![Effects of tetrahydrocannabinol (THC) and cannabidiol (CBD), adapted and updated from Russo 2003 [52] ([13,14,17,20,21,33,36,40,42,51,55,61,73,78,79,81,82,85,89-91,98,99,104-109,111-119]).](https://www.researchgate.net/profile/Ethan-Russo/publication/7555534/figure/fig2/AS:559527604625408@1510413184442/Effects-of-tetrahydrocannabinol-THC-and-cannabidiol-CBD-adapted-and-updated-from_Q320.jpg)
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A tale of two cannabinoids:
The therapeutic rationale for combining
tetrahydrocannabinol and cannabidiol
Ethan Russo
a,b,c,
*, Geoffrey W. Guy
a
a
GW Pharmaceuticals, Porton Down Science Park, Salisbury, Wiltshire SP4 0JQ, UK
b
University of Washington School of Medicine, Seattle, WA, USA
c
University of Montana Department of Pharmaceutical Sciences, MT, USA
Received 15 August 2005; accepted 18 August 2005
Summary This study examines the current knowledge of physiological and clinical effects of tetrahydrocannabinol
(THC) and cannabidiol (CBD) and presents a rationale for their combination in pharmaceutical preparations.
Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are explored, such as the capability of
THC and CBD to act as anti-inflammatory substances independent of cyclo-oxygenase (COX) inhibition. CBD is
demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while
contributing analgesic, anti-emetic, and anti-carcinogenic properties in its own right. In modern clinical trials, this has
permitted the administration of higher doses of THC, providing evidence for clinical efficacy and safety for cannabis
based extracts in treatment of spasticity, central pain and lower urinary tract symptoms in multiple sclerosis, as well
as sleep disturbances, peripheral neuropathic pain, brachial plexus avulsion symptoms, rheumatoid arthritis and
intractable cancer pain. Prospects for future application of whole cannabis extracts in neuroprotection, drug
dependency, and neoplastic disorders are further examined. The hypothesis that the combination of THC and CBD
increases clinical efficacy while reducing adverse events is supported.
c2005 Elsevier Ltd. All rights reserved.
Introduction
Cannabinoids refer to a heteromorphic group of
molecules that demonstrate activity upon cannab-
inoid receptors and are characterised by three vari-
eties: endogenous or endocannabinoids, synthetic
cannabinoids, and phytocannabinoids, which are
natural terpenophenolic compounds derived from
Cannabis spp.
In recent years, scientists have provided eluci-
dation of the mechanisms of action of cannabis
and THC with the discovery of an endocannabinoid
ligand, arachidonylethanolamide, nicknamed anan-
damide, from the Sanskrit word ananda, or ‘‘bliss’’
[1]. Anandamide inhibits cyclic AMP mediated
through G-protein coupling in target cells. Early
0306-9877/$ - see front matter
c2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2005.08.026
*Corresponding author. Present address. 2235 Wylie Avenue,
Missoula, MT 59802, USA. Tel.: +1 406 542 0151; fax: +1 406 542
0158.
E-mail addresses: erusso@gwpharm.com,erusso@monta-
nadsl.net (E. Russo).
Medical Hypotheses (2006) 66, 234–246
http://intl.elsevierhealth.com/journals/mehy
testing of its pharmacological action and behav-
ioural activity indicate similarity to THC [2], and
both are partial agonists on the CB
1
receptor. Per-
twee [3] has examined the pharmacology of can-
nabinoid receptors in detail. CB
1
receptors are
most densely demonstrated in the central nervous
system, especially in areas subserving nocicecp-
tion, short-term memory, and basal ganglia, but
are also found in the peripheral nerves, uterus, tes-
tis, bones and most body tissues. CB
2
receptors, in
contrast, are mostly found in the periphery, often
in conjunction with immune cells, but may appear
in the CNS particularly under conditions of inflam-
mation in association with microcytes. Additional
non-CB
1
and non-CB
2
receptors in endothelial and
other tissues are hypothesised [4], but not yet
cloned. Further research has elucidated analgesic
mechanisms of cannabinoids, which include effects
on numerous neurotransmitter systems and inter-
actions with the endogenous opioid system.
This paper will focus on the biochemical and
clinical effects of two phytocannabinoids, D
9
-
tetrahydrocannabinol (THC) (Fig. 1), the main
psychoactive component of cannabis, and its
non-psychoactive but highly physiologically relevant
isomer, cannabidiol (CBD) (Fig. 1). While it was orig-
inally thought that CBD was the metabolic parent to
THC in the cannabis plant, rather, they are both bio-
synthesised as THCA and CBDA from a cannabigerolic
acid precursor (Fig. 2) according to genetically
determined ratios [5], and then decarboxylated by
heat or extraction to produce THC and CBD proper.
