by John M. McPartland and Ethan B. Russo
A central tenet underlying the use of botanical remedies is that herbs contain many active ingredients. Primary active ingredients may be enhanced by secondary compounds, which act in beneficial synergy. Other herbal constituents may mitigate the side effects of dominant active ingredients. We reviewed the literature concerning medical cannabis and its primary active ingredient, Δ9-tetrahydrocannabinol (THC). Good evidence shows that secondary compounds in cannabis may enhance the beneficial effects of THC. Other cannabinoid and non-cannabinoid compounds in herbal cannabis or its extracts may reduce THC-induced anxiety, cholinergic deficits, and immunosuppression. Cannabis terpenoids and flavonoids may also increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens, and provide anti-inflammatory activity.
Cannabis is an herb; it contains hundreds of pharmaceutical compounds (Turner et al. 1980). Herbalists contend that polypharmaceutical herbs provide two advantages over single-ingredient synthetic drugs: (1) therapeutic effects of the primary active ingredients in herbs may be synergized by other compounds, and (2) side effects of the primary active ingredients may be mitigated by other compounds. Thus, cannabis has been characterized as a “synergistic shotgun,” in contrast to Marinol (Δ9-tetrahydrocannabinol, THC), a synthetic, single-ingredient “silver bullet” (McPartland and Pruitt 1999). Mechoulam et al. (1972) suggested that other compounds present in herbal cannabis might influence THC activity. Carlini et al. (1974) determined that cannabis extracts produced effects “two or four times greater than that expected from their THC content.” Similarly, Fairbairn and Pickens (1981) detected the presence of unidentified “powerful synergists” in cannabis extracts causing 330% greater activity in mice than THC alone. Other compounds in herbal cannabis may ameliorate the side effects of THC. Whole cannabis causes fewer psychological side effects than synthetic THC, seen as symptoms of dysphoria, depersonalization, anxiety, panic reactions, and paranoia (Grinspoon and Bakalar 1997). This difference in side effect profiles may also be due, in part, to differences in administration: THC taken by mouth undergoes “first pass metabolism” in the small intestine and liver, to 11-hydroxy THC; the metabolite is more psychoactive than THC itself (Browne and Weissman 1981). Inhaled THC undergoes little first-pass metabolism, so less 11-hydroxy THC is formed. Thus, “smoking cannabis is a satisfactory expedient in combating fatigue, headache and exhaustion, whereas the oral ingestion of cannabis results chiefly in a narcotic effect which may cause serious alarm” (Walton 1938, p. 49). Respiratory side effects from inhaling cannabis smoke may be ameliorated by both cannabinoid and non-cannabinoid components in cannabis. For instance, throat irritation may be diminished by anti-inflammatory agents, mutagens in the smoke may be mitigated by antimutagens, and bacterial contaminants in cannabis may be annulled by antibiotic compounds (McPartland and Pruitt 1997). The pharmaceutically active compounds in cannabis that enhance beneficial THC activity and reduce side effects are relatively unknown. The purpose of this paper is to review the biochemistry and physiological effects of those other compounds.
]104 CANNABIS THERAPEUTICS IN HIV/AIDS
MATERIALS AND METHODS
MEDLINE (1966-2000) was searched using MeSH keywords: cannabinoids,
marijuana, tetrahydrocannabinol. AGRICOLA (1990-1999) was searched
using the keywords cannabis, hemp, and marijuana. Phytochemical and ethnobotanical
databases were searched via the Agricultural Research Service
webpage <http://www.ars-grin.gov/~ngrlsb/>. All reports were scanned for
supporting bibliographic citations; antecedent sources were retrieved to the
fullest possible extent. Data validity was assessed by source (peer-reviewed
article vs. popular press), identification methodology (analytical chemistry vs.
clinical history) and the frequency of independent observations.
RESULTS AND DISCUSSION
Turner et al. (1980) listed over 420 compounds in cannabis. Sparacino et al.
(1990) listed 200 additional compounds in cannabis smoke. We will highlight
six cannabinoids beyond THC, a dozen-odd terpenoids, three flavonoids, and
one phytosterol. Other non-cannabinoids with proven pharmacological activity
include poorly characterized glycoproteins, alkaloids, and compounds that
remain completely unidentified (Gill et al. 1970).
Mechoulam and Gaoni (1967) defined “cannabinoids” as a group of C21
terpenophenolic compounds uniquely produced by cannabis. The subsequent
development of synthetic cannabinoids (e.g., HU-210) has blurred this definition,
as has the discovery of endogenous cannabinoids (e.g., anandamide), defined
as “endocannabinoids” by DiMarzo and Fontana (1995). Thus, Pate
(1999) proposed the term “phytocannabinoids” to designate the C21 compounds
produced by cannabis. Phytocannabinoids exhibit very low mammalian
toxicity, and mixtures of cannabinoids are less toxic than pure THC
(Thompson et al. 1973).
Cannabidiol (CBD) is the next-best studied phytocannabinoid after THC
(Figure 1). The investigation of CBD by marijuana researchers is rather paradoxical,
considering its concentrations are notably lower in drug varieties of
cannabis than in fiber cultivars (Turner et al. 1980).
John M. McPartland and Ethan B. Russo 105
CBD possesses sedative properties (Carlini and Cunha, 1981), and a clinical
trial showed that it reduces the anxiety and other unpleasant psychological
side effects provoked by pure THC (Zuardi et al. 1982). CBD modulates the
pharmacokinetics of THC by three mechanisms: (1) it has a slight affinity for
cannabinoid receptors (Ki at CB1 = 4350 nM, compared to THC = 41 nM,
Showalter et al. 1996), and it signals receptors as an antagonist or reverse agonist
(Petitet et al. 1998), (2) CBD may modulate signal transduction by perturbing
the fluidity of neuronal membranes, or by remodeling G-proteins that
carry intracellular signals downstream from cannabinoid receptors, and (3)CBD
is a potent inhibitor of cytochrome P450 3A11 metabolism, thus it blocks the
hydroxylation of THC to its 11-hydroxy metabolite (Bornheim et al. 1995).
The 11-hydroxy metabolite is four times more psychoactive than unmetabolized
THC (Browne and Weissman 1981), and four times more immunosuppressive
(Klein et al. 1987).
CBD provides antipsychotic benefits (Zuardi et al. 1995). It increases dopamine
activity, serves as a serotonin uptake inhibitor, and enhances norepinephrine
activity (Banerjee et al. 1975; Poddar and Dewey 1980). CBD protects
neurons from glutamate toxicity and serves as an antioxidant, more potently
than ascorbate and α-tocopherol (Hampson et al. 1998). Auspiciously, CBD
does not decrease acetylcholine (ACh) activity in the brain (Domino 1976;
Cheney et al. 1981). THC, in contrast, reduces hippocampal ACh release in
rats (Carta et al. 1998), and this correlates with loss of short-term memory consolidation.
