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Introduction: Cannabis: From Pariah to Prescription

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Cannabis has been employed in human medicine for more than 4000 years. In the last century, political prohibition led to its disappearance from the conventional pharmacopoeia, but this trend is reversing due to the broad acceptance and application of this forbidden medicine by patients with chronic and intractable disorders inadequately treated by available therapeutics. This study addresses the “road back” for cannabis medicines, and reacceptance as prescription products.Current pharmacology of the two primary therapeutic phytocannabinoids, THC and CBD, is reviewed with respect to herbal synergy and as pertains to treatment of pain, spasm and the wide range of therapeutic applications and adverse effects of cannabis.In particular, the efforts of GW Pharmaceuticals to develop cannabis based medicine extracts (CBME) are documented including cultivation of genetically-selected medical-grade cannabis cloned strains in glass houses with organic and integrated pest management techniques, and their processing employing supercritical carbon dioxide extraction and winterization. These CBMEs are then available for formulation of dosage forms including sublingual extracts and inhaled forms. An optional Advanced Delivery System (ADS) is also discussed.
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Introduction:
Cannabis:
From Pariah to Prescription
Ethan Russo
SUMMARY. Cannabis has been employed in human medicine for more
than 4000 years. In the last century, political prohibition led to its disap-
pearance from the conventional pharmacopoeia, but this trend is revers-
ing due to the broad acceptance and application of this forbidden medicine
by patients with chronic and intractable disorders inadequately treated
by available therapeutics. This study addresses the “road back” for can-
nabis medicines, and reacceptance as prescription products.
Current pharmacology of the two primary therapeutic phytocanna-
binoids, THC and CBD, is reviewed with respect to herbal synergy and
as pertains to treatment of pain, spasm and the wide range of therapeutic
applications and adverse effects of cannabis.
In particular, the efforts of GW Pharmaceuticals to develop cannabis
based medicine extracts (CBME) are documented including cultivation
of genetically-selected medical-grade cannabis cloned strains in glass
houses with organic and integrated pest management techniques, and
their processing employing supercritical carbon dioxide extraction and
winterization. These CBMEs are then available for formulation of dos-
Ethan Russo, MD, is a Clinical Child and Adult Neurologist, Clinical Assistant Pro-
fessor of Medicine, University of Washington, and Adjunct Associate Professor of
Pharmacy, University of Montana, 2235 Wylie Avenue, Missoula, MT 59802 USA
(E-mail: erusso@montanadsl.net).
[Haworth co-indexing entry note]: “Introduction: Cannabis: From Pariah to Prescription.” Russo, Ethan.
Co-published simultaneously in Journal of Cannabis Therapeutics (The Haworth Integrative Healing Press,
an imprint of The Haworth Press, Inc.) Vol. 3, No. 3, 2003, pp. 1-29; and: Cannabis: From Pariah to Prescrip-
tion (ed: Ethan Russo) The Haworth Integrative Healing Press, an imprint of The Haworth Press, Inc., 2003,
pp. 1-29. Single or multiple copies of this article are available for a fee from The Haworth Document Delivery
Service [1-800-HAWORTH, 9:00 a.m. - 5:00 p.m. (EST). E-mail address: docdelivery@haworthpress.com].
http://www.haworthpress.com/store/product.asp?sku=J175
2003 by The Haworth Press, Inc. All rights reserved.
10.1300/J175v03n03_01 1
age forms including sublingual extracts and inhaled forms. An optional
Advanced Delivery System (ADS) is also discussed. [Article copies avail-
able for a fee from The Haworth Document Delivery Service: 1-800-HAWORTH.
E-mail address: <docdelivery@haworthpress.com> Website: <http://www.
HaworthPress.com> 2003 by The Haworth Press, Inc. All rights reserved.]
KEYWORDS. Medical marijuana, cannabis, THC, cannabidiol, herbal
treatment, alternative delivery systems, psychopharmacology
The Journal of Cannabis Therapeutics is pleased to mark with this
the publication the transition of cannabis from a forbidden herb back
into the realm of prescription medicine. Although a recognized and doc-
umented therapeutic agent for more than 4000 years (Aldrich 1997;
Russo 2003; Russo 2001), cannabis became politicized in the early 20th
century, leading to its ultimate prohibition in most industrialized na-
tions. Cannabis was dropped from the National Formulary in the USA
in 1941, and the British Pharmacopoeia in 1971. Reasons for the loss of
cannabis as an available pharmaceutical were complex, related to a per-
ceived risk of abuse, but also included formidable quality control issues
such as lack of reliable or consistent supplies from India, idiosyncratic
variability of patient responses to available preparations, and the advent
of modern single product pharmacotherapy. The road back for cannabis
medicines, as it were, has been a difficult and circuitous journey, beset
by politics to a greater extent than science.
The essential features that characterize a prescription medicine re-
quire it to be of proven quality, consistency, clinical efficacy, and
safety. For the last thirty-plus years, 85% of the world’s research dollars
for cannabis have been provided by the National Institute on Drug
Abuse (NIDA), whose orientation has certainly not tended towards
proof of therapeutic efficacy for this ancient herb. The lead has thus
been taken by Europeans, whose medicine has never strayed quite so far
from the realm of vegetable materia medica. Our account will docu-
ment the progress of GW Pharmaceuticals, which, with full backing of
the UK Home Office, has achieved the feat in five years of progressing
from the idea of restoring cannabis to the pharmacy, all the way through
to submission of a lead product for regulatory approval by the Medi-
cines and Healthcare Products Regulatory Agency (MHRA, formerly
the Medicines Control Agency).
2 CANNABIS: FROM PARIAH TO PRESCRIPTION
As previously published two years ago (Whittle, Guy, and Robson
2001), many hurdles exist when considering the concept of how to pro-
duce a prescription cannabis product (p. 186):
the concept of cannabis-based medicines as botanicals as opposed
to pure cannabinoids;
selective breeding of high yielding chemovars that produce an
abundance of one particular cannabinoid;
investigation of the pharmacological properties of various canna-
binoids, i.e., cannabis is not just THC;
variability of composition of cannabis. The geographical and ge-
netic basis for variation in cannabinoid content of cannabis bio-
mass and its control to give a standardised product;
the quality aspects of cannabis biomass production;
routes of administration and optimisation of formulations to achieve
particular pharmacokinetic profiles;
regulatory issues, including health registration, and international
legal requirements;
security packaging and anti-diversionary devices which can be
used in connection with cannabis-based medicines in order to sat-
isfy statutory requirements.
As is evident, the process of preparing a botanical for approval as
medicine is comparable, but yet more complex than that for the New
Chemical Entity (NCE), or novel synthetic pharmaceutical. A formida-
ble barrier remains in the assignation and perception of cannabis as a
drug of abuse. In the USA, cannabis was placed in the most restrictive
category, Schedule I of the Controlled Substances Act in 1970, which
encompasses drugs that are dangerous and addictive and lack recog-
nized medical utility. It requires emphasis that this assignment was po-
litical and designed as a temporary, pending reassignment by the Shaffer
Commission in 1972 (Abuse 1972). President Nixon rejected their rec-
ommendations of medical access and decriminalization before even
reading the final report. Additionally, Schedule I assignation remains
anachronistic (Haines et al. 2000). Many such drugs, including canna-
bis and LSD have had clear therapeutic indications in the past. Others,
such as diamorphine (heroin), are forbidden in the USA, but retain legal
pharmaceutical status in the UK. At least, controversy about such blan-
ket proscriptions exists, and certainly with advancing knowledge, debate
and reconsideration are required. A detailed analysis of the complexi-
ties of the cannabis question in the UK is available (Whittle and Guy
Ethan Russo 3
2003). The same publication outlines scientific evidence that cannabis
based medicine extracts (CBME) may offer a distinct advantage over
THC alone (Marinol®):
1. Potentiation. Based on a concept noted for endocannabinoids and
their precursors called the “entourage effect” (Ben-Shabat et al.