It is interesting to note that the phytocannabinoids
can be considered as half-siblings to the essential
oil terpenoids with which they share a geranyl pyro-
phosphate precursor in the glandular trichomes of
the plant where they are produced. It is felt by some
authorities that these terpenoids share important
modulatory and pharmacological effects with trace
cannabinoids [6] in an elegant ‘entourage effect’
[7] that may account for synergistic activity of can-
nabis extracts over that of isolated components.
Therapeutic benefits are thus added, whilst some ad-
verse effects are attenuated. In this regard, Carlini
[8] determined that cannabis extracts produced ef-
fects two or four times greater than that expected
from their THC content, based on animal and human
studies. Similarly, Fairbairn and Pickens [9] detected
the presence of unidentified ‘powerful synergists’ in
cannabis extracts, causing 330% greater activity in
mice than THC alone. An unidentified component
of the plant (perhaps linalool?) also showed anticon-
vulsant properties of equal potency to cannabinoids
[10]. Finally, although anecdotal to some degree,
extensive surveys in the USA comparing patients’
subjective responses with synthetic THC as Marinol
â
supports a preference for whole cannabis products
[11]. In most instances, synthetic THC is considered
by patients to be more productive of intoxicating
and sedative adverse effects [12], characterised by
the authors as (p. 95), ‘dysphoric and unappealing’.
The effects of THC are well known, and include
analgesia, intoxication, short-term memory loss,
muscle relaxant and anti-inflammatory effects
[3,13] (summarised in Fig. 3, with corresponding
references).
The pharmacological profile of CBD has received
three recent excellent reviews [14,15]. Briefly sta-
ted, CBD has anti-anxiety actions [16], anti-psy-
chotic effects [17], modulates metabolism of THC
by blocking its conversion to the more psychoactive
11-hydroxy-THC [18], prevents glutamate excito-
toxicity, serves as a powerful anti-oxidant [19],
and has notable anti-inflammatory and immuno-
modulatory effects [20] (summarised in Fig. 3 with
corresponding references). Notably, CBD has re-
cently been shown to act as a TRPV1 agonist of po-
tency equivalent to capsaicin, while also inhibiting
reuptake of anandamide and its hydrolysis [21].
Thus, CBD may prove to be the first clinical
pharmaceutical to modulate endocannabinoid
function.
O
OH
delta-9-tetrah
y
drocannabinol (THC)
OH
OH
cannabidiol
Figure 1 Structures of THC and CBD.
A tale of two cannabinoids 235
The remainder of this paper will focus on the
interactions of the two compounds when adminis-
tered simultaneously and explore the theoretical
advantages of so doing in clinical application.
A review of animal studies of
simultaneously administered THC
and CBD
A great deal of the early research pertaining to inter-
actions of THC with other phytocannabinoids was
performed in Brazil in the 1970s. The seminal work
was that of Karniol and Carlini [22] who examined
various animal species with differing low-moderate
doses of THC and CBD administered IP. To summa-
rise, CBD blocked certain effects of THC: catatonia
in mice, corneal arreflexia in rabbits, increased def-
aecation and decreased ambulation in rats in the
open field after chronic administration, and aggres-
siveness in rats after REM-sleep deprivation. In con-
trast, CBD potentiated THC analgesia in mice and the
impairment of rope climbing in rats. The authors
hypothesised that CBD interacted via a dual mecha-
nism: potentiating the depressant effects of THC
while inhibiting its excitatory and emotional effects .
In an Australian study of oral dosing [23],the
‘abdominal constriction response’ to formic acid
in mice, CBD antagonised the analgesic effect of
THC. The pertinence of this model to current clin-
ical models in humans is unclear.
In a rat study with implanted brain electrodes
[24], CBD 20 mg/kg IP decreased slow-wave sleep
latency. The author posited a hypnotic effect,
but given the experimental setting, an analgesic
response may have been operative.
In a complex protocol assessing variable-inter-
val performance in rats after food deprivation
[25], the authors assessed that a ‘marijuana ex-
tract distillate’ depressed performance at most
levels of deprivation, but that IP CBD potentiates
that depression only at high levels of deprivation.
In subsequent related rat experiments [26], a 20-
fold CBD:THC ratio antagonised THC effects on
variable-interval performance, while fivefold ra-
tios seemed to potentiate THC effects. The impli-
cations for therapeutic usage in humans are not
clear from these data.