In the hippocampus THC also inhibits N-methyl-D-aspartate (NMDA)
receptor activity (Misner and Sullivan 1999; Shen and Thayer 1999), and
NMDA synaptic transmission is crucial for memory consolidation (Shimizu et
al. 2000). CBD, unlike THC, does not dampen the firing of hippocampal cells
(Heyser et al. 1993) and does not disrupt learning (Brodkin and Moerschbaecher
Consroe (1998) presented an excellent review of CBD in neurological disorders.
In some studies, it ameliorates symptoms of Huntington’s disease, such
as dystonia and dyskinesia. CBD mitigates other dystonic conditions, such as
torticollis, in rat studies and uncontrolled human studies. CBD functions as an
anticonvulsant in rats, on a par with phenytoin (Dilantin, a standard antiepileptic
CBD demonstrated a synergistic benefit in the reduction of intestinal motility
in mice produced by THC (Anderson, Jackson, and Chesher 1974). This
may be an important component of observed benefits of cannabis in inflammatory
The CBD in cannabis smoke may explain why inhaling it causes less airway
irritation and inflammation than inhalation of pure THC (Tashkin et al. 1977).
CBD imparts analgesia (more potently than THC), it inhibits erythema (much
more than THC), it blocks cyclooxygenase (COX) activity with a greater max-
106 CANNABIS THERAPEUTICS IN HIV/AIDS
imum inhibition than THC, and it blocks lipoxygenase (the enzyme that produces
asthma-provoking leukotrienes), again more effectively than THC (Evans
1991). Mice with inflammatory collagen-induced arthritis (a mouse model for
rheumatoid arthritis) were given oral CBD (5 mg/kg per day) and showed clinical
improvement, and the treatment effectively blocked progression of the arthritis
(Malfait et al. 2000).
CBD reportedly has little or no effect on the immune system (reviewed by
Klein et al. 1998), although the mouse arthritis study by Malfait et al. (2000)
showed CBD decreases the production of tumor necrosis factor (TNF) and Interferon-
gamma (IFN-γ), which are two immunomodulatory cytokines described
later. CBD actually kills bacteria and fungi, with greater potency than
THC (Klingeren and Ham 1976; ElSohly et al. 1982; McPartland 1984). Thus,
cannabis may have less microbial contamination than other herbs, an important
consideration for immunocompromised individuals (McPartland and Pruitt
Cannabinol (CBN) is the degradation product of THC (Turner et al. 1980),
and is found most often in aged cannabis products (Figure 1). CBN potentiates
the effects of THC in man (Musty et al. 1976), yet it antagonizes the effects of
THC in mice (Formukong et al. 1988). Studies reporting CBN’s effects upon
norepinephrine and dopamine also conflict–CBN may have negligible effects
on these biogenic amines (Banerjee et al. 1975), enhance their release (Poddar
and Dewey 1980), or decrease their release (Dalterio et al. 1985). CBN increases
plasma concentrations of follicle-stimulating hormone, and enhances
the production of testicular testosterone (Dalterio et al. 1985). CBN shares
some characteristics with CBD; for example, it has anti-convulsant activity
(Turner et al. 1980) and anti-inflammatory activity (Evans et al. 1991).
CBN has affinity for CB1 receptors (Ki at CB1 = 308 nM) and signals as an
agonist (Showalter et al. 1996). Further down the signal transduction cascade,
it stimulates the binding of GTP-γ-S (Petitet et al. 1998), but with half the efficacy
of THC; when CBN is added to THC, the effects are not significantly additive.
CBN has a three-fold greater affinity for CB2 receptors (Ki = 96 nM)
(Showalter et al. 1996), thus it may affect cells of the immune system more
than the central nervous system (Klein et al. 1998). CBN modulates thymocytes
(Herring and Kaminski 1999) by attenuating the activity of the c-AMP response
element-binding protein (CREB), nuclear factor κB (NF-κB), and
interleukin-2 (IL-2). IL-2 is regulated by activator protein-1 (AP-1) transcription
factor, a complex of c-Fos and c-Jun proteins (Foletta et al. 1998); CBN
inhibits the expression of these proteins in splenocytes, via decreased activation
of ERK MAP kinases (Faubert and Kaminski 2000).
Cannabichromene (CBC) is the fourth major cannabinoid, found predominantly
in tropical Cannabis spp. strains (Figure 1). Until the mid-1970s, CBC
was frequently misidentified as CBD, because CBC and CBD have nearly the
John M. McPartland and Ethan B. Russo 107
same retention times in gas chromatography. Like CBD, CBC decreases inflammation
(Wirth et al. 1980) and provides analgesic effects (Davis and
Hatoum 1983). CBC inhibits prostaglandin synthesis in vitro, but less potently
than CBD or THC (Burstein et al. 1973). CBC exhibits strong antibacterial activity
and mild antifungal activity, superior to THC and CBD in most instances
(ElSohly et al. 1982). Unlike CBD, CBC has no effect on cytochrome P450 enzymes
(Kapeghian et al. 1983), nor does it function as an anticonvulsant in rats
(Davis and Hatoum 1983).
The molecular affinity of CBC for cannabinoid receptors has not been measured.
In mice, CBC causes hypothermia, sedation, and synergizes the depressant
effects of hexobarbital (Hatoum et al. 1981). CBC also sedates dogs and
decreases muscular coordination in rats, but causes no cannabimimetic activity
in monkeys and people (Turner et al. 1980). In rats, the co-administration of
CBC with THC potentiates THC changes in heart rate, but does not potentiate
THC’s hypotensive effects (O’Neil et al. 1979). Co-administration of CBC
lowers the LD50 dose of THC in mice (Hatoum et al. 1981).
Cannabigerol (CBG) is the biosynthetic precursor of CBC, CBD, and THC,
and is present only in minor amounts (Figure 1). CBG has been called “inactive”
when compared to THC, but CBG has slight affinity for CB1 receptors,
approximately the same as CBD (Devane et al. 1988). In rat brains, CBG inhibits
the uptake of serotonin and norepinephrine, less effectively than CBD
and THC, but CBG inhibits GABA uptakemore effectively than CBD and THC
(Banerjee et al. 1975). CBG acts as an analgesic (more potently than THC), it
inhibits erythema (much more than THC), and it blocks lipoxygenase, again
more effectively than THC (reviewed by Evans 1991).
CBG has antibacterial properties (Mechoulam and Gaoni 1965). Its activity
against gram-positive bacteria, mycobacteria, and fungi is superior to that of
THC, CBD, and CBC (ElSohly et al. 1982). CBG inhibits the growth of human
oral epitheloid carcinoma cells (Baek et al. 1998).