1998; Mechoulam and Ben-Shabat 1999), various phytocannabinoid
components, whether active (CBD, CBC) or relatively inactive
(CBN) affect the cannabinoid receptor binding, pharmacokinetics
and metabolism of THC. The same may be true of non-cannabin-
oid components, such as the essential oil terpenoids (McPartland
and Russo 2001; Russo and McPartland 2003).
2. Antagonism. Cannabidiol mitigates side effects of THC (Karniol
et al. 1975; Mechoulam, Parker, and Gallily 2002), including its
intoxication liability. Additionally, other cannabis components
may be helpful in this regard, e.g., terpenoids such as pulegone, 1,
8-cineole, and a-pinene may counter the short-term memory im-
pairment engendered by THC (McPartland and Russo 2001; Russo
and McPartland 2003).
3. Summation. A number of cannabis components may contribute to
a certain therapeutic effect of THC (Williamson and Evans 2000;
McPartland and Russo 2001).
4. Pharmacokinetic. For example, CBD alters the metabolism of
THC by inhibiting its hepatic conversion to 11-OH-THC (Zuardi
et al. 1982).
5. Metabolism. Whittle and Guy (2003) argue, as have others (Tyler
1994; Russo 2001) that due to co-evolution over the millennia,
humans are better able to metabolize herbal preparations (i.e.,
cannabis) as compared to synthetic pharmaceuticals (i.e., syn-
thetic cannabinoids).
Beyond the issues of regulation and rationale, the next step is to grow
the plant. Cannabis sativa, despite its cosmopolitan propagation on the
planet, is a rather exacting species insofar as optimal production of de-
sirable medicinal cannabinoids is concerned. Such production is great-
est in unfertilized female flowering tops, most commonly known as
sinsemilla (Spanish, “without seed”), or ganja, the Sanskrit term for a
process known in India for some 2500 years (Figure 1). THC produc-
tion is increased by selecting certain strains and exposing them to ul-
traviolet light (Pate 1994). In the organization of the primary GW
Pharmaceuticals production glasshouse, David Potter and Etienne de
4 CANNABIS: FROM PARIAH TO PRESCRIPTION
Meijer have outlined additional important factors (Potter 2003; de
Meijer 2003): high yield per area, high cannabinoid purity, high inflo-
rescence to leaf ratio (“harvest index”), avoidance of diseases and pests,
production of sturdy growth conducive to subsequent processing and
ease of harvest.
Consistency is achieved by clonal propagation of cuttings from select
strains called “mother plants,” that yield shorter specimens with less
waste stem material. Successful propagation occurs with 95% of cut-
tings (Figure 2).
A decision was made to produce different cannabinoid ratios for pre-
scription CBMEs, through the use of separate high-THC and high-CBD
strains, or their combination in a fixed-ratio. This work was initiated by
HortaPharm B.V. a generation ago in Holland, and selected strains were
developed there, and the seeds imported into the UK in 1998 (de Meijer
2003). The high-THC strain was originally produced by hybridization
of ((Afghani Mexican) Colombian) genetics, said to be reminis-
cent of the commercial (if illegal) “Skunk #1” strain (Potter 2003). An
initial 400 plants grown from seed were analyzed for cannabinoid con-
centration and purity, leading to five chemovars (“chemical varieties”
or phenotypes) that were selected for commercial cultivation potential.
A high-CBD strain was similarly selected from 1600 seeds yielding a
selection of the best four chemovars. It has been determined that cannabis
Ethan Russo 5
FIGURE 1. Unfertilized female cannabis flower (photograph courtesy of GW
Pharmaceuticals).
Reprinted with permission from GW Pharmaceuticals.
plant vigor, architecture, and glandular trichome density and metabolic
efficiency in cannabinoid production are all polygenetically-determined
traits, but affected by environmental factors (de Meijer 2003; de Meijer
et al. 2003). Together, they determine the “cannabinoid quality.” The
chemovar is the primary determinant, however, of what cannabinoid ra-
tios result. Additional line selection via repetitive self-fertilization has
also been employed to maximize appropriate selection of both parents
of a hybrid (de Meijer 2003).
In this particular instance, GW Pharmaceuticals chose to produce
separate chemovars that selectively yield THC, CBD and THCV (83%
theoretical maximum), CBC (76% theoretical maximum) or even CBG
in relatively high amounts (de Meijer 2003). Although genetic modifi-
cation (GM) of cannabis has often been discussed in certain quarters, it
is abundantly clear from the above discussion that tremendous variation
of chemical parameters is readily available with application of standard
Mendelian genetic breeding techniques, and there is no rational reason
for adding to the cannabis controversy by rendering it a genetically-
modified organism (GMO).
As cannabis propagation and quality are subject to the vagaries of
weather, all the more in a cloudy and wet northern clime, artificial light-
6 CANNABIS: FROM PARIAH TO PRESCRIPTION
FIGURE 2. Clonal growth in glasshouse (photograph courtesy of GW Pharma-
ceuticals).
Reprinted with permission from GW Pharmaceuticals.
ing under glass was deemed the preferred method for pharmaceutical
production in the UK. Mother plants are grown under high-pressure so-
dium (HPS) lights continuously at 75 watts/m2PAR (Photosythetically
Active Radiation) (equivalent to 31,000 lux of natural sunlight) at 25°C
in an organic compost (“leaf mould”) to a height of 2 m, allowing prun-
ing and the production of as many as 80 more cuttings for propagation
(Potter 2003). The mother plant may be utilized for two or more
“flushes” over the next few months before its vigor diminishes.
Clones are placed in peat pots after treatment with rooting hormone,
trimming to retain one axial bud, and are grown out in polythene tunnels
under high humidity with 24 hour light for two weeks until “potting up”
(Potter 2003). Plants are continued under perpetual illumination for
about three weeks until attaining a height of 50 cm, before shifting to a
12-hour light/12-hour dark critical day-length regimen to induce flow-
ering.
All cultivation is performed in accord with Good Agricultural Prac-
tice (GAP) methods of the European Medicines Evaluation Agency in
conjunction with rules of the UK Medicines Control Agency (Medi-
cines Control 1997) for the production of a Botanical Drug Substance
(BDS). [For the approved process of medicinal cannabis cultivation in
the Netherlands, see the article in a prior issue of Journal of Cannabis
Therapeutics (Anonymous 2003)]. Microbiological safety is crucial,
and is a monitored function by regulatory agencies. In this instance GW
Pharmaceuticals chose to use some minimal mineral sources of soil en-
richment to avoid possible pathogen exposure from organic sources
(Potter 2003). However, no pesticides whatsoever have been employed.
Common pests are kept at bay by positive pressure in the glasshouses,
and utilization of integrated pest management (IPM). Pests of concern
have included spider mites (Tetanychus spp.) and onion (tobacco) thrips
(Thrips tabaci). These are controlled through release of predatory
mites, and kept at low level. For a comprehensive examination of the
topic, the reader is urged to consult the superb Hemp diseases and pests:
Management and biological control (McPartland, Clarke, and Watson
2000).
Fungal issues to date at the GW facilities have mainly pertained to
grey mold (Botrytis cinerea) and powdery mildew (Sphaerotheca macu-
laris). Control is achieved mainly by avoidance of high humidity close
to time of harvest for the former, and increasing light pressure while
avoiding excessive nitrogen exposure for the latter. When diseased
plants do arise, affected specimens are destroyed.
Ethan Russo 7
While trials of outdoor cultivation were attempted with CBD-rich
strains, daunting problems were encountered in the cool, damp British
climate (Potter 2003).
Because cannabigerol (CBG) levels are dependent upon plant matu-
rity, both the THC- and CBD-rich chemovars are harvested at the same
growth stage at the onset of senescence, at which time the flowering
tops representing 90% of the weight of the plants’ aerial portions.