+
Geranylphosphate: olivetolate geranyltransferase
CBCA synthase THCA synthase CBDA synthase
Terpenoid synthases
Essential oils
OPP
geranyl pyrophosphate
HO
OH
COOH
canna bigero lic acid
O
O
H
COOH
cannab
i
ch
r
o
m
enen
i
c ac
i
d
O
OH
COOH
delta-9-tetrah
y
drocannabinolic acid
HO
OH
COOH
olivetolic acid (pentyl form)
OH
OH
COO H
canna b
i
d
i
o
l
i
c ac
i
d
Figure 2 Biosynthetic pathways of pentyl phytocannabinoids (adapted and revised from de Meijer et al. [5]).
236 Russo and Guy
An American group [27] implicated CBD as con-
tributing to mortality and seminiferous tubule
degeneration in an usual protocol employing smoke
exposure in rats to a Turkish cannabis strain. No
separation of CBD vs. CBC (cannabichromene) was
achieved, however. These results would not be
contrasted to the extremely low-level mortality
and histological changes seen in current animal
toxicity studies performed with cannabis based
medicine (CBM) combining THC and CBD [28].
In a study of rats trained to distinguish THC in a
T-maze [29], CBD 40 mg/kg prolonged running
time, but did not affect the animals’ choices. This
high dose was employed because (p. 140), ‘‘this
dose was the minimum capable of interfering with
the discriminative performance of rats that that re-
ceived 5 mg/kg D
9
-THC’’. This slowing of run time
also disappeared within 72 h.
In a recent study in rats [30], a CBD-rich extract
containing THC did not affect spatial working mem-
Effect THC CBD Refere nces
Receptor/Non-Receptor Effects
CB1 (CNS/PNS receptors)
CB2 (peripheral receptors
Vanilloid (TRPV1) receptors
Anti- infla mmatory
COX-1, COX-2 inhibition
Immunomodulator y
++
+
-
+
-
+
±
±
-
+
-
+
Pertwee (104)
Showalter (105)
Bisogno (21)
Hampson (73)
Stott (106)
Cabral (107),Malfait (20)
CNS Effects
Anticonv ulsa nt
Mus cle r ela xant
Antinociceptive
Psyc hotropic
Anxi ol yt ic
Antipsyc ho ti c
Neuroprotective antioxidant
Antie metic
Sedation
Agitation (Alzheimer disease)
Tic reduction (Tourette syndrome)
Opiate withdrawal reduction
Migraine treatment
Bipolar disease
Dysto nia
Parkinso nia n sympto ms
Withdrawal symptoms to other drugs (reduction)
Motor neurone disease (ALS) (increased survival, function)
+
++
++
++
±
-
+
++
+
+
+
+
+
+
+
+
+
++
+
+
-
++
++
++
+
-
-
?
?
+
?
+
?
+
+
Wallace (42), Carlini (40)
Collin (61)
Pertwee (13)
Russo (108)
Zuardi (109)
Zuardi (17), Moreira (78)
Hampson (73)
Parker (99)
Nicholson (55)
Volicer (79)
Müller-Vahl (111)
Cichewicz (91), De Vry
(36)
Russo (112)
Grinspoon (113)
Consroe (85)
Venderova (51)
Labigliani (89), Dreher
(90), De Vry (36)
Raman (81), Abood (82)
Cardiovascular Effe cts
Bradycardia
Tachycardia
Hypertension
Hypo tensi on
-
+
+
-
+
-
-
+
Weil (114)
Karniol (33)
Weil (114)
Batkai (115)
Appetite/Gastrointestinal
Appetite
GI motility (slowed)
+
++
-
+
Pertwee (14)
Pertwee (14)
Anti-Carcinogenesis
Glioma (apoptosis)
Glioma cell migration
+ +
+
Sanchez (116), Massi
(117)
Vaccani (98)
Ophthalmological
Intra-ocular pressure (reduced)
Night vision
++
+
+
-
Jarvinen (118)
Russo (119)
Figure 3 Effects of tetrahydrocannabinol (THC) and cannabidiol (CBD), adapted and updated from Russo 2003 [52]
([13,14,17,20,21,33,36,40,42,51,55,61,73,78,79,81,82,85,89–91,98,99,104–109,111–119]).
A tale of two cannabinoids 237
ory or short-term memory, even in doses up to
50 mg/kg.
A review of human studies of THC
and CBD simultaneously administered
Administration of CBD orally (up to 300 mg) and IV
(up to 30 mg) in volunteers were felt to be inactive
in early experiments [31], with similar conclusions
after IV infusion by another group [32].
