The Cannarchist
05-15-2007, 08:47 PM
"Cannabinoid medicines and the need for the scientific method "
Ethan B. Russo ,GW Pharmaceuticals, Vashon, Washington, USA
To gain the widespread trust of physicians and medical
consumers, cannabinoid medicines must be standardized,
efficacious and safe preparations as demonstrated
in statistically significant randomized clinical trials
(RCTs) acceptable to regulatory bodies in various
countries and adhering to the modern scientific
method.
Dr. Grinspoon has stated that a dual status for cannabinoid
medicines (approved vs. illegal) is developing [1].
However, US Food and Drug Administration (FDA)-
approved medicines and crude herbal materials cannot
be considered equivalent when it comes to their status
as modern medicines. Herbal cannabis as currently
available for patient use is a highly variable product
with respect to composition. Procedures for standardized
prescription botanical products have been formalized
in the USA [2], providing a blueprint for regulatory
approval of phytopharmaceuticals (botanical
medicines). Although there is no proven etiological
association of cannabis smoking to the development of
lung cancer [3], it is inarguable that it produces lung
irritation, chronic cough and pulmonary cytological
alterations [4]. Communal sharing of cannabis cigarettes
may pose infectious disease risks, such as transmission
of meningococcal meningitis [5]. These facts
alone render smoked cannabis ineligible for regulatory
acceptance as a prescription product in most nations.
Existing state laws allowing medicinal use of cannabis
still require physician recommendation and supervision;
most practitioners would prefer to prescribe an
FDA-approved pharmaceutical form.
Although vaporization of cannabis below its combustion
point reduced respiratory complaints [6] and serum
carbon monoxide levels [7], it failed to eliminate all
potentially carcinogenic polyaromatic hydrocarbons
[8], and remains as inefficient and unpredictable as
smoking in THC delivery [7, 9]. Assertion that smoked
cannabis may be “the gold standard” for cannabinoids
is unsubstantiated, as a notable dearth of published
RCT data exists [10, 11] and represent only first steps
in a long journey toward FDA approval. Anecdotal
claims of efficacy for smoked cannabis mean little in
the regulatory realm [12]. Studies of smoked cannabis,
its inhaled vapor [7] or pure THC [13] reveal steep
pharmacokinetic THC curves and evidence of marked
intoxicating effects at reported therapeutic dosages. A
delivery system that allows relief without undesirable
adverse events is necessary. Material must also be free
of pathogenic micro-organisms. Problems in cultivation
in Dutch and Canadian government-approved
herbal cannabis programs have led authorities to
gamma-irradiate their products.
Progress is apparent in developing other cannabis
based prescription medicines. Large scale clinical trials
have been undertaken, notably in Europe, as with investigation
of Cannador cannabis extract in treatment
of spasticity associated with multiple sclerosis (MS)
[14] and other disorders.
The most advanced program is that for Sativex®, an
oromucosal spray derived from two standardized whole
cannabis extracts, Tetranabinex® (rich in tetrahydrocannabinol,
THC) and Nabidiolex® (rich in cannabidiol,
CBD) [15], providing 2.7 mg of THC, 2.5 mg
of CBD and other components with each actuation.
Extracts derive from clonal strains grown in organic
media under climate-control in accordance with Good
Agricultural and Manufacturing Practices. Phytocannabinoids,
terpenoids and others are monitored to ensure
consistency [16, 17].
Sativex was approved for prescription in Canada for
central neuropathic pain in multiple sclerosis in June
2005. It is available on a named-patient basis in the
United Kingdom and the Catalunya Autonomous Region
(Spain). The FDA has granted an Investigational
New Drug Application for Sativex to proceed to advanced
stage clinical trials for intractable cancer pain
in the USA.
Numerous Phase II-III clinical trials of Sativex have
been completed in central and peripheral neuropathic
pain, spasticity, and urinary symptoms in MS, rheumatoid
arthritis and cancer pain [18-26], with significant
benefits in intractable symptoms failing to respond to
conventional treatment. Visual analogue scales of intoxication
after initial dose titration most frequently
remained in single digits on a 100-point scale, proving
this preparation need not produce psychoactive change
to achieve therapeutic benefit. Most patients desire
symptom control from medicine, not euphoria or any
alteration in mental status or capabilities.