Drying under a stream of dehumidified air from 25 down to 12% mois-
ture content is then achieved under dark conditions to minimize canna-
binoid oxidation (Whittle, Guy, and Robson 2001). The resultant mixture
of dried unfertilized flowers, stalks and leaves yields 15% THC or 8%
CBD in the respective chemovars (Figures 3, 4, and 5).
Interestingly, in the “raw” state, much of the THC and CBD are in the
form of cannabinoid acids, THCA and CBDA, which are low in canna-
binoid pharmacological activity. It is only after decarboxylation by pro-
gressive oxidation over time, after heating, or in the extraction process,
that significant THC and CBD levels are produced and pharmacologi-
cal benefits are obtained.
8 CANNABIS: FROM PARIAH TO PRESCRIPTION
FIGURE 3. High CBD strain in GW Pharmaceuticals glasshouse (photograph
courtesy of David Downs, PhD, GW Pharmaceuticals).
Reprinted with permission from GW Pharmaceuticals.
Historically, cannabis extracts were ethanol-based, dating back to the
experiments of O’Shaughnessy in India in the 19th century (O’Shaughnessy
1838-1840). GW Pharmaceuticals has opted for a more modern tech-
nique employing supercritical CO2extraction (Whittle, Guy, and Robson
2001). This has distinct advantages, as organic materials are extracted at
approximately body temperature with retention of essential oil terpenoid
components that seemingly contribute to medicinal effects of cannabis
(McPartland and Russo 2001). Additionally, no solvent residue remains
after the process. Although such extraction does include some waxy
ballast, this is easily removed by “winterization,” or chilling in an etha-
nol solution. The resultant liquid CBME is then ready for pharmaceuti-
cal preparation.
Whereas oral ingestion and smoking have been favored methods of
application in the past, they are not likely to be the primary modes of ad-
ministration in the future of clinical cannabis as a prescription medi-
cine. Oral administration, such as with Marinol®(synthetic THC, or
“dronabinol” in sesame oil) was introduced into the USA market in
Ethan Russo 9
FIGURE 4. High THC strain in GW Pharmaceuticals glasshouse (photograph
courtesy of David Downs, PhD, GW Pharmaceuticals).
Reprinted with permission from GW Pharmaceuticals.
1986, but has been relatively little employed (Russo 2002). Reasons in-
clude expense, delayed onset of effects in the range of 90-120 minutes,
lack of practical titration of dosage, and a pronounced tendency toward
dysphoria or other mental complaints from being “too high.” In part,
this may relate to hepatic first-pass conversion of THC to 11-OH-THC,
which may possess a higher degree of psychoactivity according to some
authorities. Interestingly, the presence of CBD, which is present in nat-
ural cannabis, but obviously absent in Marinol®, impedes this hepatic
conversion by inhibition of cytochrome P450 3A11 (Browne and
Weissman 1981).
Although smoking of cannabis was an acknowledged delivery sys-
tem in the past, with cigarettes from the Grimault et Cie Company
among others, and endorsement by such experts as Walter E. Dixon in
England (Dixon 1899, 1921) and Walther Straub in Germany (Straub
10 CANNABIS: FROM PARIAH TO PRESCRIPTION
FIGURE 5. Dried cannabis ready for processing (photograph courtesy of GW
Pharmaceuticals).
Reprinted with permission from GW Pharmaceuticals.
1931), it is highly unlikely that regulatory agencies such as the Food
and Drug Administration (FDA) would ever approve a drug delivery
system that produces bronchial irritation and contains pyrolytic end-
products that are potentially carcinogenic (Tashkin et al. 2002). Vapor-
ization technology presents a viable option, preserving as it does the
rapid bronchial absorption of cannabis components, and retaining the
ability to titrate dosage rapidly. It is in initial stages of investigation
(Gieringer 1996; Gieringer 1996; Gieringer 2001; Russo and Stortz
2003). This approach will require both elucidation of the pharma-
cokinetics of the vaporization technique, and approval of the hardware
as a medical device. As will be discussed, GWP has developed an in-
haled device (patent application GB0126150.2) that employs a metallic
or ceramic surface coated with CBME that is heated by electrical cur-
rent. The process is triggered by inhalation, employing the Advanced
Dispensing System (ADS) (vide infra) providing the advantages of
smoked cannabis (rapid onset, ready dosage titratability), but without
hazards posed by smoke particles or inhalation of solvents.
Inhaled, non-smoked delivery of isolated THC has been previously
investigated (Tashkin et al. 1977), but curiously, the isolated molecule
is quite irritating to the bronchioles and induces a cough reflex despite
its notable bronchodilatory benefits (Williams, Hartley, and Graham
1976). Biophysical parameters for this method of delivery are exacting,
and have been recently reviewed (Whittle, Guy, and Robson 2001). Par-
ticles of diameter greater than 10 µ fail to reach the bronchioles. Those
below 1 µ are mostly re-expired. It is only those particles in the 1-2 µ
range that stand the best chance to be absorbed from the alveoli. Inas-
much as THC is an extremely viscous molecule that sticks to any vessel,
dispersion in a solvent such as alcohol or propylene glycol is most often
necessary, and introduces its own adverse effect issues in pulmonary
application. This search for modern alternatives to smoked cannabis
continues, however, through the use of a metered dose inhaler (Wilson
et al. 2002) for THC. Although some seemingly represent that THC rep-
resents the sum total of important pharmacological effects of cannabis
(Wachtel et al. 2002), others counter (McPartland and Russo 2001;
Russo and McPartland 2003) in contrast, that the presence of other
phytocannabinoid and terpenoid component such as myrcene, with its
analgesic and anti-inflammatory effects (Rao, Menezes, and Viana
1990; Lorenzetti et al. 1991), or a-pinene, which is also a bronchodilator
(Falk et al. 1990), or apigenin, wich is a non-sedating flavonoid in can-
nabis (Viola et al. 1995), contribute demonstrably to its clinical attrib-
Ethan Russo 11
utes. This debate will continue, engendering as it does the basic conflict
between single-component “modern” pharmacology, and old-fashioned
but resurgent notions of phytotherapeutic synergy.
Suppository forms of cannabis have been documented as far back as
Ancient Egypt (Mannische 1989; Russo 2002), and the Victorian era
(Farlow 1889). Modern research effort has also revived the concept,
most often with D9-THC-hemisuccinate (Broom et al. 2001; Elsohly et
al. 1991). This method lacks convenience, is less subject to allow titra-
tion of dosage, and may be cosmetically unacceptable, especially in
particular American consumers.
Transdermal delivery of cannabinoids is an attractive possibility as
consumers have found “patches” to be a convenient method of drug de-
livery via this parenteral, long-acting method. Problems with this method
have been previously outlined (Whittle, Guy, and Robson 2001). In es-
sence, they include the lipophilic nature of cannabis components, the
need for carrier molecules or other facilitators of transdermal absorp-
tion, and results to date that approximate only 10% of necessary serum
levels (Challapalli and Stinchcomb 2002). Finally, the gradient of trans-
port of cannabinoids through the skin is such that a used patch would
still retain 90% or more of initial dosage, and would thereby represent a
theoretical diversion risk upon disposal.
GW Pharmaceuticals primary efforts to date have focused on an ap-
proach employing a sub-lingual or oro-mucosal spray of CBME in etha-
nol and propylene glycol solution. The oro-mucosal preparation employs
a pump action aerosol spray (Robson and Guy 2003; Whittle and Guy
2003) (Figure 6). This dispersion of materials allows reasonably rapid
absorption (45 minutes), preserving the ability to titrate dosage, avoid-
ing excessive swallowing of material, and producing an area under the
curve that is comparable to that for smoked or intravenous administra-
tion of THC (Whittle and Guy 2003). Experiments in the UK with a
simple unadorned device have demonstrated no major compliance
problems, nor diversion of CBME to the black market. There are no
plans to introduce pharmaceutical products with CBME in the UK,
Western European or British Commonwealth nations with added secu-
rity devices. However, it is anticipated that such security would be a
necessary prerequisite in the USA for Drug Enforcement Administra-
tion (DEA) and Food and Drug Administration (FDA) approval (Figure 7).