In Brazil in 1974, effects of THC up to 30 mg and
CBD up to 60 mg orally were studied in varying ra-
tios in blinded fashion in 40 male subjects [33].
CBD at doses 15–60 mg evidenced few effects of
its own, but effectively countered effects of
30 mg of THC including tachycardia, disturbed time
tasks and strong psychological reactions. Interest-
ingly, with higher doses of THC (p. 175), ‘‘symp-
toms appeared in ‘waves’ during which the
subjects reported strong feelings of anxiety reach-
ing sometime a near panic state’’. (These com-
plaints are similar to those voiced by Marinol
â
patients currently when the dosage is not toler-
ated; perhaps enterohepatic circulation is opera-
tive.) With addition of CBD, the authors observed
(p. 176), ‘‘CBD also changed the symptoms in such
a way that the subjects receiving the mixtures
showed less anxiety and panic but reported more
pleasurable effects’’. Unfortunately, this state-
ment was interpreted in context by the anonymous
author(s) of a US Federal Register article [34] (p.
20065) as follows, ‘‘Most importantly, CBD appears
to potentiate the euphorigenic and reinforcing ef-
fects of THC which suggests that the interaction
between THC and CBD is synergistic and may actu-
ally contribute to the abuse of marijuana’’. This
contention is unsupported by any of the cited liter-
ature. Furthermore, as the context of the discus-
sion pertains to smoked cannabis in the USA, it is
impertinent, as North American drug strains of can-
nabis are virtually devoid of CBD-content [35].No
epidemiological data are evident in any of the
world’s literature that supports the allegation that
the presence of CBD contributes or promotes can-
nabis abuse. In fact, the neutral antagonism of
CB
1
receptors by CBD should actually reduce risk
of development of tolerance [36] (vide infra).
In 1975, Hollister and Gillespie [37] noted very
little THC–CBD interaction clinically in humans,
except for a delayed onset and prolongation of
THC effects that was so slight as to be felt negligi-
ble by the authors, who actually suggested it
appropriate to ignore the CBD content of test
cannabis.
In a test of smoked placebo cannabis with or
with THC and a sixfold higher dose of CBD [38],
the ‘high’ of THC was significantly attenuated
when CBD was present: 11/15 subjects felt the ef-
fects of THC alone as greater than the
combination.
In a similar protocol [39], co-administration of
smoked CBD with THC attenuated THC effects
including tachycardia, impairment on stance stabil-
ity on a wobble board, and ability to track on a pur-
suit meter.
In 1981, cannabidiol was tested as an anticonvul-
sant in Brazil [40]. Fifteen patients with frequent
attacks of unresponsive ‘secondarily generalized
epilepsy’ (seizures of partial onset with secondary
generalisation), aged 14–49, were treated with
CBD vs. placebo in double-blind fashion. Three of
eight treated patients had complete seizure con-
trol with 200 mg of CBD per day, and a fourth with
300 mg per day. One was improving, but was
unavailable for follow-up. One other was markedly
improved, two somewhat, and one not at all. Nei-
ther laboratory changes, nor major adverse effects
were noted; merely some somnolence in four sub-
jects. The latter has been misinterpreted in much
subsequent literature to support a sedative prop-
erty of CBD.
As, subsequent recent work has confirmed pow-
erful anticonvulsant effects of THC and the key
role of the endocannabinoid system in regulating
seizure thresholds [41,42], it is logical to think that
THC:CBD combinations may produce effective
anticonvulsants.
Additional clinical experimentation in normal
subjects [16], THC provoked anxiety that was
antagonised by concomitant CBD administration.
When given alone, subjective assessments of CBD
effects included such terms (p. 249) as, ‘quick wit-
ted’ and ‘clear minded’.
Modern clinical trials of cannabis
extracts containing THC and CBD
Cannador
A recent small clinical trial of THC and an oral can-
nabis extract (Cannador) was performed with 16
subjects. Neither was observed to reduce spastic-
ity, and adverse events were reported as greater
in the extract group even at low dosages [43].
Numerous criticisms were subsequently voiced in
this regard [44] such that the plant extract was
poorly categorised, and employed sub-optimal oral
administration with no real dose titration. An
238 Russo and Guy
additional study in Switzerland [45] with more pa-
tients and doses of up to 15 mg THC with 6 mg
CBD equivalent PO divided did provided better re-
sults with reduction in spasms (p< 0.05) and no sig-
nificant side effects vs. placebo.