No dose tolerance or significant withdrawal symptoms
have been observed with Sativex in up to five years of
Safety-Extension studies, even upon abrupt discontinuation
[19].
The onset of therapeutic effects of Sativex after
oromucosal administration is in 15-40 minutes [27]
with steady pharmacokinetic contour [28]. This is
much less than the 1-2 hour interval noted with THC in
sesame oil [29], and sufficiently fast to allow titration
to symptom relief without reinforcement. Most clinical
trial subjects have stabilized on an effective tolerable
dose of Sativex within 7-10 days via self-titration. In
over 2000 patient-years of clinical trial and SAFEX
monitoring and two year’s market experience in Canada,
no abuse or diversion has resulted.
Three studies have examined adverse event profiles of
patients employing smoked cannabis in governmentapproved
programs in Canada [30], and the Netherlands
[31, 32]. A comparison to Sativex SAFEX patients
confirms that adverse events with smoked cannabis
are far more frequent and prominent [12], especially
for cognitive function and alertness. In contrast,
cough and pulmonary complaints are not reported with
Sativex.
Sativex has proven itself distinct from mere THC due
to its unique composition and delivery. CBD contributes
notably as an analgesic and anti-inflammatory
antioxidant [33-35], but also attenuates intoxication,
tachycardia and other THC effects [15, 36]. CBD provides
beneficial immunodulatory effects in autoimmune
disorders (rheumatoid arthritis, inflammatory
bowel disease) via inhibition of tissue necrosis factoralpha
[37] and adenosine uptake via its A2A receptor
[38]. However, North American and most European
cannabis drug strains are virtually devoid of CBD [39-
41].
Marinol did demonstrated analgesic benefit in central
neuropathic pain in MS [42]. Similar benefits were
noted with Sativex [25] but with a lower adverse event
profile, despite that total doses of THC were 2 ½ times
higher in the Sativex group, demonstrating the contribution
of CBD to improvement in THC’s therapeutic
index [12].
In an RCT in intractable cancer pain, Sativex produced
statistically significant analgesic efficacy, while
Tetranabinex (without CBD) did not [26], highlighting
the necessity of providing the most efficacious preparation
possible in this challenging clinical context.
Finally, will patients give up cannabis smoking for a
prescription alternative? Yes, apparently. Some 50% of
Sativex clinical trial subjects have had therapeutic or
recreational exposure to cannabis. Some 70% of subjects
experienced sufficient benefit to request its continuation
in SAFEX studies [12]. No differences in
efficacy in cannabis-experienced vs. cannabis-naïve
Sativex patients have ever been evident.
The evidence supports the feasibility of developing a
cannabis-based medicine that adheres to regulatory
norms without exceptions. Advantages of such an approach
are numerous and include necessary safety,
quality controls and accountability exclusive of the
black market gamble.
Patients worldwide are seeking symptom relief with an
approved pharmaceutical that their physicians can
prescribe with confidence that is standardized, safe,
effective and reimbursed by governmental agencies
and third-party payers. Thus, there may be a clear division
between those who are ill, and those seeking a
thrill. Sativex is the new gold standard for cannabinoid
medicines and with its advent, one solution to the cannabis
prescription problem is close at hand.
Acknowledgements
The author is Senior Medical Advisor of GW Pharmaceuticals.
References
1. Grinspoon L. On the future of cannabis as medicine.
Cannabinoids. 2007 (in press).
2. Food and Drug Administration. Guidance for
industry: Botanical drug products. In: Services
UDoHaH, editor: US Government; 2004. p. 48.
3. Hashibe M, Morgenstern H, Cui Y, Tashkin DP,
Zhang ZF, Cozen W, et al. Marijuana use and the
risk of lung and upper aerodigestive tract cancers:
results of a population-based case-control study.
Cancer Epidemiol Biomarkers Prev.. 2006
;15(10):1829-34.
4. Tashkin DP. Smoked marijuana as a cause of
lung injury. Monaldi Arch Chest Dis..
2005;63(2):93-100.
5. Zanocco V. Meningococcal cases linked by sharing
joints. [cited 2005 April 8]; Available from:
http://www.vch.ca/news/docs/2005_04_07_meni
ng_joints.pdf
6. Earleywine M, Smucker Barnwell S. Decreased
respiratory symptoms in cannabis users who vaporize.
Harm Reduct J. 2007;4(1):11.