Thus, an additional Advanced Delivery System (ADS) has been devel-
oped (Figure 8). The ADS is a hand-held computerized encrypted de-
vice which may (Robson and Guy 2003; Whittle and Guy 2003):
12 CANNABIS: FROM PARIAH TO PRESCRIPTION
1. remind patients of times dosing is due
2. record daily patterns and fluctuations in doses employed
3. allow remote computer monitoring of dosage employed by re-
searchers or clinicians
4. render the device secure, tamper-proof, and patient-specific through
individual codes
5. allow delivery of a variety of dosage forms (e.g., CBME with
THC-CBD 1:1 ratio for daily usage, with high-THC preparation
for sudden bouts of pain)
6. be suitable for usage with controlled drugs such as methadone or
diamorphine (heroin).
CLINICAL STUDY DESIGN
As will be seen subsequently, initial Phase I studies of CBME exam-
ined pharmacokinetics and adverse effects of the materials in normal
Ethan Russo 13
FIGURE 6. Pump Action Sublingual Spray as utilized in the United Kingdom
(photograph courtesy of GW Pharmaceuticals).
Reprinted with permission from GW Pharmaceuticals.
volunteers with monitoring of dose-response parameters, as well as
pulse, blood pressure and subjective and objective assessments of in-
toxication. Although criticized, the current “gold standard” in pharma-
ceutical assessment is the double-blind randomized placebo-controlled
clinical trial (RCT). An accepted variation in this approach that is
worthwhile in contexts in which true blinding is difficult to achieve (as
with cannabis) or in assessment of unpredictable diseases (such as mul-
tiple sclerosis) is presented by the N-of-1 trial design, achieved through
a series of randomized, placebo controlled studies in which each subject
serves as their own control (Guyatt et al. 1990). In fact, this approach to
cannabis clinical trials was specifically endorsed by the American Insti-
tute of Medicine (Joy, Watson, and Benson 1999).
In assessing target conditions for initial studies, GWP relied on a sur-
vey of clinical cannabis patients and their conditions. In 1998, some
3516 self-selected patients who contacted the company were sent sur-
vey forms, of which 2458 were completed (70% response rate) (Robson
and Guy 2003). Of 787 current or past cannabis users, the greatest rep-
14 CANNABIS: FROM PARIAH TO PRESCRIPTION
FIGURE 7. Sublingual spray as part of Advanced Delivery System (photograph
courtesy of GW Pharmaceuticals).
Reprinted with permission from GW Pharmaceuticals.
resentation was among patients with MS or various arthritic conditions.
This contrasts with the situation in the USA, where HIV/AIDS is more
highly represented, but where chronic pain remains a prime concern
(Corral 2001; Gieringer 2001).
Another priority in selection of patients for clinical investigation in-
volved a decision to study those with intractable conditions that had
failed to be symptomatically controlled by available conventional pharma-
ceuticals. This was based on a philosophical decision to demonstrate
that CBME would not merely be equal in efficacy to standard drugs, but
rather, offer tangible advantages in difficult clinical contexts. A deci-
sion was also made to add CBME to patients’ existing pharmaceutical
regimens to provide a baseline comparison.
For MS patients, entry criteria included the presence of one or more
poorly controlled symptom despite best available treatment: pain, spasm,
spasticity, tremor or urinary difficulty, whether frequency, urgency,
nocturia or incontinence (Robson and Guy 2003; Whittle and Guy
2003). Patient exclusions were similar to those employed in previous
studies of cannabis or Marinol®: history of serious drug or alcohol
abuse, schizophrenia, uncontrolled cardiovascular conditions including
hypertension, impaired hepatic or renal function, and epilepsy. All na-
Ethan Russo 15
GW Pharmaceuticals
ADS Components
Drug incorporated into
cartridge
Drug cannot be dispensed
without device
Contains drug/patient
information
Tamper evident
Solid, liquid, inhaled,
injectable dosage forms
Recognises patient
Recognises drug
Controls release of drug from
cartridge
Patient dosage reminder
Can dispense 16 different
drugs at one time
Retrieves dose regimen info
from device
Supplies patient usage data
Receives remote change of
regimen
Re-charges batteries
Cartridge Device Dock
FIGURE 8. Diagram of Advanced Delivery System (ADS) (courtesy of GW
Pharmaceuticals).
Reprinted with permission from GW Pharmaceuticals.
tional norms for clinical research and Guidelines for Good Clinical
Practice (GCP) were followed.
Noting past historical data on individual idiosyncrasies of dosing and
responses to cannabis by patients, a requirement was pursued to deliver
initial THC:CBD 1:1 CBME dosages in open-label fashion with close
monitoring, in an attempt to establish initial individual dose guidelines.
This was then followed by randomized double-blind crossover compar-
isons of that preparation versus placebo and high-THC and high-CBD
CBMEs. Subsequent monitoring employed an array of subjective mea-
sures (via visual analogue scales, or VAS) and objective measures on
examination and laboratory study. Patients who demonstrated benefits
in initial studies were given the option of entering long-term safety
studies, and a majority of patient-subjects chose to do so (Robson and
Guy 2003). The results of these trials form the basis for the remainder of
this publication.
THC AND CBD: SUMMARY OF CURRENT KNOWLEDGE
Although this author has emphasized the biochemical and physiolog-
ical contribution importance of other cannabis components (minor
cannabinoids, terpenoids and flavonoids) to the medical therapeutic
benefits of cannabis (McPartland and Russo 2001), it is clear from the
data that exist to date that two entities provide the greatest effects:
D9-tetrahydrocannabinol and cannabidiol. A complete analysis of cur-
rent knowledge is beyond our scope, but it is appropriate to briefly sum-
marize current knowledge of their contributions (Table 1).