A British group examined 667 MS patients taking
placebo, Marinol
â
(synthetic THC) or Cannador
capsules over 15 weeks, with daily doses up to
25 mg THC equivalent (CAMS Study) [46]. While
no change was seen in Ashworth Scales, improve-
ment was observed on 10 m walking time, and
subjective pain and spasticity (p= 0.003). Interest-
ingly, fewer relapses were noted in the Cannador
group during the study course, suggesting possible
neuroprotective effects. Data from the same
cohort were assessed for benefit on tremor, but no
treatment benefit was observed [47]. In follow-up
after one year, however, improvement was noted
in spasticity for Marinol, but not Cannador [48].
In a recent review, it was suggested that this result
points to THC as the active component and even
that CBD detracts from therapeutic benefit [49].
Further data presented below will possibly support
a different conclusion.
Cannador has also been assessed in treatment
of parkinsonian dyskinesia, but without benefit
in a four-week trial [50]. Better results were re-
ported in a Czech survey study of Parkinson dis-
ease in which oral herbal cannabis with no
analysis of cannabinoid content was taken for
longer periods of time with improvement in mul-
tiple symptoms [51].
Cannador is an ethanolic extract that has not
been particularly well characterised as to compo-
nents or pharmacokinetics in published sources.
Although labelled as ‘standardised’, clear variation
in cannabinoid content has been reported in avail-
able studies with THC:CBD ratios noted as 2.5:0.9
[45], unspecified [43], or 2.5:1.25 = 2:1[46,50],or
just 2.5 mg of THC with no mention of CBD [47].
It is supplied as oral gelatine capsules in oil.
Experience with oromucosal cannabis
based medicines
Sativex
â
is a highly standardised medicinal product
composed of liquid carbon dioxide extracts from
selected strains of cloned cannabis plants culti-
vated employing Good Agricultural Practice
(GAP), to provide high and reproducible yields of
THC and CBD. Sativex is a 1:1 combination from
two clonal cannabis cultivars yielding a high THC
extract (Tetranabinex
â
) and a high CBD extract
(Nabidiolex
â
). The dried of unfertilised female
flowers are extracted and refined utilising Good
Manufacturing Practice (GMP) produce a botanical
drug substance (BDS) of defined composition with
controlled reproducibility batch to batch. THC
and CBD comprise some 70% (w/w) of the total
BDS, with minor cannabinoids (5–6%), terpenoids
(6–7%, most GRAS (Generally Recognized as Safe)),
sterols (6%), triglycerides, alkanes, squalene,
tocopherol, carotenoids and other minor compo-
nents (also GRAS) derived from the plant material.
BDS is formulated into a spray for oromucosal
administration with each 100 lL pump-action spray
providing 2.7 mg of THC and 2.5 mg of CBD, the
minor components, plus ethanol:propylene glycol
excipients, and 0.05% peppermint as flavouring
[52].
Extensive pharmacokinetic and pharmacody-
namic studies have been undertaken with the three
extracts in normal volunteers. Pertinent observa-
tions comparing extracts in context include the
following:
(1) The preparation has onset of activity in 15–
40 min, which allows patients to titrate dosing
requirements according to symptoms, with a
very acceptable profile of adverse events.
(2) When CBD and THC extracts were co-adminis-
tered as sublingual drops, the rate of appear-
ance of THC in serum was marginally
increased possibly suggesting a stimulation
of THC absorption [53].
(3) The appearance of 11-OH–THC was reduced
when CBD was co-administered with THC
extracts [53].
(4) THC T
max
was later following the 1:1 mixture
as compared to high-THC possibly due to CBD
delaying THC absorption [54].
Observations (2) and (4) may appear contradic-
tory, but the findings are unlikely to have great
clinical significance. While patients differed,
sometimes markedly, in pharmacokinetic values,
especially with respect to cannabidiol, in all in-
stances, reliable serum levels of THC and CBD
were produced via the oromucosal route.
In a Phase I study of sleep and cognitive ef-
fects in eight normal volunteers [55], the
THC:CBD 1:1 combination produced less sedation
than THC-predominant extract and rather, some
alerting properties. Although memory impairment
was noted the following day after 15 mg THC ex-
tract, none was apparent with concomitant
administration of CBD. The 1:1 mixture produced
therapeutic advantages over effects seen with
single components, as CBD counteracted residual
effects of THC on daytime sleep latencies and
memory.
A tale of two cannabinoids 239
In a subsequent Phase II clinical trial in 20 patients
with intractable neurogenic symptoms [56], signifi-
cant improvements (all p< 0.05) were seen as fol-
lows: THC- and CBD-predominant extracts on pain
(especially neuropathic), THC- and 1:1 extracts on
spasm, THC extract on spasticity, THC extract on
appetite, and 1:1 extract on sleep. Post-hoc analysis
revealed that overall symptom control was best with
THC:CBD 1:1 (p< 0.0001), and in a subset of patients
with MS (p< 0.0002), and intoxication was less than
with THC-predominant extract.
