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Cannabis is more than simply Delta(9)-tetrahydrocannabinol

Authors:
Psychopharmacology (2003) 165:431–432
DOI 10.1007/s00213-002-1348-z
LETTER TO THE EDITORS
Ethan B. Russo · John M. McPartland
Cannabis is more than simply D
9
-tetrahydrocannabinol
Received: 13 August 2002 / Accepted: 30 October 2002 / Published online: 19 December 2002
Springer-Verlag 2002
In response to your recent publication comparing
subjective effects of D
9
-tetrahydrocannabinol and herbal
cannabis (Wachtel et al. 2002), a number of comments are
necessary. The first concerns the suitability of the chosen
“marijuana” to assay the issues at hand. NIDA cannabis
has been previously characterized in a number of studies
(Chait and Pierri 1989; Russo et al. 2002), as a crude low-
grade product (2–4% THC) containing leaves, stems and
seeds, often 3 or more years old after processing, with a
stale odor lacking in terpenoids. This contrasts with the
more customary clinical cannabis employed by patients in
Europe and North America, composed solely of unseeded
flowering tops with a potency of up to 20% THC.
Cannabis-based medicine extracts (CBME) (Whittle et al.
2001), employed in clinical trials in the UK (Notcutt
2002; Robson et al. 2002), are extracted from flowering
tops with abundant glandular trichomes, and retain full
terpenoid and flavonoid components.
In the study at issue (Wachtel et al. 2002), we are
informed that marijuana contained 2.11% THC, 0.30%
cannabinol (CBN), and 0.05% (CBD). The concentration
of the latter two cannabinoids is virtually inconsequential.
Thus, we are not surprised that no differences were seen
between NIDA marijuana with essentially only one
cannabinoid, and pure, synthetic THC. In comparison,
clinical grade cannabis and CBME customarily contain
high quantities of CBD, frequently equaling the percent-
age of THC (Whittle et al. 2001).
Carlini et al. (1974) determined that cannabis extracts
produced effects “two or four times greater than that
expected from their THC content, based on animal and
human studies”. Similarly, Fairbairn and Pickens (1981)
detected the presence of unidentified “powerful syner-
gists” in cannabis extracts, causing 330% greater activity
in mice than THC alone.
The clinical contribution of other CBD and other
cannabinoids, terpenoids and flavonoids to clinical can-
nabis effects has been espoused as an “entourage effect”
(Mechoulam and Ben-Shabat 1999), and is reviewed in
detail by McPartland and Russo (2001). Briefly summa-
rized, CBD has anti-anxiety effects (Zuardi et al. 1982),
anti-psychotic benefits (Zuardi et al. 1995), modulates
metabolism of THC by blocking its conversion to the
more psychoactive 11-hydroxy-THC (Bornheim and
Grillo 1998), prevents glutamate excitotoxicity, serves
as a powerful anti-oxidant (Hampson et al. 2000), and has
notable anti-inflammatory and immunomodulatory effects
(Malfait et al. 2000).
Terpenoid cannabis components probably also con-
tribute significantly to clinical effects of cannabis and boil
at comparable temperatures to THC (McPartland and
Russo 2001). Cannabis essential oil demonstrates seroto-
nin receptor binding (Russo et al. 2000). Its terpenoids
include myrcene, a potent analgesic (Rao et al. 1990)
and anti-inflammatory (Lorenzetti et al. 1991), beta-
caryophyllene, another anti-inflammatory (Basile et al.
1988) and gastric cytoprotective (Tambe et al. 1996),
limonene, a potent inhalation antidepressant and immune
stimulator (Komori et al. 1995) and anti-carcinogenic
(Crowell 1999), and alpha-pinene, an anti-inflammatory
(Gil et al. 1989) and bronchodilator (Falk et al. 1990).
Are these terpenoid effects significant? A dried sample
of drug-strain cannabis buds was measured as displaying
an essential oil yield of 0.8% (Ross and ElSohly 1996), or
a putative 8 mg per 1000 mg cigarette. Buchbauer et al.
(1993) demonstrated that 20–50 mg of essential oil in the
ambient air in mouse cages produced measurable changes
in behavior, serum levels, and bound to cortical cells.
Similarly, Komori et al. (1995) employed a gel of citrus
fragrance with limonene to produce a significant antide-
pressant benefit in humans, obviating the need for
continued standard medication in some patients, and also
improving CD4/8 immunologic ratios. These data would
E. B. Russo (
)
)
Montana Neurobehavioral Specialists,
900 North Orange Street, Missoula, MT, 59802 USA
e-mail: erusso@blackfoot.net
J. M. McPartland
Faculty of Health and Environmental Science,
UNITEC,
Private Bag 92025, Mt Albert, Auckland, New Zealand
strongly support a demonstrable clinical role for cannabis
terpenoids.
Flavonoid components of cannabis, especially likely to
be of benefit in oral or sublingual administration, include
apigenin, a unique agent that has strong anti-anxiety
effects without sedation (Salgueiro et al. 1997).