Receptor Effects
THC is a partial agonist at both CB1and CB2receptors (Pertwee
1998; Showalter et al. 1996). In contrast, CBD has little activity, and
perhaps slight antagonistic activity at CB1, while greater activity at CB2
(Showalter et al. 1996). Of great importance, it has recently been dem-
onstrated that cannabidiol stimulates vanilloid receptors (VR1) with
similar efficacy to capsaicin, and inhibits uptake of the endocanna-
binoid anandamide (AEA), and weakly inhibits its hydrolysis (Bisogno
et al. 2001). These new findings have important implications in eluci-
dating the pain-relieving and anti-inflammatory effects of CBD. In a
16 CANNABIS: FROM PARIAH TO PRESCRIPTION
Ethan Russo 17
TABLE 1. Therapeutic/Adverse Effects of THC and CBD
Effect THC CBD Reference
Receptor/Non-Receptor Effects
CB1(CNS receptors) ++ ± (Pertwee 1998)
CB2(Peripheral receptors) + ++ (Showalter et al. 1996)
Vanilloid Receptors + (Bisogno et al. 2001)
Anti-inflammatory + + (Hampson et al. 1998)
Immunomodulatory + ++ (Malfait et al. 2000; Cabral 2001)
CNS Effects
Anticonvulsant + ++ (Wallace, Martin, and DeLorenzo 2002;
Carlini and Cunha 1981)
Muscle Relaxant + ++ (Petro 1980)
Antinociceptive ++ + (Pertwee 2001)
Catalepsy ++ ++ (O'Shaughnessy 1838-1840)
Psychotropic ++ (Russo 2001)
Anxiolytic + (Zuardi and Guimaraes 1997)
Antipsychotic ++ (Zuardi and Guimaraes 1997)
Neuroprotective antioxidant activity + ++ (Hampson et al. 1998)
Antiemetic ++ (Chang et al. 1979)/(Guy et al. 2002)
Sedation (reduced spontaneous activity) + + (Zuardi and Guimaraes 1997)
Agitation (Alzheimer disease) + (Volicer et al. 1997)
Tic reduction + (Müller-Vahl et al. 1999)
Withdrawal effects (reduction) + (Cichewicz and Welch 2002; Reynolds
1890)
Migraine + (Russo 2001; Russo 1998)
Bipolar disease + (Grinspoon and Bakalar 1998)
Cardiovascular Effects
Bradycardia + (Weil, Zinberg, and Nelsen 1968)
Tachycardia + ditto
Hypertension + ditto
Hypotension + (Adams et al. 1977)
Appetite/Gastrointestinal
Appetite + (da Orta 1913)
Motility (slowed) + (Pertwee 2001)
Neonatal feeding (endocannabinoid) + (Fride 2002)
Anti-Carcinogenesis
Melanoma (apoptosis, angiogenesis) + (Casanova et al. 2003)
Breast (prolactin receptor) + (De Petrocellis et al. 1998)
Glioma (apoptosis) + + (Sanchez et al. 1998; Vaccani, Massi,
and Parolaro 2003)
Leukemia (apoptosis) + (McKallip et al. 2002)
Pulmonary (blocks carcinogenesis
enzymatically)
+ (Roth et al. 2001)
Pulmonary
Bronchodilation + (Williams, Hartley, and Graham 1976;
Tashkin et al. 1977)
Ophthalmological
Intra-ocular pressure (reduced) ++ + (Merritt et al. 1980; Jarvinen, Pate, and
Laine 2002)
Night vision (improved) +* (Russo et al. 2003; West 1991)
Adapted and expanded from (Whittle, Guy, and Robson 2001; Whittle and Guy 2003).
* New indication. See final article in this publication.
manner of interpretation, CBD may be considered the first clinical
agent that modulates endocannabinoid function.
Anti-Inflammatory and Immunomodulatory Effects
The benefits of cannabis and cannabinoids on inflammation have
been extensively documented. The following are suggested as reviews
(Hampson et al. 1998; Pertwee 2001; Burstein 1992; Russo 2001). Both
THC and CBD have important roles in these observations. Of increas-
ing interest is the recent demonstration that CBD possesses both anti-in-
flammatory and immunomodulatory benefits in an animal model of
rheumatoid arthritis (Malfait et al. 2000). Although there has been great
concern expressed as to immunological damage by cannabis, such ef-
fects are usually demonstrable in laboratory assays at levels 50-100
times the psychoactive dose (Cabral 2001). Deleterious clinical effects
of cannabis in HIV (Abrams et al. 2002), and chronic medical usage
(Russo et al. 2002) have not been demonstrated.
Central Nervous System Effects
Of prime importance in cannabinoid therapeutics is pain control or
antinociception (Pertwee 2001; Russo 2001). One of the primary func-
tions of the endogenous cannabinoid system is modulation of pain con-
trol, in parallel with the endogenous opioid and vanilloid systems. THC
is the main contributor of cannabis to control of pain, via its actions on
CB1, which occur in key areas of the spinal cord, and brainstem. A pur-
ported “comprehensive” review of the analgesic effects of cannabinoids
concluded that they have little demonstrated benefit (Campbell et al.
2001), but this pronouncement produced strong refutation (Russo 2001)
and more considered subsequent support (Baker et al. 2003) in some
quarters. Countless testimonials attest to the unique benefits of cannabis
in difficult cases of neuropathic pain (Grinspoon and Bakalar 1997),
and other unusual and intractable conditions, such as familial Mediter-
ranean fever (Holdcroft et al. 1997).
The cataleptic effects of high doses of THC were noted by O’Shaugh-
nessy in 1839 (O’Shaughnessy 1838-1840), and this effect remains part
of the tetrad of behavioral effects sought in laboratory animals as a sign
of cannabinoid activity.
Cannabis was noted to have anticonvulsant effects in the 19th cen-
tury. Primary focus of therapeutic benefit on seizures of partial onset
has focused on CBD (Carlini and Cunha 1981), while it was generally
18 CANNABIS: FROM PARIAH TO PRESCRIPTION
believed that THC was proconvulsant. Epileptic patients have generally
claimed otherwise (Corral 2001), and it was recently demonstrated that
endocannabinoids modulate seizure thresholds, and that THC exerts an
anticonvulsant effect, as well (Wallace, Martin, and DeLorenzo 2002).
Migraine is a neurochemical and vascular disorder of exceeding
complexity, whose treatment remains extremely problematical. The
multi-modality effects of cannabis seem to support its historical role in
both symptomatic and prophylactic treatment (Russo 1998; Russo 2001).
While THC has received the bulk of the attention in therapeutic applica-
tion, this author’s experience with Marinol®treatment would seem to
support that the benefits on chronic migraine treatment do not mirror
the high efficacy of historical claims in the Victorian era. Current dis-
coveries of the endocannabinoid modulation and vanilloid receptor ef-
fects of CBD discussed above (Bisogno et al. 2001) would seem to
support that cannabidiol is a necessary component to successful pro-
phylaxis in migraine.
Antidepressant and anti-anxiety effects of cannabis date to ancient
India in the Atharva Veda, and the Scythians (Herodotus 1998). Cer-
tainly, an antidepressant effect of cannabis has been observed in chronic
disease (Herodotus 1998; Russo et al. 2002; Regelson et al. 1976). In
general, THC is considered psychotropic, while CBD generally is not
(reviewed in Russo 2001). Rather, cannabidiol is noteworthy for its
anxiolytic, sedative and antipsychotic effects (Zuardi and Guimaraes
1997). Interestingly, THC (as Marinol®) was recently observed to pro-
duce weight gain and reduce agitation in demented Alzheimer disease
patients (Volicer et al. 1997). Unfortunately, CBD was not examined,
but very likely would have contributed to the clinical benefits. Anec-
dotal reports support benefit of THC in mood-stabilization in bipolar
disease (Grinspoon and Bakalar 1998).
The antispasmodic effects of cannabis were observed in such dis-
eases as tetanus in the 19th century, producing cures of fatal diseases,
and palliation of chronic disorders (O’Shaughnessy 1838-1840). Mus-
cle relaxant properties of cannabis in multiple sclerosis were noted
more recently (Petro 1980; Grinspoon and Bakalar 1997), and have re-
cently been reviewed in detail (Baker et al. 2003; Consroe 1998; Petro
2002). These will form the focus of many of the study results subse-
quently discussed in this publication. As if the muscle relaxant and
anti-spasmodic benefits of cannabis were insufficient, it has recently
been demonstrated that cannabinoid agonists positively influence the
immunological parameters of demyelinating diseases such as experi-
mentally allergic encephalomyelitis (Baker et al. 2000). In the past year,
Ethan Russo 19
a small clinical trial of THC and a cannabis extract was performed with
16 subjects. Neither was observed to reduce spasticity, and adverse
events were reported in the extract group (Killestein et al. 2002). Nu-
merous criticisms were subsequently voiced in this regard (Russo
2003). Among these were that the plant extract was poorly categorized;
in fact, it contained a fixed ratio of THC to CBD with maximum doses
of 5 mg of THC and 2 mg of CBD per day. The study additionally em-
ployed oral administration with no real dose titration. An additional
study in Switzerland with more patients (57) and doses of up to 15 mg
THC with 6 mg CBD divided tid has provided better results with reduc-
tion in spasms to the p < 0.05 level and no significant side effects vs.
placebo (Vaney et al. 2002). A study of an even larger cohort of MS pa-
tients in the UK is pending publication.