7. Abrams DI, Vizoso HP, Shade SB, Jay C, Kelly
ME, Benowitz NL. Vaporization as a smokeless
cannabis delivery system: a pilot study. Clin
Pharmacol Ther. 2007 (in press).
8. Gieringer D, St. Laurent J, Goodrich S. Cannabis
vaporizer combines efficient delivery of THC
with effective suppression of pyrolytic compounds.
J Cannabis Ther. 2004;4(1):7-27.
9. Hazekamp A, Ruhaak R, Zuurman L, van Gerven
J, Verpoorte R. Evaluation of a vaporizing device
(Volcano) for the pulmonary administration of
tetrahydrocannabinol. J Pharm Sci.
2006;95(6):1308-17.
10. Abrams DI, Hilton JF, Leiser RJ, Shade SB,
Elbeik TA, Aweeka FT, Benowitz NL, Bredt
BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF,
Mulligan K, Bacchetti P, McCune JM, Schambelan
M. Short-term effects of cannabinoids in patients
with HIV-1 infection. A randomized, placbocontrolled
clinical trial. Ann Intern Med.
2003;139:258-66.
11. Abrams DI, Jay CA, Shade SB, Vizoso H, Reda
H, Press S, Kelly ME, Rowbotham MC, Petersen
KL. Cannabis in painful HIV-associated sensory
neuropathy: a randomized placebo-controlled trial.
Neurology. 2007;68(7):515-21.
12. Russo EB. The solution to the medicinal cannabis
problem. In: Schatman ME, editor. Ethical issues
in chronic pain management. Boca Raton, FL:
Taylor & Francis 2006. p. 165-94.
13. Miller J, Meuwsen I, ZumBrunnen T, de Vries
M. A Phase I evaluation of pulmonary dronabinol
administered via a pressurized metered dose inhaler
in helathy volunteers. American Academy of
Neurology; 2005; Miami Beach, FL; 2005.
14. Zajicek J, Fox P, Sanders H, Wright D, Vickery
J, Nunn A, Thompson A; UK MS Research
Group. Cannabinoids for treatment of spasticity
and other symptoms related to multiple sclerosis
(CAMS study): multicentre randomised placebocontrolled
trial. Lancet. 2003;362(9395):1517-26.
15. Russo EB, Guy GW. A tale of two cannabinoids:
the therapeutic rationale for combining tetrahydrocannabinol
and cannabidiol. Med Hypotheses.
2006;66(2):234-46.
16. Potter D. Growth and morphology of medicinal
cannabis. In: Guy GW, Whittle BA, Robson P,
editors. Medicinal uses of cannabis and cannabinoids.
London: Pharmaceutical Press 2004. p. 17-
54.
17. de Meijer E. The breeding of cannabis cultivars
for pharmaceutical end uses. In: Guy GW, Whittle
BA, Robson P, editors. Medicinal uses of cannabis
and cannabinoids. London: Pharmaceutical
Press 2004. p. 55-70.
18. Wade DT, Makela P, Robson P, House H, Bateman
C. Do cannabis-based medicinal extracts
have general or specific effects on symptoms in
multiple sclerosis? A double-blind, randomized,
placebo-controlled study on 160 patients. Mult
Scler. 2004;10(4):434-41.
19. Wade DT, Makela PM, House H, Bateman C,
Robson PJ. Long-term use of a cannabis-based
medicine in the treatment of spasticity and other
symptoms in multiple sclerosis. Mult Scler.
2006;12:639-45.
20. Wade DT, Robson P, House H, Makela P, Aram
J. A preliminary controlled study to determine
whether whole-plant cannabis extracts can improve
intractable neurogenic symptoms. Clin Rehabil.
2003;17:18-26.
21. Notcutt W, Price M, Miller R, Newport S, Phillips
C, Simmonds S, Sansom C. Initial experiences
with medicinal extracts of cannabis for
chronic pain: results from 34 “N of 1” studies.
Anaesthesia. 2004;59:440-52.
22. Berman JS, Symonds C, Birch R. Efficacy of two
cannabis based medicinal extracts for relief of
central neuropathic pain from brachial plexus
avulsion: results of a randomised controlled trial.
Pain. 2004;112(3):299-306.