Finally, although anecdotal, this author (E.B.R.) has
had the opportunity to interview an estimated 200 patients
who have employed Marinol and clinical cannabis,
whether smoked or ingested. In no instance were the
effects of the former considered of equal efficacy to
cannabis, but rather more productive of dysphoric and
sedative adverse effects (Calhoun et al. 1998).
In essence, clinical cannabis demonstrates herbal
synergy and is more than a simply a vehicle for THC
administration.
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... Several scientific attempts have been made to classify cannabis plants based on their phytochemical composition. Cannabis products used for medicinal purposes usually contain a high content of the biologically active D 9 -THC, but it is becoming clear that multiple cannabis compounds are involved in its various therapeutic effects (Russo and McPartland, 2003). High-throughput genotyping of a diverse collection of cannabis germplasm showed that genetic differences between hemp and marijuana are not limited to genes involved in D 9 -THC production (Sawler et al., 2015). ...
... Initial speculation of the entourage effect came after a study found endogenous lipids were able to modulate the activity of an endogenous cannabinoid (Ben-Shabat et al., 1998). Subsequent investigation came in the form of perspective reviews (Russo and McPartland, 2003;Russo, 2011;Russo and Marcu, 2017), as well as investigating the interactions between different phytocannabinoids, mostly CBD and D 9 -THC (Johnson et al., 2010;Casey et al., 2017;Pamplona et al., 2018). However, more recently, a variety of studies have examined the role of terpenes in phytocannabinoid-mediated antitumor activity (Blasco-Benito et al., 2018), cell cytotoxicity (Namdar et al., 2019), and direct interactions with cannabinoid receptors (Santiago et al., 2019;Finlay et al., 2020). ...
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Cannabidiol and other cannabinoids were examined as neuroprotectants in rat cortical neuron cultures exposed to toxic levels of the neurotransmitter, glutamate. The psychotropic cannabinoid receptor agonist Δ9-tetrahydrocannabinol (THC) and cannabidiol, (a non-psychoactive constituent of marijuana), both reduced NMDA, AMPA and kainate receptor mediated neurotoxicities. Neuroprotection was not affected by cannabinoid receptor antagonist, indicating a (cannabinoid) receptor-independent mechanism of action. Glutamate toxicity can be reduced by antioxidants. Using cyclic voltametry and a fenton reaction based system, it was demonstrated that Cannabidiol, THC and other cannabinoids are potent antioxidants. As evidence that cannabinoids can act as an antioxidants in neuronal cultures, cannabidiol was demonstrated to reduce hydroperoxide toxicity in neurons. In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol was superior to both a-tocopherol and ascorbate in protective capacity. Recent preliminary studies in a rat model of focal cerebral ischemia suggest that cannabidiol may be at least as effective in vivo as seen in these in vitro studies.
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Oral administration of an infusion of lemongrass (Cymbopogon citratus) fresh leaves to rats produced a dose-dependent analgesia for the hyperalgesia induced by subplantar injections of either carrageenin or prostaglandin E2, but did not affect that induced by dibutyryl cyclic AMP. These results indicate a peripheral site of action which was confirmed with the essential oil obtained by steam distillation of the leaves. Silica gel column fractionation of the essential oil allowed the identification of myrcene as the major analgesic component in the oil. Identification of the components was made by thin-layer chromatography and checked by mass spectrometry. The peripheral analgesic effect of myrcene was confirmed by testing a standard commercial preparation on the hyperalgesia induced by prostaglandin in the rat paw test and upon the contortions induced by intraperitoneal injections of iloprost in mice. In contrast to the central analgesic effect of morphine, myrcene did not cause tolerance on repeated injection in rats. This analgesic activity supports the use of lemongrass tea as a "sedative" in folk medicine. Terpenes such as myrcene may constitute a lead for the development of new peripheral analgesics with a profile of action different from that of the aspirin-like drugs.
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Myrcene, a monoterpene isolated from lemon grass oil (Cymbopogon citratus) has been investigated for antinociception in mice by a low temperature (51.5 +/- 0.5 degrees C) hot plate method and by the acetic acid-induced writhing test. Significant inhibition of nociception was seen in the tests with myrcene at doses of 10 and 20 mg kg-1 (i.p.) or at 20 and 40 mg kg-1 (s.c.), respectively. The antinociceptive effect was significantly antagonized by naloxone (1 mg kg-1) or yohimbine (2 mg kg-1). The results suggest that myrcene is capable of inducing antinociception in mice, probably mediated by alpha 2-adrenoceptor stimulated release of endogenous opioids.
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Marijuana cigarettes of three different potencies (0.0%, 1.4% and 2.7% delta-9-tetrahydrocannabinol (THC) content) provided by the National Institute on Drug Abuse (NIDA) were compared on a variety of characteristics, including physical appearance, weight, burn rate, and deliveries of total particulate matter and carbon monoxide. Significant differences between the different potency cigarettes were obtained on most measures. These differences could be relevant to the design and interpretation of pharmacologic/toxicologic and behavioral studies conducted with these cigarettes. The possible basis for these observed differences, methods for minimizing some of them, and other potential problems related to the use of NIDA marijuana cigarettes are discussed.