In another Phase II study of intractable chronic
pain [57], in 24 subjects who did not employ rescue
medication, visual analogue scales (VAS) were 5.9
for placebo, 5.45 for CBD, 4.63 for THC and 4.4
for 1:1 THC:CBD extracts (p< 0.001). Sleep was
also most improved on the latter (p< 0.001). Of
28 subjects, 11 preferred THC:CBD overall, while
14 found THC and THC:CBD equally satisfactory.
Once more, for pain in the MS patients, THC:CBD
produced best results (p< 0.0042).
In a Phase II, open label study of THC-predomi-
nant and 1:1 THC:CBD extracts vs. placebo in pa-
tients with intractable lower urinary tract
symptoms, both active groups had significant
improvement in urgency, cumber and volume of
incontinence episodes, frequency, nocturia, daily
total void volume, catheterised and urinary incon-
tinence pad weights [58].
Once again, in a Phase III study of intractable
pain associated with brachial plexus injury [59],
roughly equivalent benefits were noted in Box
Scale-11 pain scores with THC-predominant
(p= 0.002) and THC:CBD 1:1 extracts (p= 0.005).
On the basis of these results with oromucosal
cannabis based medicines, Professor Carlini has
stated [60] (p. 463), ‘However, any possible doubts
that might exist on whether or not D
9
-THC is an
useful medicine for MS symptoms, were removed
by the results obtained in four very recent random-
ized, double-blind, placebo-controlled trials’.
In a study of 189 subjects with clinically defi-
nite MS with associated spasticity from 12 Euro-
pean centres, patients were randomised 2:1 to
receive self-titrated daily doses of THC:CBD 1:1
(N= 124) or placebo (N= 65) in a double blind
trial of eight weeks duration [61]. The THC:CBD
oromucosal cannabis based medicine produced
statistically significant objective benefit on spas-
ticity on Motricity Index of lower extremities,
as well as subjective improvement in NRS mea-
sures of spasticity, and responder analysis with
a very acceptable adverse event profile compared
to placebo.
In a controlled double-blind clinical trial of
intractable central neuropathic pain [62],66MS
subjects showed mean Numerical Rating Scale
(NRS) analgesia favouring THC:CBD 1:1 extract over
placebo (p= 0.009), with sleep disturbances scores
also positive (p= 0.003). There were no major
changes in neuropsychological test measures vs.
placebo. In marked contrast, results in two articles
examining Marinol in central or peripheral neuro-
pathic pain with oral doses up to 25 mg revealed
no clear benefit on pain or allodynia, and with poor
tolerance to adverse events [63,64]. A study of two
subjects with similar doses for 2–5 years showed
initial decrements in pain, but with unsustained
temporal improvement [65]. Better results were
seen in a Swedish study [66], limiting Marinol doses
to 10 mg/d in 24 subjects with central neuropathic
pain due to MS. Median numerical pain scale in final
week favoured Marinol (p= 0.02), as did median
pain relief (p= 0.035). Authors rated analgesic ef-
fect as ‘modest’. While number needed to treat
(NNT) to attain a 30% decrement in pain were com-
parable in this study vs. Sativex, the reduction of
pain on a numerical rating scale favoured the latter
(1.0 vs. 0.6), as did side effect profile particularly
for somnolence and headache, despite much higher
total doses of THC and the concomitant usage of
additional medicines for neuropathic pain. These
differences point to either an advantage of oromu-
cosal administration of phytocannabinoids, a
reduction of THC adverse events due to inclusion
of CBD, or both.
In a Phase III, double-blind placebo-controlled
trial of peripheral neuropathic pain characterised
by allodynia [67], THC:CBD 1:1 produced highly sta-
tistically significant improvements in pain levels
with additional benefit on static and dynamic allo-
dynia measures.
In a Phase III, double-blind placebo-controlled
trial in 160 subjects with various symptoms of MS
[68], THC:CBD 1:1 significantly reduced spasticity
over placebo (p= 0.001) without significant ad-
verse effects on mood or cognition. In a long-term
safety-extension study (SAFEX), some 137 patients
elected to continue on THC:CBD 1:1 [69]. On VAS
of symptoms, rapid declines were noted over the
first 12 weeks in pain (n= 47), spasm (n= 54), spas-
ticity (n= 66), bladder problems (n= 57), and tre-
mor (n= 35), with slower sustained improvements
for more than one year. Interestingly, no tolerance
was noted with mean THC:CBD 1:1 doses actually
declining over time. Furthermore, VAS of intoxica-
tion in the cohort measured in the single digits out
of 100 and did not differ significantly from placebo.