23. Brady CM, DasGupta R, Dalton C, Wiseman OJ,
Berkley KJ, Fowler CJ. An open-label pilot study
of cannabis based extracts for bladder dysfunction
in advanced multiple sclerosis. Mult Scler.
2004;10:425-33.
24. Blake DR, Robson P, Ho M, Jubb RW, McCabe
CS. Preliminary assessment of the efficacy, tolerability
and safety of a cannabis-based medicine
(Sativex) in the treatment of pain caused by
rheumatoid arthritis. Rheumatology (Oxford).
2006;45(1):50-2.
25. Rog DJ, Nurmiko T, Friede T, Young C. Randomized
controlled trial of cannabis based medicine
in central neuropathic pain due to multiple
sclerosis. Neurology. 2005;65(6):812-9.
26. Johnson JR, Potts R. Cannabis-based medicines
in the treatment of cancer pain: a randomised,
double-blind, parallel group, placebo controlled,
comparative study of the efficacy, safety and tolerability
of Sativex and Tetranabinex in patients
with cancer-related pain. British Pain Society;
2005 March 8-11; Edinburgh, Scotland; 2005.
27. Robson P, Guy GW. Clinical studies of cannabisbased
medicine. In: Guy GW, Whittle BA, Robson
P, editorss. Medicinal uses of cannabis and
cannabinoids. London: Pharmaceutical Press
2004. p. 229-70.
28. Guy GW, Flint ME. A single centre, placebocontrolled,
four period, crossover, tolerability
study assessing pharmacokinetic effects, pharmacokinetic
characteristics and cognitive profiles of
as single dose of three formulations of cannabis
based medicine extracts (CBMEs)(GWPD9901),
plus a two period tolerability study comparing
pharmacodynamic effects and pharmacokinetic
characteristics of a single dose of a cannabis based
medicine extract given via two administration
routes (GWPD9901 EXT). J Cannabis Ther.
2003;3(3):35-77.
29. Calhoun SR, Galloway GP, Smith DE. Abuse
potential of dronabinol (Marinol). J Psychoactive
Drugs. 1998;30(2):187-96.
30. Lynch ME, Young J. Report on a case series of
patients using medicinal marijuana marijuana for
management of chronic pain under the Canadian
Medical Marijuana Access Regulations. Symposium
on the Cannabinoids; 2005; Clearwater, FL:
International Cannabinoid Research Society;
2005. p. 42.
31. Janse AFC, Breekveldt-Postma NS, Erkens JA,
Herings RMC. Medicinal gebruik van cannabis.:
PHARMO Instituut [Institute for Drug Outcomes
Research]; 2004 April 2004.
32. Gorter RW, Butorac M, Cobian EP, van der Sluis
W. Medical use of cannabis in the Netherlands.
Neurology. 2005;64(5):917-9.
33. McPartland JM, Russo EB. Cannabis and cannabis
extracts: Greater than the sum of their parts? J
Cannabis Ther. 2001;1(3-4):103-32.
34. Pertwee RG. Cannabidiol as a potential medicine.
In: Mechoulam R, editor. Cannabinoids as therapeutics.
Basel, Switzerland: Birkhäuser Verlag
2005. p. 47-65.
35. Hampson AJ, Grimaldi M, Axelrod J, Wink D.
Cannabidiol and (-)Delta9-tetrahydrocannabinol
are neuroprotective antioxidants. Proc Natl Acad
Sci U S A. 1998;95(14):8268-73.
36. Nicholson AN, Turner C, Stone BM, Robson PJ.
Effect of delta-9-tetrahydrocannabinol and cannabidiol
on nocturnal sleep and early-morning
behavior in young adults. Journal of clinical psychopharmacology.
2004;24(3):305-13.
37. Malfait AM, Gallily R, Sumariwalla PF, Malik
AS, Andreakos E, Mechoulam R, et al. The
nonpsychoactive cannabis constituent cannabidiol
is an oral anti-arthritic therapeutic in murine collagen-
induced arthritis. Proc Natl Acad Sci U S
A. 2000;97(17):9561-6.
38. Carrier EJ, Auchampach JA, Hillard CJ. Inhibition
of an equilibrative nucleoside transporter by
cannabidiol: a mechanism of cannabinoid immunosuppression.
Proc Natl Acad Sci U S A.
2006;103(20):7895-900.