Delta-8-THC (Δ8-THC) is an isomer of delta-9-THC; it differs only by the
location of the double bond in the cyclohexal “C” ring. The Ki of Δ8-THC is
126 nM (Compton et al. 1993), and this loosely correlates with human studies,
which show Δ8-THC is less psychoactive than Δ9-THC (Hollister 1974). The
chemical stability of Δ8-THC and its relative ease of synthesis compared to
Δ9-THC, have made Δ8-THC the template for the development of two important
synthetic derivatives, the extremely potent psychoactive CB1 agonist,
HU-210 (Mechoulam and Ben-Shabat 1999), and the non-psychoactive antiemetic
and neuroprotectant, HU-211 (dexanabinol) (Achiron et al. 2000;
Biegon and Joseph 1995; Gallily et al. 1997). Δ8-THC was employed clinically
in an important study (Abrahamov and Mechoulam 1995) in which 8
children with hematological malignancies were treated with the drug over the
course of 8 months at a dose of 18 mg/m2 to treat chemotherapy-associated
108 CANNABIS THERAPEUTICS IN HIV/AIDS
nausea and vomiting. Interestingly, not only was this agent uniformly effective
as an antiemetic, but it was also free of psychoactive effects in this age range
Tetrahydrocannabivarin (THCV) is a propyl analogue of Δ9-THC, primarily
appearing in indica and afghanica varieties of cannabis, such as hashish
from Nepal (Merkus 1971), dagga from South Africa (Boucher et al. 1977),
and in plants cultivated from seeds from Zambia (Pitts et al. 1992) (Figure 1).
THCV is only 20-25% as psychoactive as Δ9-THC (Hollister 1974). It has a
quicker onset of action than Δ9-THC (Gill et al. 1970), and is of briefer duration
(Clarke 1998). THCV may be clinically effective in migraine treatment
(Personal communication, HortaPharm, November 2000). Kubena and Barry
(1972) suggested THCV synergizes the effects of THC, but did not hypothesize
a mechanism. As a legal fine point, this analogue is not controlled in the
Netherlands, and is not specified in the USA as a Schedule I drug, but would
likely be considered illegal under the Controlled Substance Analogue Enforcement
Act of 1986 (Public Law 99-570). THCV is of interest from a medical-legal
standpoint in that is has been suggested as a biochemical marker of illicit
cannabis use, since it is not a metabolite of Marinol (synthetic THC) (ElSohly
et al. 1999).
The unique smell of cannabis does not arise from cannabinoids, but from
over 100 terpenoid compounds (Turner et al. 1980). Terpenoids derive from
repeating units of isoprene (C5H8), such as monoterpenoids (with C10 skeletons),
sesquiterpenoids (C15), diterpenoids (C20), and triterpenoids (C30). The
final structure of terpenoids ranges from simple linear chains to complex
polycyclic molecules, and they may include alcohol, ether, aldehyde, ketone,
or ester functional groups. These compounds are easily extracted from plant
material by steam distillation or vaporization. This distillate is called the essential
oil or volatile oil of the plant. A range of researchers cite different
yields of essential oil from different types of cannabis: Martin et al. (1961)
cited yields of 0.05-0.11% essential oil from fresh, green leaves and flowers of
mixed male and female plants, from feral hemp growing in Canada. Nigram et
al. (1965) yielded 0.1% essential oil from fresh, whole, male plants from Kashmir.
Malingré et al. (1973) yielded 0.12% essential oil from fresh leaves of
“strain X” obtained from birdseed in the Netherlands. Ross and ElSohly
(1996) yielded 0.29% essential oil from fresh marijuana buds, reputed to be the
Afghani variety “Skunk #1.” Drying the plant material led to a loss of water
content and net weight, concentrating the essential oil to 0.80% in buds that
had been dried at room temperature for one week (Ross and ElSohly 1966).
John M. McPartland and Ethan B. Russo 109
Field-cultivated cannabis yields about 1.3 liter of essential oil per metric ton
of freshly harvested plant material (Mediavilla and Steinemann 1997). Preventing
pollination increases the yield of essential oil–18 l/ha in sinsemilla
crops, versus 8 l/ha in pollinated crops (Meier and Mediavilla 1998). The composition
of terpenoids varies between strains of cannabis (Mediavilla and
Steinemann 1997), and varies between harvest dates (Meier and Mediavilla
Many terpenoids vaporize near the same temperature as THC, which boils
at 157°C (see Figures 1-2). Terpenoids are lipophilic and permeate lipid membranes.
Many cross the blood-brain barrier (BBB) after inhalation (Buchbauer
et al. 1993; Nasel et al. 1994).
Meschler and Howlett (1999) discussed several mechanisms by which
terpenoids modulate THC activity. For instance, terpenoids may bind to
cannabinoid receptors. Thujone, from Artemisia absinthium, has a weak affinity
for CB1 receptors (Ki at CB1 = 130,000 nM). Terpenoids might modulate
the affinity of THC for its own receptor, by sequestering THC, by perturbing
annular lipids surrounding the receptor, or by increasing the fluidity of neuronal
membranes. Further downstream, terpenoids may alter the signal cascade by
remodeling G-proteins. Terpenoids may alter the pharmacokinetics of THC by
changing the BBB; cannabis extracts are known to cause a significant increase
in BBB permeability (Agrawal et al. 1989). Terpenoids may also act on other
receptors and neurotransmitters. Some terpenoids act as serotonin uptake inhibitors
(as does Prozac), enhance norepinephrine activity (as do tricyclic
antidepressants), increase dopamine activity (as do monoamine oxidase inhibitors
and bupropion), and augment GABA (as do baclofen and the benzodiazepines).
Recently, strong serotonin activity at the 5-HT1A and 5-HT2a receptors
has been demonstrated (Russo et al. 2000; Russo 2001) that may support synergistic
contributions of terpenoids on cannabis-mediated pain and mood effects.
Further studies are in progress to identify the most active terpenoid
components responsible, and whether synergism of the components is demonstrable.
The essential oil of cannabis is traditionally employed as an anti-inflammatory
in the respiratory and digestive tracts without known contraindications at
physiological dosages (Franchomme and Pénoël 1990). The essential oil of
black pepper, Piper nigrum, has a composition of terpenes that is qualitatively
quite similar to that of cannabis (Lawless 1995). It has often been claimed
anecdotally, that smoked cannabis may substitute for nicotine in attempts at
smoking cessation. Aside from cannabinoid influences, current evidence supports
this contention based on terpene content and its activity. A recent study
has shown that inhalation of black pepper essential oil vapor significantly reduced
withdrawal symptoms and anxiety in tobacco smokers (Rose and Behm
1994). Interestingly, the authors posited not a central biochemical mechanism,
110 CANNABIS THERAPEUTICS IN HIV/AIDS
John M. McPartland and Ethan B. Russo 111
FIGURE 1. Phytocannabinoids
(% dry weight)
Δ-9-tetrahydrocannabinol (THC) 0.1-25% 157 Euphoriant
cannabidiol (CBD) 0.1-2.89% 160-180 Anxiolytic
cannabinol (CBN) 0.0-1.6% 185 Oxidation
cannabichromene (CBC) 0.0-0.65% 220 Antiinflammatory
cannabigerol (CBG) 0.03-1.15% MP
but rather a peripheral one assuming physical cues of bronchial sensation as
operative in the origin of the benefit. The true scope of the essential oil benefits
in this context may be quite a bit broader.