Kirsten Müller-Vahl has pioneered the use of cannabis and THC in
Tourette syndrome, demonstrating a marked reduction in tic behavior
and obsessive-compulsive preoccupation (Muller-Vahl et al. 2003;
Müller-Vahl et al. 1999).
The antiemetic effect of THC in morning sickness was noted as early
as the 19th century (Wright 1862), and was further elucidated in the last
two decades (Chang et al. 1979). A tremendous body of knowledge in
this context that has been historically ignored was recently published in
this journal (Musty and Rossi 2001). This pertained to state-sponsored
studies in the USA in cancer chemotherapy. Pooling available data in
some 768 patients, oral THC provided 76-88% relief of nausea and
vomiting, while smoked cannabis figures supported 70-100% relief in
the various surveys. Also worthy of inclusion here, an Israeli study of 8
children receiving highly emetogenic chemotherapy for hematological
malignancies with oral D8-THC (a trace and more stable component of
cannabis) was 100% effective in allaying vomiting in 480 dose applica-
tions! Surprisingly, slight euphoria was noted in only one subject, caus-
ing the authors to surmise that the appreciation of the cannabis “high” is
a developmental phenomenon. Shockingly, this study has never been
followed by more similar investigations.
Surprisingly as well, it has just been demonstrated that CBD also has
anti-emetic benefits in motion sickness in rodents (Guy et al. 2002), an
indication that has wide implications, including space flight.
Although THC and cannabis are often attacked as productive of ad-
diction, it is well documented from the 19th century that prominent phy-
sicians claimed benefit of Indian hemp in treatment of alcohol, morphine
and cocaine dependencies (Reynolds 1890). As is becoming a recurrent
20 CANNABIS: FROM PARIAH TO PRESCRIPTION
theme, the claims of the Victorian era are resonating with modern scien-
tists who subsequently prove their biochemical and physiological basis.
This benefit has been strikingly demonstrated in the laboratory, through
“opiate-sparing” by THC (Cichewicz et al. 1999), and more recently,
the effect of THC to mitigate opiate-withdrawal symptoms, and block
the formation of dependency (Cichewicz and Welch 2002).
One of the most exciting and pressing areas of neurological investi-
gation surrounds the emerging concept of neuroprotection. If one were
able to prevent the progressive cell death of parkinsonism, amyotrophic
lateral sclerosis, Alzheimer and Huntington diseases, the inevitable de-
terioration and ultimate demise that these disorders eventuate might
well be mitigated or arrested. This is the promise that may accrue to
THC and CBD from the research of Hampson et al. (1998) in their dem-
onstration that these agents are capable of blocking NMDA receptors in
glutamate toxicity.
Cardiovascular Effects
A pioneering study in 1968 documented transient tachycardia and
hypertension induced by THC in experimental subjects (Weil, Zinberg,
and Nelsen 1968). Overall however, a mild hypotensive effect of CBD
is observed (Adams et al. 1977). Recently, concerns have been raised
with respect to cannabis as an inciting influence in myocardial infarc-
tion (Mittleman et al. 2001), but no significant epidemiological basis is
evident for such claims (Sidney et al. 1997).
Appetite/Gastrointestinal
The appetite stimulating power of cannabis and THC are among the
most well known effects (or side effects). This phenomenon was first
documented in the West by the physician and explorer, Garcia da Orta,
in India in the 16th century (da Orta 1913), but repeatedly studied sub-
sequently. It was this effect that led to an approved indication for THC
(as Marinol®) in the USA in 1992. Recently, smoked cannabis and THC
demonstrated benefits in appetite and weight gain in hospitalized AIDS
subjects (Abrams et al. 2002).
THC slows gut motility (reviewed in Pertwee 2001), providing addi-
tional support to the known analgesic and anti-inflammatory benefits in
such disorders as Crohn’s disease, ulcerative colitis, and idiopathic
bowel syndrome (spastic colon).
Ethan Russo 21
A much better understanding of the critical role of tonic endocanna-
binoid function in normal ontogeny has recently been elucidated when
Ester Fride and colleagues investigated the role of anandamide in initia-
tion of neonatal feeding, and inevitable demise with its blockade (Fride
2002). Therapeutic use in “failure-to-thrive” states and cystic fibrosis
(Fride 2002) are obvious putative applications.
Anti-Carcinogenesis
Whereas, governmental pronouncements have long sought to indict
marijuana and THC as contributors to the incidence of cancer, closer
analysis has failed to demonstrate epidemiological support for signifi-
cant danger, even with smoked cannabis (Ware and Tawfik 2001). Lit-
tle publicity, in contrast, has accrued to an increasing number of studies
that demonstrate anti-carcinogenesis by THC.
Legitimate concerns surround the use of smoked cannabis, and its
contribution to pulmonary irritation, bronchitis symptoms, and possible
neoplastic sequelae (Tashkin 2001). However, recent study indicates
that THC and even cannabis smoke block the activity of a key enzyme
in pulmonary carcinogenesis (Roth et al. 2001), perhaps explaining the
observation that there are still no documented cases of lung cancer in
cannabis-only smokers.
THC also has been demonstrated to promote apoptosis (programmed
cell death) in malignant conditions including: leukemia (McKallip et al.
2002) via CB2stimulation, gliomas (Sanchez et al. 1998), and mela-
noma (Casanova et al. 2003), in which tumor angiogenesis is also inhib-
ited. Additionally, two types of breast tumor cell lines were inhibited by
THC (De Petrocellis et al. 1998), apparently via prolactin receptor ef-
fects. This is obviously a fertile area for further research.
Pulmonary
As noted above, the primary medical concerns about cannabis re-
volve around its pulmonary sequelae. It requires emphasis that these
may be totally avoided through alternative delivery techniques. That
notwithstanding, it seems that emphysematous deterioration, even in
cannabis smokers, is a lower risk than previously surmised (Tashkin et
al. 1997). Actual therapeutic application of THC in asthma, as previ-
ously attempted (Tashkin et al. 1977; Williams, Hartley, and Graham
1976), may soon become a reality with improved vaporizers or CBME
applications.
22 CANNABIS: FROM PARIAH TO PRESCRIPTION
Ophthalmological
The ability of cannabis and THC to lower intra-ocular pressure in
glaucoma was serendipitously discovered in the late 1970s by a variety
of patients and researchers (Randall and O’Leary 1998; Merritt et al.
1980). What is more compelling perhaps, in the long run, is the fact that
there is more to glaucoma treatment than merely controlling pressure.
Even effective management with conventional pharmacology fails to
avert visual loss over time. Rather, an emerging concept supports that
prospect that glaucoma represents a progressive vascular retinopathy
that requires a neuroprotectant to preserve vision (Jarvinen, Pate, and
Laine 2002). This is an area where cannabis and cannabinoids shine.
As will be discussed in the final entry in this publication, cannabis
and cannabinoids also seem to have a role in improving night vision and
in treatment of other degenerative eye conditions (Russo et al. 2003).
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... ch as Cannabis Culture or High Times, or via the Inter- net to those who live in jurisdictions where this endeavor is legal. Outdoor, indoor, or hydroponic techniques are possible. Recent reviews outline good agricultural practice in cultivation of cannabis (Anonymous, 2003), its hus- bandry for medical usage in an industrial setting (Potter, 2004;E. B. Russo, 2003), and a primer on cannabis genet- ics (E. P. de Meijer et a]., 2003). Emphasis should focus on potent medicinal strains, scrupulous organic cultivation of female plants, clonal selection and augmentation, and appropriate processing, all combined with best available techniques of harm reduction. ...
... Further data on the raising of the plant material through application of Mendelian genetics are available (E. de Meijer, 2004; E. P. de Meijer et al., 2003), as is further information on its organic husbandry (Potter, 2003;E. B. Russo. 2003), processing with supercritical carbon dioxide extraction and production of cannabis-based med- icine extracts (CBME;E. B. Russo, 2003;Whittle, Guy, & Robson, 2003). ...