39. ElSohly MA, Ross SA, Mehmedic Z, Arafat R,
Yi B, Banahan BF, 3rd. Potency trends of delta9-
THC and other cannabinoids in confiscated marijuana
from 1980-1997. J Forensic Sci.
2000;45(1):24-30.
40. Mehmedic Z, Martin J, Foster S, ElSohly MA.
Delta-9-THC and other cannabinoids content of
confiscated marijuana: potency trends, 1993-
2003. International Association of Cannabis as
Medicine; 2005 September 9-10; Leiden, Netherlands:
International Association of Cannabis as
Medicine; 2005.
41. King LA, Carpentier C, Griffiths P. Cannabis
potency in Europe. Addiction. 2005;100(7):884-
6.
42. Svendsen KB, Jensen TS, Bach FW. Does the
cannabinoid dronabinol reduce central pain in
multiple sclerosis? Randomised double blind placebo
controlled crossover trial. BMJ.
2004;329(7460):253.
Ethan B. Russo ,GW Pharmaceuticals, Vashon, Washington, USA
To gain the widespread trust of physicians and medical
consumers, cannabinoid medicines must be standardized,
efficacious and safe preparations as demonstrated
in statistically significant randomized clinical trials
(RCTs) acceptable to regulatory bodies in various
countries and adhering to the modern scientific
method.
Dr. Grinspoon has stated that a dual status for cannabinoid
medicines (approved vs. illegal) is developing [1].
However, US Food and Drug Administration (FDA)-
approved medicines and crude herbal materials cannot
be considered equivalent when it comes to their status
as modern medicines. Herbal cannabis as currently
available for patient use is a highly variable product
with respect to composition. Procedures for standardized
prescription botanical products have been formalized
in the USA [2], providing a blueprint for regulatory
approval of phytopharmaceuticals (botanical
medicines). Although there is no proven etiological
association of cannabis smoking to the development of
lung cancer [3], it is inarguable that it produces lung
irritation, chronic cough and pulmonary cytological
alterations [4]. Communal sharing of cannabis cigarettes
may pose infectious disease risks, such as transmission
of meningococcal meningitis [5]. These facts
alone render smoked cannabis ineligible for regulatory
acceptance as a prescription product in most nations.
Existing state laws allowing medicinal use of cannabis
still require physician recommendation and supervision;
most practitioners would prefer to prescribe an
FDA-approved pharmaceutical form.
Although vaporization of cannabis below its combustion
point reduced respiratory complaints [6] and serum
carbon monoxide levels [7], it failed to eliminate all
potentially carcinogenic polyaromatic hydrocarbons
[8], and remains as inefficient and unpredictable as
smoking in THC delivery [7, 9]. Assertion that smoked
cannabis may be “the gold standard” for cannabinoids
is unsubstantiated, as a notable dearth of published
RCT data exists [10, 11] and represent only first steps
in a long journey toward FDA approval. Anecdotal
claims of efficacy for smoked cannabis mean little in
the regulatory realm [12]. Studies of smoked cannabis,
its inhaled vapor [7] or pure THC [13] reveal steep
pharmacokinetic THC curves and evidence of marked
intoxicating effects at reported therapeutic dosages. A
delivery system that allows relief without undesirable
adverse events is necessary. Material must also be free
of pathogenic micro-organisms. Problems in cultivation
in Dutch and Canadian government-approved
herbal cannabis programs have led authorities to
gamma-irradiate their products.
Progress is apparent in developing other cannabis
based prescription medicines. Large scale clinical trials
have been undertaken, notably in Europe, as with investigation
of Cannador cannabis extract in treatment
of spasticity associated with multiple sclerosis (MS)
[14] and other disorders.
The most advanced program is that for Sativex®, an
oromucosal spray derived from two standardized whole
cannabis extracts, Tetranabinex® (rich in tetrahydrocannabinol,
THC) and Nabidiolex® (rich in cannabidiol,
CBD) [15], providing 2.7 mg of THC, 2.5 mg
of CBD and other components with each actuation.
Extracts derive from clonal strains grown in organic
media under climate-control in accordance with Good
Agricultural and Manufacturing Practices. Phytocannabinoids,
terpenoids and others are monitored to ensure
consistency [16, 17].