Pate (1994), McPartland (1997), and McPartland, Clarke and Watson
(2000), have reviewed the pesticidal properties of cannabis attributable to its
terpenoid content. The essential oil of Eugenia dysenterica was recently demonstrated
to have significant inhibitory effects on Cryptococcus neoformans
strains isolated from HIV patients with cryptococcal meningitis (Costa et al.
2000). Key components of that oil were common to cannabis: β-caryophyllene,
α-humulene, α-terpineol, and limonene.
Additionally, monoterpenes such as those abundant in cannabis resin have
been suggested to: (1) inhibit cholesterol synthesis, (2) promote hepatic en-
112 CANNABIS THERAPEUTICS IN HIV/AIDS
FIGURE 1 (continued)
(% dry weight)
Δ-8-tetrahydrocannabinol (Δ-8-THC) 0.0-0.1% 175-178 Resembles
tetrahydrocannabivarin (THCV) 0.0-1.36% < 220 Analgesic Euphoriant *Structures of constituents obtained from Bissett and Wichtl 1994; British Medical Association 1997; Buckingham 1992; Iversen 2000; Tisserand and Balacs 1995; Turner et al. 1980. †Concentrations of constituents (v/w or w/w) were calculated from various sources. Cannabinoid concentrations (presented as a range, including cannabinoids and cannabinoidic acids) were primarily obtained from Small, 1979; Veszki et al., 1980; Fournier et al., 1987; and Pitts et al., 1992. Terpenoid data (presented as maximum values) were calculated from Ross and El Sohly, 1996; and Mediavilla and Steinemann, 1997. Flavonoid data came from Paris et al., 1976; and Barrett et al., 1986. §Boiling/melting points (MP) recorded at atmospheric pressure (760 mmHg) unless otherise noted; values obtained from various sources, primarily Buckingham, 1992; Guenther, 1948; Parry, 1918; and Mechoulam (personal communication, April 2001). O CH3 CH3 OH H3C O OH John M. McPartland and Ethan B. Russo 113 FIGURE 2. Terpenoid essential oil components of cannabis. Cannabis Constituent Structure* Concentration† Boiling Point °C§ Properties β-myrcene 0.47% 166-168 Analgesic Antiinflammatory Antibiotic Antimutagenic β-caryophyllene 0.05% 119 Antiinflammatory Cytoprotective (gastric mucosa) Antimalarial d-limonene 0.14% 177 Cannabinoid agonist? Immune potentiator Antidepressant Antimutagenic linalool 0.002% 198 Sedative Antidepressant Anxiolytic Immune potentiator pulegone 0.001% 224 Memory booster? AChE inhibitor Sedative Antipyretic 1,8-cineole (eucalyptol) > 0.001% 176 AChE inhibitor
α-pinene 0.04% 156 Antiinflammatory
zyme activity to detoxify carcinogens, (3) stimulate apoptosis in cells with
damaged DNA, and (4) inhibit protein isoprenylation implicated in malignant
deterioration (Jones 1999).
Myrcene, specifically β-myrcene, a noncyclic monoterpene, is the most
abundant terpenoid produced by cannabis (Ross and ElSohly 1996; Mediavilla
and Steinemann 1997). It also occurs in high concentrations in hops (Humulus
lupulus) and lemongrass (Cymbopogon citratus). Myrcene is a potent analgesic,
acting at central sites that are antagonized by naloxone (Rao et al. 1990).
Myrcene also works via a peripheral mechanism shared by CBD, CBG, and
CBC–by blocking the inflammatory activity of prostaglandin E2 (Lorenzetti et
al. 1991). This activity is expressed by other terpenoids in cannabis smoke,
114 CANNABIS THERAPEUTICS IN HIV/AIDS
FIGURE 2 (continued)
Cannabis Constituent Structure* Concentration† Boiling
α-terpineol 0.02% 217-218 Sedative
terpineol-4-ol 0.0004% 209 AChE inhibitor
p-cymene 0.0004% 177 Antibiotic
borneol 0.008% 210 Antibiotic
Δ-3-carene 0.004% 168 Antiinflammatory
such as carvacrol, which is more potent than THC or CBG (Burstein et al.
1975). The activity of many terpenoids may be cumulative: unfractionated
cannabis essential oil exhibits greater antiinflammatory activity than its individual
constituents, suggesting synergy (Evans et al. 1987).
Myrcene also synergizes the antibiotic potency of other essential oil components,
against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa,
and a specific strain of Escherichia coli (Onawunmi et al. 1984).
Myrcene inhibits cytochrome P450 2B1, an enzyme implicated in the metabolic
activation of promutagens (De Oliveira et al. 1997). Aflatoxin B1 is a
promutagen produced by Aspergillus flavus and Aspergillus parasiticus, two
fungal contaminants of moldy marijuana (reviewed by McPartland and Pruitt
1997). After aflatoxin B1 is metabolized by P450 2B1, it becomes extremely
hepatocarcinogenic. Myrcene blocks this metabolism, as do other terpenoids
in cannabis, including limonene, α-pinene, α-terpinene, and citronellal (De
Oliveira et al. 1997).
β-Caryophyllene is the most common sesquiterpenoid in cannabis (Mediavilla
and Steinemann 1997). It is the main component of copaiba balsam, from
Copaifera spp. (Lawless 1995), which is a popular oral and topical anti-inflammatory
agent in Brazil (Basile et al. 1988). The latter authors were able to
demonstrate anti-inflammatory effects of the oleoresin in rats comparable to
phenylbutazone, in reduction of granuloma formation. A decreased vascular
permeability to injected histamine was also observed.
A gastric cytoprotective effect of β-caryophyllene was demonstrated in rats
against challenge with absolute ethanol and hydrochloric acid (Tambe et al.
1996). This benefit was noted without influence on gastric acid or pepsin secretion.
The authors suggested this agent as clinically safe, and potentially useful.
Campbell et al. (1997) have demonstrated a moderate antimalarial effect
against two strains of Plasmodium falciparum by an essential oil rich in
β-caryophyllene and α-terpineol.
Limonene is a monocyclic monoterpenoid and a major constituent of citrus
rinds (Tisserand and Balacs 1995). It finds extensive use as a solvent and in the
perfumery and flavor industries. Because of limonene’s widespread occurrence
and application, its biological activity is well known. Limonene is highly
absorbed by inhalation and quickly appears in the bloodstream (Falk-Flilipsson
et al. 1993). According to Ross and ElSohly (1996), limonene is the second
most common terpenoid in an unidentified cultivar of cannabis.
Limonene may have a low-affinity interaction with cannabinoid receptors
(Meschler and Howlett 1999). Studies of long-term inhalation of lemon fragrance
(predominately limonene) have demonstrated inhibition of thymic involution
in stress-induced immunosuppression in mice (Ortiz de Urbina et al.
