al. Mult Scler. 200755
  56. 56. 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 56 Unlike Marinol, at single doses of 4 sprays, 8 sprays and 16 sprays, Sativex does not produce short-term cognitive impairment
  57. 57. 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 57
  58. 58. 0 4 8 12 16 20 24 18 26 34 42 50 58 66 74 SpraysperDay 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. 200758
  59. 59. 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. 59
  60. 60. Other Regulatory Issues
  61. 61. 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. 61
  62. 62. 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) 62
  63. 63. 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? 63
  64. 64. 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 64
  65. 65. 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 65
  66. 66. 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. 66

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