Sativex was approved for prescription in Canada for
central neuropathic pain in multiple sclerosis in June
2005. It is available on a named-patient basis in the
United Kingdom and the Catalunya Autonomous Region
(Spain). The FDA has granted an Investigational
New Drug Application for Sativex to proceed to advanced
stage clinical trials for intractable cancer pain
in the USA.
Numerous Phase II-III clinical trials of Sativex have
been completed in central and peripheral neuropathic
pain, spasticity, and urinary symptoms in MS, rheumatoid
arthritis and cancer pain [18-26], with significant
benefits in intractable symptoms failing to respond to
conventional treatment. Visual analogue scales of intoxication
after initial dose titration most frequently
remained in single digits on a 100-point scale, proving
this preparation need not produce psychoactive change
to achieve therapeutic benefit. Most patients desire
symptom control from medicine, not euphoria or any
alteration in mental status or capabilities.
No dose tolerance or significant withdrawal symptoms
have been observed with Sativex in up to five years of
Safety-Extension studies, even upon abrupt discontinuation
[19].
The onset of therapeutic effects of Sativex after
oromucosal administration is in 15-40 minutes [27]
with steady pharmacokinetic contour [28]. This is
much less than the 1-2 hour interval noted with THC in
sesame oil [29], and sufficiently fast to allow titration
to symptom relief without reinforcement. Most clinical
trial subjects have stabilized on an effective tolerable
dose of Sativex within 7-10 days via self-titration. In
over 2000 patient-years of clinical trial and SAFEX
monitoring and two year’s market experience in Canada,
no abuse or diversion has resulted.
Three studies have examined adverse event profiles of
patients employing smoked cannabis in governmentapproved
programs in Canada [30], and the Netherlands
[31, 32]. A comparison to Sativex SAFEX patients
confirms that adverse events with smoked cannabis
are far more frequent and prominent [12], especially
for cognitive function and alertness. In contrast,
cough and pulmonary complaints are not reported with
Sativex.
Sativex has proven itself distinct from mere THC due
to its unique composition and delivery. CBD contributes
notably as an analgesic and anti-inflammatory
antioxidant [33-35], but also attenuates intoxication,
tachycardia and other THC effects [15, 36]. CBD provides
beneficial immunodulatory effects in autoimmune
disorders (rheumatoid arthritis, inflammatory
bowel disease) via inhibition of tissue necrosis factoralpha
[37] and adenosine uptake via its A2A receptor
[38]. However, North American and most European
cannabis drug strains are virtually devoid of CBD [39-
41].
Marinol did demonstrated analgesic benefit in central
neuropathic pain in MS [42]. Similar benefits were
noted with Sativex [25] but with a lower adverse event
profile, despite that total doses of THC were 2 ½ times
higher in the Sativex group, demonstrating the contribution
of CBD to improvement in THC’s therapeutic
index [12].
In an RCT in intractable cancer pain, Sativex produced
statistically significant analgesic efficacy, while
Tetranabinex (without CBD) did not [26], highlighting
the necessity of providing the most efficacious preparation
possible in this challenging clinical context.
Finally, will patients give up cannabis smoking for a
prescription alternative? Yes, apparently. Some 50% of
Sativex clinical trial subjects have had therapeutic or
recreational exposure to cannabis. Some 70% of subjects
experienced sufficient benefit to request its continuation
in SAFEX studies [12]. No differences in
efficacy in cannabis-experienced vs. cannabis-naïve
Sativex patients have ever been evident.
The evidence supports the feasibility of developing a
cannabis-based medicine that adheres to regulatory
norms without exceptions. Advantages of such an approach
are numerous and include necessary safety,
quality controls and accountability exclusive of the
black market gamble.
Patients worldwide are seeking symptom relief with an
approved pharmaceutical that their physicians can
prescribe with confidence that is standardized, safe,
effective and reimbursed by governmental agencies
and third-party payers. Thus, there may be a clear division
between those who are ill, and those seeking a
thrill. Sativex is the new gold standard for cannabinoid
medicines and with its advent, one solution to the cannabis
prescription problem is close at hand.
Acknowledgements
The author is Senior Medical Advisor of GW Pharmaceuticals.
References
1. Grinspoon L. On the future of cannabis as medicine.
Cannabinoids. 2007 (in press).
2. Food and Drug Administration. Guidance for
industry: Botanical drug products. In: Services
UDoHaH, editor: US Government; 2004. p. 48.