In a cohort of 18 volunteers who abruptly stopped
THC:CBD 1:1, no significant evidence for a with-
drawal syndrome was observed. Rather, patients
suffered recrudescence of symptoms after 7–10
240 Russo and Guy
days, but easily re-titrated to prior dosages with
renewed efficacy.
Finally, the recently announced results of a Phase
III study comparing THC:CBD 1:1, THC-predominant
extract and placebo in intractable pain due to can-
cer unresponsive to opiates [70] with strong neuro-
pathic pain components, demonstrated that
THC:CBD 1:1 produced highly statistically signifi-
cant improvements in analgesia (p= 0.0142), while
the THC-predominant extract failed to do so in this
trial, confirming the key importance of the inclusion
of CBD in the preparation.
Analysis of sleep parameters in seven Phase II
and III trials of MS and neuropathic pain and two
corresponding SAFEX studies to date demonstrate
significant to highly statistically significant and
durable benefits of THC:CBD 1:1 on this important
clinical symptom [71].
These trials, combined with their safety-exten-
sion studies comprise some 1500 subjects and
1000 patient-years of experience, during which no
abuse or diversion of THC:CBD 1:1 have occurred,
and no tolerance or withdrawal effects have been
noted [69,72]. Thus, the fears expressed in the
Federal Register [34] with respect to CBD–THC
interactions appear unfounded.
New horizons in phytocannabinoid
therapeutics
Neuroprotection
The seminal work describing the neuroprotective
roles of THC and CBD has been that of Hampson
et al. [73]. Both phytocannabinoids protected
equally against glutamatergic neurotoxicity medi-
ated by NMDA, AMPA, or kainate receptors, and this
effect was not antagonized by SR1414716A, thus
demonstrating it to be operative independently of
cannabinoid receptor activation. The group addi-
tionally investigated the effects of THC and CBD
on reactive oxygen species (ROS), finding them
equal to that of the BHT and HU-211 (dexanabinol).
CBD was considerably more potent as an antioxidant
than ascorbate or tocopherol. Recent work has also
shown that CBD reversed binge ethanol-induced
neurotoxicity via a cannabinoid receptor-indepen-
dent antioxidant mechanism [74], and prevented
cerebral infarction via a 5-HT
1A
receptor dependent
mechanism [75]. Activity of CBD at that receptor
has been independently confirmed [76], supporting
a role in migraine and anxiety treatment.
Cannabidiol was shown to prevent b-amyloid in-
duced toxicity in the PC12 phaeochromocytoma
model of Alzheimer disease [77], increasing cell
survival, while decreasing reactive oxygen species
(ROS) production, lipid peroxidation, caspase 3 lev-
els, DNA fragmentation and intracellular calcium.
A recent study [78] in mice supports the pros-
pect that CBD has antipsychotic properties without
extrapyramidal side-effects. Thus, CBD might im-
prove symptoms of agitation and behavioural issues
previously treated to advantage with THC alone in
a clinical Alzheimer population [79].
One article has described the palliative use of
cannabis in motor neurone disease, or amyotrophic
lateral sclerosis (ALS) [80]. THC has previously been
shown to delay motor deterioration and increase
survival in a mouse model of ALS [81]. That work
was recently extended to demonstrate that the
addition of CBD further slowed disease progression
with a 14% improvement in motor performance,
and a trend toward extension of survival beyond
that previously achieved with THC alone [82].
The intriguing survey supporting symptomatic
improvement in Parkinson disease (PD) after pro-
longed usage was previously mentioned [51]. This
finding is lent additional credence by the demon-
stration that equivalent benefits were observed
with THC and CBD in preventing damage produced
by injection of 6-hydroxydopamine into the median
forebrain bundle of experimental animals [84],a
result independent of cannabinoid receptor ef-
fects, but more likely due to antioxidant activity
and regulation of glial influences upon neurones.
This would support a neuroprotective benefit be-
yond the issue of symptomatic relief that would
warrant additional trials, particularly with a mixed
THC:CBD preparation.
Dystonic disorders are frequently progressive
degenerative diseases, wherein CBD was employed
in isolation and demonstrated benefit [85].
CBD treatment was attempted in Huntington’s
disease [86], but with little benefit seen over the
6-week trial. Perhaps the length of treatment was
too short, and may support the concept of additional
trials, particularly with a THC:CBD preparation.