John M. McPartland and Ethan B. Russo 115
Limonene was the primary component of the essential oil mixture employed
by Komori et al. (1995), in their clinical study of immune function and
depressive states in humans. The key result of this experiment was the ability
to markedly reduce the dosage of, or even eliminate the need for, synthetic antidepressant
As mentioned in the myrcene section, limonene protects against aflatoxin
B1-induced cancer by inhibiting the hepatic metabolism of the promutagen to
its active form. Limonene also blocks this process at two earlier steps by inhibiting
the growth of Aspergillus fungi and inhibiting their production of aflatoxins
(Greene-McDowelle et al. 1999). Limonene and other terpenoids suppress the
growth of many species of fungi and bacteria, demonstrated in hundreds of
published studies (reviewed by McPartland 1997).
Limonene blocks the carcinogenesis induced by benz[α]anthracene (Crowell
1999), a component of the “tar” generated by the combustion of herbal cannabis.
Thus, this terpenoid may reduce the harm caused by inhaling cannabis
smoke. Limonene blocks carcinogenesis by multiple mechanisms. It detoxifies
carcinogens by inducing Phase II carcinogen-metabolizing enzymes (Crowell
1999). It selectively inhibits the isoprenylation of Ras proteins, thus blocking
the action of mutant ras oncogenes (Hardcastle et al. 1999). It induces redifferentiation
of cancer cells (by enhancing expression of transforming growth
factor β1 and growth factor II receptors), and it induces apoptosis of cancer
cells (Crowell 1999). Orally administered limonene is currently undergoing
Phase II clinical trials in the treatment of breast cancer (Vigushin et al. 1998);
it also protects against lung, liver, colon, pancreas, and skin cancers (Vigushin
et al. 1998; Crowell 1999; Setzer et al. 1999).
Linalool is a noncyclic monoterpenoid, commonly extracted from lavender
(Lavandula spp.), rose (Rosa spp.), and neroli oil (from Citrus aurantium). It
usually constitutes 5% or less of cannabis essential oil (Ross and ElSohly
1996). Linalool nevertheless exhibits strong biological activity. Buchbauer et
al. (1993) assayed the sedative effects of over 40 terpenoids upon inhalation
by mice; linalool was the most powerful, reducing mouse motility 73% after 1
hour of inhalation. The study demonstrated that other terpenoids found in cannabis,
such as citronellol and α-terpineol, are also deeply sedating upon inhalation,
even in lowconcentrations. Furthermore, combinations of these terpenoids
(e.g., neroli oil) are synergistic in their sedative effects. These terpenoids may
mitigate the anxiety provoked by pure THC. Inhalation of such terpenoids also
provides antidepressant effects (Komori et al. 1995).
Reducing anxiety and depression will improve immune function via the
neuroendocrine system, by damping down the hypothalamic-pituitary-adrenal
(HPA) axis. Hence, inhalation of terpenoids reduces the secretion of HPA
stress hormones (e.g., corticosterone), and normalizes CD4-CD8 ratios (Komori
et al. 1995). By a similar mechanism, terpenoids in Ginkgo biloba inhibit
116 CANNABIS THERAPEUTICS IN HIV/AIDS
corticosterone secretion by attenuating corticotropin-releasing factor (CRF)
expression (Marcihac et al. 1998). CRF not only induces corticosterone secretion
via the HPA axis, it is also associated with anxiety. Rodríguez de Fonseca
et al. (1996) showed that the psychoactive cannabinoid HU-210 caused a release
of CRF. Thus, the terpenoids act synergistically with non-psychoactive
CBD, which may decrease CRF by inhibiting IFN-γ (Malfait et al. 2000).
Pulegone, a monocyclic monoterpenoid, is a minor constituent of cannabis
(Turner et al. 1980). Higher concentrations of pulegone are found in rosemary
(Rosmarinus officinalis), “the herb of remembrance.” Pulegone may alleviate
a major side effect of THC–loss of short-term memory consolidation. THC
causes acetylcholine (ACh) deficits in the hippocampus. Hippocampal ACh
deficits are also seen in people with Alzheimer’s disease. Alzheimer’s patients
can be treated with tacrine (Cognex), a drug that increases ACh activity by
inhibiting acetylcholinesterase (AChE). Indeed, tacrine has blocked THC-induced
memory loss behavior in rats. Pulegone exhibits the same activity as
tacrine, that of AChE inhibition (Miyazawa et al. 1997). Other terpenoids in
cannabis also provide AChE inhibition, including limonene, limonene oxide,
α-terpinene, γ-terpinene, terpinen-4-ol, carvacrol, l-and d-carvone, 1,8-cineole,
p-cymene, fenchone, and pulegone-1,2-epoxide (Perry et al. 1996; McPartland
and Pruitt 1999). The beneficial effects of AChE inhibitors, however, are decreased
in individuals carrying the E4 subtype of the apolipoprotein E gene,
ApoE E4 (Poirier et al. 1995). Pulegone has also demonstrated significant sedative
and antipyretic properties in a study in rats (Ortiz de Urbina et al. 1989).
1,8-Cineole, a bicyclic monoterpenoid, is a minor constituent of cannabis
and the major aromatic found in Eucalyptus species. Studies show the inhalation
of 1,8-cineole increases cerebral blood flow and enhances cortical activity
(Nasel et al. 1994). Brain function is enhanced by administering terpenoids
that improve cerebral blood flow, much as the ginkgolides in Ginkgo biloba
(Russo 2000). Similarly, cerebral blood flow increases after inhaling cannabis
smoke, and this increase is not related to plasma levels of THC (Mathew and
A stimulatory effect on rat locomotion was demonstrated employing a
1,8-cineole-rich essential oil of rosemary with a terpene profile similar to that
of cannabis (Kovar et al. 1987). Blood levels correlated with the degree of
stimulation observed. Antinociceptive and anti-inflammatory effects of 1,8-
cineole were demonstrated at high doses in rats, using carrageenan rat paw and
cotton pellet-induced granuloma models (Santos and Rao 2000). An analgesic
effect of an essential oil was demonstrated in another animal study, and correlated
with the 1,8-cineole concentration (Aydin et al. 1999).
1,8-Cineole demonstrated antibacterial activity against Bacillus subtilis,
and antifungal properties against Trichophyton mentagrophytes, Cryptococcus
neoformans, and Candida albicans (Hammerschmidt et al. 1993). In subse-
John M. McPartland and Ethan B. Russo 117
quent assays, this essential oil component was cidal against Candida albicans
and Escherichia coli, and bacteriostatic against Staphylococcus aureus (Carson
and Riley 1995). In a rat study, 1,8-cineole prevented the sexual transmission
of Herpes simplex virus type 2 (HSV-2). HSV-2 is a frequently comorbid
condition with HIV, and its prevention has been suggested as one method of
lowering HIV transmission risks (Gwanzura et al. 1998).