... data on the raising of the plant material through application of Mendelian genetics are available (E. de Meijer, 2004; E. P. de Meijer et al., 2003), as is further information on its organic husbandry (Potter, 2003;E. B. Russo. 2003), processing with supercritical carbon dioxide extraction and production of cannabis-based med- icine extracts (CBME;E. B. Russo, 2003;Whittle, Guy, & Robson, 2003). ...
Chapter
Full-text available
The herb cannabis is derived from the Old World species Cannabis sativa L. Cannabis indica and C. ruderalis may also merit species status. Cannabis has a history as an analgesic agent that spans at least 4000 years, including a century of usage in mainstream Western medicine. Quality control issues, and ultimately political fiat eliminated this agent from the modern pharmacopoeia, but it is now resurgent. The reasons lie in the remarkable pharmacological properties of the herb and new scientific research that reveals the inextricable link that cannabinoids possess with our own internal biochemistry. In essence, the cannabinoids form a system in parallel with that of the endogenous opioids in modulating pain. More important, cannabis and its endogenous and synthetic counterparts may be uniquely effective in pain syndromes in which opiates and other analgesics fail.
... The lobby to decriminalise cannabis for medicinal purpose because of its asserted capacity to heal and relieve pain has a lengthy history (see Joy and Mack 2000;Booth 2003;Backes 2014;Wedman-St Louis 2019;Younger 2018;Bridgeman 2017;Freckelton 2016aFreckelton , 2016bRusso 2003). Latterly, in Australia the Victorian Law Reform Commission (2015) recommended a scheme for the legalisation of a closely regulated scheme for cultivation and manufacture of cannabis products for medicinal use. ...
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This article situates the movement for the legalisation of medicinal cannabis within the bigger picture of the impetus toward recreational cannabis legalisation. It describes the role played by children with epileptic syndromes in the medicinal cannabis law reform campaigns in the United Kingdom, and Queensland, New South Wales and Victoria in Australia. Noting the ‘rule of rescue’ and the prominence in media campaigns of children in Australian and English cases of parental disputation with clinicians about treatment for their children, it reviews whether paediatric epilepsy is a suitable test case for the legalisation of medicinal cannabis. Taking into account the vested commercial interests of Big Cannabis, the current medico-scientific knowledge of the efficacy of medicinal cannabis in controlling paediatric epileptic seizures, and issues of dignity, health privacy, and the enduring digital footprints of media coverage, the article commences discussion about the ethics of the media, parents, politicians and entrepreneurial doctors utilising parents’ testimonials about the effects of medicinal cannabis as part of the cannabis law reform movement.
... Despite legal repudiations of the therapeutic benefits of 'cannabis', the resurgence in the last two decades of organized 'medical marijuana' movements in Canada, the United States, Israel, New Zealand, the United Kingdom and in many parts of Europe (Lee, 2012) has done much to transform the object-materialities of 'cannabis'. Principal among these changes has been the rapid proliferation of 'cannabis' products, transforming both the drug itself, along with the ways it may be ingested (Russo, 2013). Notably, a pharmaceutical formulation of tetrahydrocannabinol (THC), with the generic name of dronabinol, has been available under prescription throughout North America and Europe for some time (Holland, 2010). ...
Chapter
Drawing from the Actor-Network-Theory of John Law and Bruno Latour, this chapter departs from ‘common-sense’ accounts of the ontological identity of drugs such as cannabis to explore the myriad relations in which cannabis is enacted. Alert to the ontological contingency of cannabis, the chapter exposes the heterogeneity of the drug, its divergent natures, cultures and materialities. I argue that cannabis should not be regarded as a stable, singular entity, given the diversity of relations, practices, semiotic registers and political squabbles in which the drug is produced as an object of knowledge and practice. The ‘object-materialities’ at work in the production of cannabis effectively distribute the drug across the three ontological registers commonly used to differentiate psychoactive substances: medicine, non-drug and drug. Cannabis is constituted as medicine in debates regarding ‘medical marijuana’, as a non-drug in cultures and practices indicative of the normalisation of cannabis, and finally as a drug in statutes prohibiting ‘cannabis’ use, and the biomedical research which legitimizes this prohibition. I close by assessing some of the policy and research implications of this divergence, offering an approach to cannabis more accommodating of its ontological proliferations.
... What is more, CBD inhibits uptake of the endocannabinoid anandamide (AEA), and weakly inhibits its hydrolysis. The presence of this component in available cannabis based medicine extracts portends to vastly extend the clinical applications and therapeutic efficacy of this re-emerging modality [118][119][120]. ...
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Full-text available
OBJECTIVES: This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis. METHODS: Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources. RESULTS: Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging. CONCLUSION: Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.
... What is more, CBD inhibits uptake of the endocannabinoid anandamide (AEA), and weakly inhibits its hydrolysis. The presence of this component in available cannabis based medicine extracts portends to vastly extend the clinical applications and therapeutic efficacy of this re-emerging modality [118][119][120]. ...
... What is more, CBD inhibits uptake of the endocannabinoid anandamide (AEA), and weakly inhibits its hydrolysis. The presence of this component in available cannabis based medicine extracts portends to vastly extend the clinical applications and therapeutic efficacy of this re-emerging modality [118][119][120]. ...
... What is more, CBD inhibits uptake of the endocannabinoid anandamide (AEA), and weakly inhibits its hydrolysis. The presence of this component in available cannabis based medicine extracts portends to vastly extend the clinical applications and therapeutic efficacy of this re-emerging modality [118][119][120]. ...
Data
Full-text available
OBJECTIVES: This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis. METHODS: Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources. RESULTS: Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging. CONCLUSION: Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.
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Cannabis is the most widely used illicit substance, especially among young people. Cannabis use is extremely commonplace and frequently comorbid with psychiatric disorders that raise questions about the etiology. The use of cannabis is an aggravating factor of all psychiatric disorders. Psychiatric complications are related to the age of onset, duration of exposure and individual risk factors of the individual (mental and social health). The panic attack is the most common complication. The link with psychosis is narrow that leads to increased prevention for vulnerable populations. Cannabis is also an indicator of increased depressive vulnerability and an aggravating factor for bipolar disorder.
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Full-text available
Objective To establish whether cannabis is an effective and safe treatment option in the management of pain. Design Systematic review of randomised controlled trials. Data sources Electronic databases Medline, Embase, Oxford Pain Database, and Cochrane Library; references from identified papers; hand searches. Study selection Trials of cannabis given by any route of administration (experimental intervention) with any analgesic or placebo (control intervention) in patients with acute, chronic non-malignant, or cancer pain. Outcomes examined were pain intensity scores, pain relief scores, and adverse effects. Validity of trials was assessed independently with the Oxford score. Data extraction Independent data extraction; discrepancies resolved by consensus. Data synthesis 20 randomised controlled trials were identified, 11 of which were excluded. Of the 9 included trials (222 patients), 5 trials related to cancer pain, 2 to chronic non-malignant pain, and 2 to acute postoperative pain. No randomised controlled trials evaluated cannabis; all tested active substances were cannabinoids. Oral delta-9-tetrahydrocannabinol (THC) 5-20 mg, an oral synthetic nitrogen analogue of THC 1 mg, and intramuscular levonantradol 1.5-3 mg were about as effective as codeine 50-120 mg, and oral benzopyranoperidine 2-4 mg was less effective than codeine 60-120 mg and no better than placebo. Adverse effects, most often psychotropic, were common.