Such a combination may well prove to effect neuro-
protective benefits in MS in the long term, having a
strong theoretical basis [87]. Given the failure of
various glutamate antagonists in efforts at neuro-
protection in this and other conditions, phytocanna-
binoid approaches certainly appear warranted.
Cannabinoids and dependency
A simple perusal of the medical literature will
confirm that considerable concern continues in
A tale of two cannabinoids 241
context as to the drug abuse liability of THC prep-
arations. However, that substance in isolation has
proven to pose little risk [12]. To the extent that
rapidly rising serum levels promote reward and
addictive potential of a given pharmaceutical
[88], it is certainly arguable that the addition of
CBD to THC would reduce psychoactive attraction,
and that an oromucosal delivery eliminates the
steep slope pharmacokinetic profile of cannabis
smoking [54]. Additionally, cannabinoid receptor
blockade by CBD may well reduce addiction poten-
tial [36], and support its usage as an ‘anti-addic-
tive’ compound [72]. Interestingly, THC and CBD
have both been demonstrated to potentiate the
extinction of cocaine and amphetamine condi-
tioned incentive learning in rats, supporting clini-
cal studies claiming benefit of cannabis on
cocaine addiction in Brazil [89] and Jamaica [90].
The fact that THC potentiates opiate analgesia,
eliminates morphine tolerance and reduces with-
drawal [91] highlights the rationale of cannabi-
noid–opiate combinations for treatment of
severe and chronic pain. Recently, it was shown
that interleukin-1 (IL-1) antagonises morphine and
underlies development of tolerance [92]. As THC
and CBD both suppress IL-1 secretion in humans in
mononuclear cells in vitro [93], it is possible that
this mechanism may also play a helpful role in
addiction issues with a combined pharmaceutical.
Neoplastic disease
THC has demonstrated cytotoxic benefits and anti-
angiogenic effects in a wide variety of cell lines
(reviewed in [94,95]). CBD has also proven active
as a cytostatic/cytotoxic, especially in gliomas
where it inhibits cell migration leading to tumour
invasion [96], decreases oxidative mitochondrial
metabolism with decrease in cell survival and
inducing apoptosis in vitro and in vivo [97], and
additionally inhibits cell migration, underlying
metastatic mechanisms, independently of CB
1
and
CB
2
[98]. Given the analgesic effect of the THC:CBD
combination in cancer treatment discussed above
[70], the side benefit of THC and CBD [99] in che-
motherapy-associated nausea, and these primary
effects on tumour growth and spread, a strong
rationale is currently present for their application
in additional clinical trials.
Conclusion
Various publications have presented the position
that THC accounts for the main effects [100], the
analgesic and other medicinal benefits [101] of
cannabis. This paper supports a distinct view that
CBD and perhaps other cannabis components [6]
achieve synergy with THC [102] consisting of poten-
tiation of benefits, antagonism of adverse effects,
summation (a
`la the entourage effect), pharmaco-
kinetic advantages (in CBD suppression of
11-hydroxylation of THC), and metabolism (e.g.,
lower toxicity of a ‘natural product’ as compared
to synthetic COX-inhibitor anti-inflammatory).
The range of effects of the phytocannabinoids on
pathophysiological processes is truly impressive,
and suggests broad applicability in their future
therapeutic application.
The recent discovery that the propyl phytocann-
abinoid, tetrahydrocannabivarin (THCV) (Fig. 4), is
a potent antagonist at the CB1 receptor [103] sup-
ports the notion that we yet have a great deal to
learn about the therapeutic potential of this vener-
able medicinal plant.
The data herein presented strongly support the
therapeutic rationale for combining THC and CBD
for therapeutic usage.
Conflict of interest/role of funding
Source
The author has been a consultant for GW Pharma-
ceuticals since 1998, and has received grants-in-
aid, travel expenses, research support, stock
options and salary in this regard.
Search strategy and selection criteria
References for this review were identified by
searches of PubMed/National Library of Medicine
O
OH
tetrahydrocannabivarin
Figure 4 Tetrahdrocannabivarin (THCV), a propyl phy-
tocannabinoids with potent antagonist properties at CB
1
[103].
242 Russo and Guy
database from 1966 to June 2005 for articles perti-
nent to cannabidiol and its combination with THC
in English, French, Spanish, Portuguese and Italian.
Additional sources were identified in the author’s
extensive personal library of books and files.
Acknowledgements
The author thank Richard Musty for suggesting cer-
tain references and Emma Brierley and Alice Mead
for suggested revisions.
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