Perry et al. (2000) demonstrated that 1,8-cineole was an inhibitor of human
erythrocyte acetylcholinesterase, but that an essential oil of Salvia lavandulaefolia
containing 1,8-cineole and other terpenoids produced a synergistic
inhibition of acetylcholinesterase that suggested utility in the clinical treatment
of Alzheimer’s disease. A similar mechanism may operate in cannabis
essential oil with the same components.
α-Pinene, a bicyclic monoterpenoid, was effective in prevention of acute
inflammation in a carrageenan-induced plantar edema model (Gil et al. 1989).
A pharmacokinetics study of inhaled α-pinene in humans demonstrated 60%
uptake, and a relative bronchodilation effect (Falk et al. 1990). After 1 hour of
inhalation, α-pinene produced a 13.8% increase in mouse motility measures
(Buchbauer et al. 1993). α-Pinene has inhibited acetylcholinesterase in a variety
of assays (Perry et al. 1996; McPartland and Pruitt 1999), suggesting utility
in the clinical treatment of Alzheimer’s disease. The antibiotic properties of
α-pinene, α-terpineol, and terpinen-4-ol have been demonstrated against
Staphylococcus aureus, S. epidermidis and Propionibacterium acnes (Raman
et al. 1995). α-Pinene and its isomer β-pinene were both cytotoxic in vitro
against Hep-G2 (human hepatocellular carcinoma) and Sk-Mel-28 (human
melanoma) tumor cell lines (Setzer et al. 1999).
α-Terpineol, terpinen-4-ol, and 4-terpineol are three closely related monoterpenoids.
Inhalation of α-terpineol reduced mouse motility 45% (Buchbauer
et al. 1993). Burits and Bucar (2000) demonstrated that 4-terpineol exhibits
“respectable” radical scavenging and antioxidant properties. Terpinen-4-ol,
α-terpineol, and α-pinene demonstrated dose-dependent antibiotic properties
against Staphylococcus aureus, S. epidermidis and Propionibacterium acnes
(Raman et al. 1995). Similar studies have demonstrated antimicrobial activity
against a wide range of pathogenic organisms, excluding Pseudomonas (Carson
and Riley 1995). Campbell et al. (1997) have demonstrated a moderate
antimalarial effect against two strains of Plasmodium falciparum by an essential
oil with major α-terpineol and α-caryophyllene components.
Cymene, or p-cymene, a monoterpenoid, is active against Bacterioides
fragilis, Candida albicans, and Clostridium perfringens (Carson and Riley
118 CANNABIS THERAPEUTICS IN HIV/AIDS
Borneol, a bicyclic monoterpenoid, was tested in walnut oil as an external
treatment for purulent otitis media (Liu 1990), where it proved to be 98% effective
(P < 0.001), to a greater degree than neomycin, and without toxicity. Δ3-Carene, a bicyclic monoterpenoid, was effective in prevention of acute inflammation in a carrageenan-induced plantar edema model (Gil et al. 1989). FLAVONOIDS Flavonoids are aromatic, polycyclic phenols. Cannabis produces about 20 of these compounds, as free flavonoids and conjugated glycosides (Turner et al. 1980). Paris et al. (1976) estimated that cannabis leaves consist of 1% flavonoids. Some flavonoids are volatile, lipophilic, permeate membranes, and apparently retain pharmacological activity in cannabis smoke (Sauer et al. 1983). Flavonoids may modulate the pharmacokinetics of THC, via a mechanism shared by CBD, the inhibition of P450 3A11 and P450 3A4 enzymes. Naringenin, a flavonoid in grapefruit juice, also inhibits these enzymes, thus blocking the metabolism of cyclosporine, caffeine, benzodiazepines, and calcium antagonists (Fuhr 1998). Two related enzymes, P450 3A4 and P450 1A1, metabolize environmental toxins from procarcinogens to their activated forms. Thus, P450-suppressing compounds serve as chemoprotective agents, shielding healthy cells from the activation of benzo[α]pyrene and aflatoxin B1 (Offord et al. 1997), which are two procarcinogens potentially found in cannabis smoke (McPartland and Pruitt 1997). Apigenin is a flavone found in nearly all vascular plants (Figure 3). It exerts a wide range of biological effects, including many properties shared by terpenoids and cannabinoids. Apigenin is the primary anxiolytic agent found in chamomile, Matricaria recutita, (reviewed in Russo 2000). It selectively binds with high affinity to central benzodiazepine receptors, which are located in α- and β-subunits of GABAA receptors (Salgueiro et al. 1997); this anxiolytic activity is not associated with the unwanted side effects caused by synthetic benzodiazepines, such as muscular relaxation, amnesia, and sedation. Apigenin inhibits the production of tumor necrosis factor-alpha (TNF-α), a cytokine primarily expressed by monocytes and macrophages (Gerritsen et al. 1995). TNF-α induces and maintains inflammation, a pathological condition in rheumatoid arthritis and multiple sclerosis. THC decreases TNF-α, probably by a nonreceptor-mediated mechanism (Burnette-Curley and Cabral 1995), although one study suggested THC might induce TNF-α (Shivers et al. 1994). Either way, apigenin provides beneficial suppression of TNF-α, whether in concert with THC or counteracting THC. John M. McPartland and Ethan B. Russo 119 Apigenin and other flavonoids interact with estrogen receptors, and appear to be the primary estrogenic agents in cannabis smoke (Sauer et al. 1983). Although apigenin has a high affinity for estrogen receptors (especially β-estrogen receptors), it has low estrogenic activity; apigenin actually inhibits estradiolinduced proliferation of breast cancer cells (Wang and Kurzer 1998). Quercetin is a flavonol found in nearly all vascular plants, including cannabis (Turner et al. 1980). Quercetin is a potent antioxidant; by some measures more potent than ascorbic acid, α-tocopherol, and BHT (Gadow et al. 1997). Combinations of quercetin and other antioxidants work synergistically (Hud- 120 CANNABIS THERAPEUTICS IN HIV/AIDS FIGURE 3. Flavonoid and phytosterol components of cannabis. Cannabis Constituent Structure* Concentration† Boiling Point °C§ Properties apigenin > 0.1% 178 Anxiolytic
quercetin > 0.1% 250 Antioxidant
cannflavin A 0.02% 182 COX inhibitor
β-sitosterol ? 134 Antiinflammatory
son and Mahgoub 1981). The antioxidant potential of quercetin and other
flavonoids should be tested against CBD, another potent antioxidant (Hampson
et al. 1998). Perhaps flavonoids can induce chemical reduction of CBD, effectively
recycling CBD as an antioxidant. Flavonoids block free radical formation
at several steps: by scavenging superoxide anions (in both enzymatic and
non-enzymatic systems), by quenching intermediate peroxyl and alkoxyl radicals,
and by chelating iron ions, which catalyze many Fenton reactions leading
to free radical formation (Musonda and Chipman 1998).