Article
The antinociceptive effects of various mu opioids given p.o. alone and in combination with Delta-9-tetrahydrocannabinol (Delta(9)-THC) were evaluated using the tail-flick test. Morphine preceded by Delta(9)-THC treatment (20 mg/kg) was significantly more potent than morphine alone, with an ED50 shift from 28.8 to 13.1 mg/kg. Codeine showed the greatest shift in ED,, value when administered after Delta(9)-IHC (139.9 to 5.9 mg/kg). The dose-response curves for oxymorphone acid hydromorphone were shifted 5- and 12.6-fold, respectively. Methadone was enhanced 4-fold, whereas its derivative, I-alpha-acetylmethadol, was enhanced 3-fold. The potency ratios after pretreatment with Delta(9)-THC for heroin and meperidine indicated significant enhancement (4.1 and 8.9, respectively). Pentazocine did not show a parallel shift in its dose-response curve with Delta(9)-THC. Naloxone administration (1 mg/kg s.c.) completely blocked the antinociceptive effects of morphine p.o. and codeine p.o. The Delta(9)-THC-induced enhancement of morphine and codeine was also significantly decreased by naloxone administration. Naltrindole (2 mg/kg s.c.) did not affect morphine or codeine antinociception but did block the enhancement of these two opioids by Delta(9)-THC. No effect was seen when nor-binaltorphimine was administered 2 mg/kg s.c. before morphine or codeine. Furthermore, the enhancements of morphine and codeine were not blocked by nor-binaltorphimine. We find that many mu opioids are enhanced by an inactive dose of Delta(9)-THC p.o. The exact nature of this enhancement is unknown. We show evidence of involvement of mu and possibly delta opioid receptors as a portion of this signaling pathway that leads to a decrease in pain perception.
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Induction of the carcinogen-metabolizing enzyme cytochrome P4501A1 (CYP1A1) is a key step in the development of tobacco-related cancers. To determine if marijuana smoke activates CYP1A1, a murine hepatoma cell line expressing an inducible CYP1A1 gene (Hepa-1) was exposed in vitro to tar extracts prepared from either tobacco, marijuana, or placebo marijuana cigarettes. Marijuana tar induced higher levels of CYP1A1 messenger RNA (mRNA) than did tobacco tar, yet resulted in much lower CYP1A1 enzyme activity. These differences between marijuana and tobacco were primarily due to Delta (9)-tetrahydrocannabinol (Delta (9)-THC), the psychoactive component of marijuana. Here we show that Delta (9)-THC acts through the aryl hydrocarbon receptor complex to activate transcription of CYP1A1. A 2-mug/ml concentration of Delta (9)-THC produced an average 2.5-fold induction of CYP1A1 mRNA, whereas a 10-mug/ml concentration of Delta (9)-THC produced a 4.3-fold induction. No induction was observed in Hepa-1 mutants lacking functional aryl-hydrocarbon receptor or aryl-hydrocarbon receptor nuclear translocator genes. At the same time, Delta (9)-THC competitively inhibited the CYP1A1 enzyme, reducing its ability to metabolize other substrates. Spiking tobacco tar with Delta (9)-THC resulted in a dose-dependent decrease in the ability to generate CYP1A1 enzyme activity as measured by the ethoxyresorufin-o-deethylase (EROD) assay. This inhibitory effect was confirmed by Michaelis-Menton kinetic analyses using recombinant human CYP1A1 enzyme expressed in insect microsomes. This complex regulation of CYP1A1 by marijuana smoke and the Delta (9)-THC that it contains has implications for the role of marijuana as a cancer risk factor.
Article
Background: Preliminary studies suggested that delta-9-tetrahydrocannabinol (THC), the major psychoactive ingredient of Cannabis sativa L., might be effective in the treatment of Tourette syndrome (TS). This study was performed to investigate for the first time under controlled conditions, over a longer-term treatment period, whether THC is effective and safe in reducing tics in TS. Method: In this randomized, double-blind, placebo-controlled study, 24 patients with TS, according to DSM-III-R criteria, were treated over a 6-week period with up to 10 mg/day of THC. Tics were rated at 6 visits (visit 1, baseline; visits 2-4, during treatment period; visits 5-6, after withdrawal of medication) using the Tourette Syndrome Clinical Global Impressions scale (TS-CGI), the Shapiro Tourette- Syndrome Severity Scale (STSSS), the Yale Global Tic Severity Scale (YGTSS), the self-rated Tourette Syndrome Symptom List (TSSL), and a videotape-based rating scale. Results: Seven patients dropped out of the study or had to be excluded, but only 1 due to side effects. Using the TS-CGI, STSSS, YGTSS, and video rating scale, we found a significant difference (p < .05) or a trend toward a significant difference (p < .05) between THC and placebo groups at visits 2, 3, and/or 4. Using the TSSL at 10 treatment days (between days 16 and 41) there was a significant difference (p < .05) between both groups. ANOVA as well demonstrated a significant difference (p = .037). No serious adverse effects occurred. Conclusion: Our results provide more evidence that THC is effective and safe in the treatment of tics. It, therefore, can be hypothesized that the central cannabinoid receptor system might play a role in TS pathology.
Article
EDITOR—Campbell et al's paper on whether cannabinoids are effective and safe in the management of pain purports to be qualitative and systematic,1 but it is neither. Because it focused on two clinically questionable synthetic cannabinoids and oral delta-9-tetrahydrocannabinol (THC) without providing any focus on the synergistic components of herbal cannabis, and examined only certain facets of the broad topic of pain, it ensured that a conclusion of limited efficacy was reached. That is not news. What is surprising, in contrast, is that the authors chose to broaden the alleged impact of their limited investigation to relegate the use of cannabis and cannabinoids to a back seat in future analgesic applications. This contention is not supported by their limited data. I see nothing published about pioneering British doctors and their clinical successes with cannabis extracts in a myriad of painful conditions between 1840 and 1940.2-4 I see virtually nothing of modern scientific studies showing the multifactorial benefits of cannabis on a range of neurotransmitter systems, which I have reviewed.5 No mention is made of bureaucratic and political obstructions to clinical research into cannabis; one cannot show results when the requisite studies are not permitted. Thus until recently we have been left with an overwhelming (but ignored) body of anecdotal evidence from patients and their doctors. What is truly newsworthy here is that the BMJ has ignored peer review and editorial standards in a scandalous manner. The popular media have seized the opportunity, and in the process valuable laboratory and clinical research, and their funding, in analgesia and pain control have been severely compromised. Great shame accrues to the journal as a result. Instead of probity we have propaganda. Footnotes Competing interests Professor Russo has been a scientific adviser to GW Pharmaceuticals (a manufacturer of cannabis-based medicine extracts), which has reimbursed expenses for travel with regard to visits and clinical research. He is also the editor in chief of Journal of Cannabis Therapeutics.
Article
Objective: To review the feasibility and effectiveness of n-of-1 randomized controlled trials (n-of-1 trials) in clinical practice. Design: Individual trials were double-blind, randomized, multiple crossover trials. The impact of n-of-1 trials was determined by eliciting physicians' plans of management and confidence in those plans before and after each trial. Setting: Referral service doing n-of-1 trials at the requests of community and academic physicians. Object of Analysis: All trials were planned, started, and completed by the n-of-1 service. Measures of Outcome: The proportion of planned n-of-1 trials that were completed and the proportion that provided a definite clinical or statistical answer. A definite clinical answer was achieved if an n-of-1 trial resulted in a high level of physician's confidence in the management plan. Specific criteria were developed for classifying an n-of-1 trial as providing a definite statistical answer. Main Results: Seventy-three n-of-1 trials were planned in various clinical situations. Of 70 n-of-1 trials begun, 57 were completed. The reasons for not completing n-of-1 trials were patients' or physicians' noncompliance or patients' concurrent illness. Of 57 n-of-1 trials completed, 50 provided a definite clinical or statistical answer. In 15 trials (39% of trials in which appropriate data were available), the results prompted physicians to change their "prior to the trial" plan of management (in 11 trials, the physicians stopped the drug therapy that they had planned to continue indefinitely). Conclusion: We interpret the results as supporting the feasibility and usefulness of n-of-1 trials in clinical practice.