3. Hashibe M, Morgenstern H, Cui Y, Tashkin DP,
Zhang ZF, Cozen W, et al. Marijuana use and the
risk of lung and upper aerodigestive tract cancers:
results of a population-based case-control study.
Cancer Epidemiol Biomarkers Prev.. 2006
;15(10):1829-34.
4. Tashkin DP. Smoked marijuana as a cause of
lung injury. Monaldi Arch Chest Dis..
2005;63(2):93-100.
5. Zanocco V. Meningococcal cases linked by sharing
joints. [cited 2005 April 8]; Available from:
http://www.vch.ca/news/docs/2005_04_07_meni
ng_joints.pdf
6. Earleywine M, Smucker Barnwell S. Decreased
respiratory symptoms in cannabis users who vaporize.
Harm Reduct J. 2007;4(1):11.
7. Abrams DI, Vizoso HP, Shade SB, Jay C, Kelly
ME, Benowitz NL. Vaporization as a smokeless
cannabis delivery system: a pilot study. Clin
Pharmacol Ther. 2007 (in press).
8. Gieringer D, St. Laurent J, Goodrich S. Cannabis
vaporizer combines efficient delivery of THC
with effective suppression of pyrolytic compounds.
J Cannabis Ther. 2004;4(1):7-27.
9. Hazekamp A, Ruhaak R, Zuurman L, van Gerven
J, Verpoorte R. Evaluation of a vaporizing device
(Volcano) for the pulmonary administration of
tetrahydrocannabinol. J Pharm Sci.
2006;95(6):1308-17.
10. Abrams DI, Hilton JF, Leiser RJ, Shade SB,
Elbeik TA, Aweeka FT, Benowitz NL, Bredt
BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF,
Mulligan K, Bacchetti P, McCune JM, Schambelan
M. Short-term effects of cannabinoids in patients
with HIV-1 infection. A randomized, placbocontrolled
clinical trial. Ann Intern Med.
2003;139:258-66.
11. Abrams DI, Jay CA, Shade SB, Vizoso H, Reda
H, Press S, Kelly ME, Rowbotham MC, Petersen
KL. Cannabis in painful HIV-associated sensory
neuropathy: a randomized placebo-controlled trial.
Neurology. 2007;68(7):515-21.
12. Russo EB. The solution to the medicinal cannabis
problem. In: Schatman ME, editor. Ethical issues
in chronic pain management. Boca Raton, FL:
Taylor & Francis 2006. p. 165-94.
13. Miller J, Meuwsen I, ZumBrunnen T, de Vries
M. A Phase I evaluation of pulmonary dronabinol
administered via a pressurized metered dose inhaler
in helathy volunteers. American Academy of
Neurology; 2005; Miami Beach, FL; 2005.
14. Zajicek J, Fox P, Sanders H, Wright D, Vickery
J, Nunn A, Thompson A; UK MS Research
Group. Cannabinoids for treatment of spasticity
and other symptoms related to multiple sclerosis
(CAMS study): multicentre randomised placebocontrolled
trial. Lancet. 2003;362(9395):1517-26.
15. Russo EB, Guy GW. A tale of two cannabinoids:
the therapeutic rationale for combining tetrahydrocannabinol
and cannabidiol. Med Hypotheses.
2006;66(2):234-46.
16. Potter D. Growth and morphology of medicinal
cannabis. In: Guy GW, Whittle BA, Robson P,
editors. Medicinal uses of cannabis and cannabinoids.
London: Pharmaceutical Press 2004. p. 17-
54.
17. de Meijer E. The breeding of cannabis cultivars
for pharmaceutical end uses. In: Guy GW, Whittle
BA, Robson P, editors. Medicinal uses of cannabis
and cannabinoids. London: Pharmaceutical
Press 2004. p. 55-70.
18. Wade DT, Makela P, Robson P, House H, Bateman
C. Do cannabis-based medicinal extracts
have general or specific effects on symptoms in
multiple sclerosis? A double-blind, randomized,
placebo-controlled study on 160 patients. Mult
Scler. 2004;10(4):434-41.
19. Wade DT, Makela PM, House H, Bateman C,
Robson PJ. Long-term use of a cannabis-based
medicine in the treatment of spasticity and other
symptoms in multiple sclerosis. Mult Scler.
2006;12:639-45.
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