Free radicals activate NF-κB, a transcription factor protein that induces the
expression of oncogenes, inflammation, and apoptosis. Quercetin arrests the
formation of NF-κB, by blocking the PKC-induced phosphorylation of an inhibitory
subunit of NF-κB called IκB (Musonda and Chipman 1998), consequently
quercetin hinders carcinogenesis and inflammatory diseases. NF-κB
also plays a role in the activation of HIV-1 (Greenspan 1993), so quercetin
may hinder the replication of that virus. In a similar fashion, silymarin (a
flavonoid produced by milk thistle, Silybum marianum) impedes NF-κB-induced
replication of the hepatitis C virus, and thus inhibits hepatic carcinoma
(McPartland 1996). These flavonoids may synergize with CBN, which also
downregulates NF-κB (Herring and Kaminski 1999), thereby counteracting
the effects of THC, which may increase NF-κB activity (Daaka et al. 1997).
Cannflavin A is one of a pair of prenylated flavones apparently unique to
cannabis (Barrett et al. 1986). The yield of cannflavin A is 0.02% of dry herb.
This compound is a potent inhibitor of prostaglandin E2 in human rheumatoid
synovial cells, with an IC50 of 31 ng/ml, about 30 times more potent than aspirin
in that system (Barrett et al. 1986). Cannflavin A inhibits cyclooxygenase
(COX) enzymes and lipoxygenase (LO) enzymes more potently than THC
(Evans et al. 1987). However, these assays were done with alcohol-extracted
cannflavin; we question whether cannflavin is sufficiently volatile. Other phenols
related to flavonoids are volatile and apparently retain pharmacological
activity in cannabis smoke, such as eugenol and p-vinylphenol (Burstein et al.
β-Sitosterol was demonstrated in significant concentrations in the red oil
extract of cannabis (Fenselau and Hermann 1972). In animal assays, this
phytosterol reduced acute inflammation 65% and chronic edema 40.6% (Gomez
et al. 1999). This agent has been the subject of most interest as the active ingredient
of Serenoa repens, the saw palmetto, and Urtica dioica, the nettle,
wherein β-sitosterol acts as a 5-α-reductase inhibitor. In numerous trials (Wilt
et al. 1998; McPartland and Pruitt 2000), standardized extracts of saw palmetto
have proven equivalent or superior to finasteride in treatment of benign
John M. McPartland and Ethan B. Russo 121
Does the body absorb non-cannabinoids in physiologically relevant concentrations?
In the absence of experimental data, we can estimate, using
limonene as an example of AChE inhibition. According to Ross and ElSohly
(1996), fresh, female flowering tops consist of 0.29% essential oil. Air drying
of female flowering tops decreases their moisture content (MC) from approximately
85% MC to 15% MC, with a concomitant loss in water weight
(McPartland and Pruitt 1997). Although some essential oil is volatilized and
lost in the drying process, the remaining terpenoids become concentrated. The
concentration of essential oil in air-dried cannabis is 0.8%, and limonene consists
of 17.2% of the essential oil (Ross and ElSohly 1996). Thus, air-dried
cannabis consists of 0.14% limonene; therefore a 500 mg cannabis cigarette
(which is half the size of a standard tobacco cigarette) would contain 0.7 mg
limonene. If we assume the systemic bioavailability of limonene from smoking
cannabis is 18%, the same as THC (Ohlsson et al. 1980), then 0.13 mg
would be absorbed. Distributing this dose evenly in the total body water of a 70
kg man, without metabolism or sequestration, would produce a maximum tissue
concentration of 1.3 μM. This concentration is an order of magnitude below
the IC50 concentration of limonene’s inhibition of AChE (Miyazawa et al.
1997). Hence, limonene must synergize with other AChE inhibitors in order to
Vaporizer technology may improve the bioavailability of limonene and
other compounds, which volatilize around the same temperature as THC (see
Figures 1-3). Vaporizers are smoking apparati that heat cannabis to 185°C
(365°F), which vaporizes THC but is below the ignition point of combustible
plant material. Vaporized cannabis emits a thin gray vapor, whereas combusted
cannabis produces a thick smoke. Thus, vaporizers deliver a better cannabinoid-
to-tar ratio than cigarettes or water pipes (Gieringer 1996). In a recent
study, traces of THC were vaporized at temperatures as low as 140°C (284°F)
and the majority of THC vaporized by 185°C (365°F); benzene and other carcinogenic
vapors did not appear until 200°C (392°F), and cannabis combustion
occurred around 230°C (446°F) (Gieringer 2001).
Concerning bioavailability, it should be mentioned that cannabis compounds
need not be absorbed systemically through the lungs to produce CNS
activity. Inhaled compounds may reach receptors in the olfactory bulb, sending
mood-altering messages via olfactory nerves directly to the limbic region
and hippocampus. This route may be responsible for some sedative effects of
terpenoids upon inhalation (Buchbauer et al. 1993).
The paucity of research concerning non-THC synergists in cannabis is periodically
criticized (Mechoulam et al. 1972; McPartland and Pruitt 1999; Russo
2000). We have highlighted several cannabinoids, terpenoids, and flavonoids
122 CANNABIS THERAPEUTICS IN HIV/AIDS
that deserve further attention regarding their contributions to the effects of
clinical cannabis. Most of the data we present here is based on in vitro experiments
or animal studies. Clearly the next step should involve human clinical
trials of each constituent, alone, or in combination with THC, or combined
with a cocktail of cannabis compounds.
Abrahamov, A., and R. Mechoulam. 1995. An efficient new cannabinoid antiemetic in
pediatric oncology. Life Sci 56(23-24):2097-102.
Achiron, A., S. Miron, V. Lavie, R. Margalit, and A. Biegon. 2000. Dexanabinol
(HU-211) effect on experimental autoimmune encephalomyelitis: implications for
the treatment of acute relapses of multiple sclerosis. J Neuroimmunol 102(1):26-31.
Agrawal, A.K., P. Kumar, A. Gulati, and P.K. Seth. 1989. Cannabis-induced neurotoxicity
in mice: effects on cholinergic (muscarinic) receptors and blood brain barrier
permeability. Res Commun Subst Abuse 10:155-68.
Anderson, P.F., D.M. Jackson, and G.B. Chesher. 1974. Interaction of delta-9-tetrahydrocannabinol
and cannabidiol on intestinal motility in mice. J Pharm Pharmacol
Aydin, S., T. Demir, Y. Ozturk, and K.H. Baser. 1999. Analgesic activity of Nepeta
italica L. Phytother Res 13(1):20-3.
Baek, S.H., Y.O. Kim, J.S. Kwag, K.E. Choi, W.Y. Jung, and D.S. Han. 1998. Boron
trifluoride etherate on silica-A modified Lewis acid reagent (VII). Antitumor activity
of cannabigerol against human oral epitheloid carcinoma cells. Arch Pharmacol
Banerjee, S.P., S.H. Snyder, R. Mechoulam. 1975. Cannabinoids: influence on neurotransmitter
uptake in rat brain synaptosomes. J Pharmacol Exper Therap 194:
Barrett, M.L., A.M. Scutt, and F.J. Evans. 1986. Cannflavin A and B, prenylated flavones
from Cannabis sativa L. Experientia 42:452-3.
Basile, A.C., J.A. Sertie, P.C. Freitas, and A.C. Zanini. 1988. Anti-inflammatory activity
of oleoresin from Brazilian Copaifera. J Ethnopharmacol 22(1):101-9.
Biegon, A., and A.B. Joseph. 1995. Development of HU-211 as a neuroprotectant for
ischemic brain damage. Neurol Res 17(4):275-80.
Bisset, N.G. and M. Wichtl. 1994. Herbal drugs and phytopharmaceuticals: A handbook
for practice on a scientific basis. Stuttgart, Boca Raton: Medpharm Scientific
Publishers, CRC Press.
Bornheim, L.M., K.Y. Kim, J. Li, B.Y. Perotti, and L.Z. Benet. 1995. Effect of
cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in
mouse brain. Drug Metab Dispos 23:825-31.
Boucher, F., M. Paris, and L. Cosson. 1977. Mise en évidence de deux type chimques
chez le Cannabis sativa originaire d’Afrique du Sud. Phytochem 16:1445-8.
British Medical Association. 1997. Therapeutic uses of cannabis. Amsterdam: Harwood
John M. McPartland and Ethan B. Russo 123
Brodkin, J., and J.M. Moerschbaecher. 1997. SR141716A antagonizes the disruptive
effects of cannabinoid ligaands on learning in rats. J Pharmacol Exper Therap
Browne, R.G., and A. Weissman. 1981. Discriminative stimulus properties of delta
9-tetrahydrocannabinol: mechanistic studies. J Clin Pharmacol 21(8-9 Suppl):
Buchbauer, G., L. Jirovetz, W. Jager, C. Plank, and H. Dietrich. 1993. Fragrance compounds
and essential oils with sedative effects upon inhalation. J Pharm Sci
Buckingham, J., editor. 1992. Dictionary of natural products. London: Chapman &
Burits, M., and F. Bucar. 2000. Antioxidant activity of Nigella sativa essential oil.
Phytoth Res 14(5):323-8.
Burnette-Curley, D., and G.A. Cabral. 1995. Differential inhibition of RAW264.7
macrophage tumoricidal activity by Δ9-tetrahydrocannabinol. Proc Soc Exp Biol
Burstein, S., C. Varanelli, and L.T. Slade. 1975. Prostaglandins and Cannabis–III. Inhibition
of biosynthesis by essential oil components of marihuana. Biochemical
Burstein, S., E. Levin, and C. Varanelli. 1973. Prostaglandins and Cannabis–II. Inhibition
of biosynthesis by the naturally occurring cannabinoids. Biochem Pharmacol
Burstein, S., P. Taylor, F.S. El-Feraly, C. Turner. 1976. Prostaglandins and Cannabis–
V. Identification of p-vinylphenol as a potent inhibitor of prostaglandin synthesis.
Biochem Pharmacol 25:2003-4.
Campbell, W.E., D.W. Gammon, P. Smith, M. Abrahams, and T.D. Purves. 1997.
Composition and antimalarial activity in vitro of the essential oil of Tetradenia
riparia. Planta Med 63(3):270-2.
Carlini, E.A., and J.M. Cunha. 1981. Hypnotic and antiepileptic effects of cannabidiol.
J Clin Pharmacol 21:417S-27S.
Carlini, E.A., I.G. Karniol, P.F. Renault, and C.R. Schuster. 1974. Effects of marihuana
in laboratory animals and man. Brit J Pharmacol 50:299-309.
Carson, C.F., and T.V. Riley. 1995. Antimicrobial activity of the major components of
the essential oil of Melaleuca alternifolia. J Appl Bacter 78(3):264-9.
Carta, G., F. Nava, and G.L. Gessa. 1998. Inhibition of hippocampal acetylcholine release
after acute and repeated Δ9-tetrahydrocannabinol in rats. Brain Res 809:1-4.
Cheney, D.L., A.V. Revuelta, and E. Costa. Marijuana and cholinergic dynamics. In G.
Pepeu and H. Ladinsky, eds., 1981. Cholinergic mechanisms: Phylogenetic aspects,
central and peripheral synapses, and clinical significance. New York: Plenum
Clarke, R.C. 1998. Hashish! Los Angeles, CA: Red Eye Press.
Compton, D.R., K.C. Rice, B.R. DeCosta, R.K. Razdan, L.S. Melvin, M.R. Johnson,
and B.R. Martin. 1993. Cannabinoid structure-activity relationships: correlation of
receptor binding and in vivo activities. J Pharmacol Exp Therap 265:218-26.
Consroe, P. 1998. Brain cannabinoid systems as targets for the therapy of neurological
disorders. Neurobiol Dis 5:534-51.
124 CANNABIS THERAPEUTICS IN HIV/AIDS
Costa, T.R., O.F. Fernandes, S.C. Santos, C.M. Oliveira, L.M. Liao, P.H. Ferri, J.R.
Paula, H.D. Ferreira, B.H. Sales, and M.R. Silva. 2000. Antifungal activity of volatile
constituents of Eugenia dysenterica leaf oil. J Ethnopharmacol 72(1-2): 111-7.
Crowell, P.L. 1999. Prevention and therapy of cancer by dietary monoterpenes. J Nutr
Daaka, Y., W. Zhu, H. Friedman, and T.W. Klein. 1997. Induction of interleukin-2 receptor
α gene by Δ9-tetrahydrocannabinol is mediated by nuclear factor κB and
CB1 cannabinoid receptor. DNA Cell Biol 16:301-9.
Dalterio, S., D. Mayfield, A. Bartke, W. Morgan. 1985. Effects of psychoactive and
non-psychoactive cannabinoids on neuroendocrine and testicular responsiveness in
mice. Life Sci 36:1299-306.
Davis, W.M., and N.S. Hatoum. 1993. Neurobehavioral actions of cannabichromene
and interactions with Δ9-tetrahydrocannabinol. Gen Pharmacol 14(2):247-52.
De Oliverira, A.C., L.F. Ribeiro-Pinto, J.R. Paumgartten. 1997. In vitro inhibition of
CYP2B1 monooxygenase by beta-myrcene and other monoterpenoid compounds.
Toxicol Lett 92:39-46.
Devane, W.A., F.A. Dysarz, M.R. Johnson, L.S. Melvin, A.C. Howlett. 1998. Determination
and characterization of a cannabinoid receptor in rat brain. Molecular
Di Marzo, V. and A. Fontana. 1995. Anandamide, an endogenous cannabinomimetic
eicosanoid: “killing two birds with one stone.” Prostagland Leukotr Essent Fatty
Domino, E.F. 1976. Effect of Δ9-terahydrocannabinol and cannabinol on rat brain acetylcholine.
In Nahas G.G., Panton W.D.M., Idanpaan-Heikkila J.E., eds. Marijuana:
chemistry, biochemistry, and cellular effects. New York: Springer-Verlag:
ElSohly, H.N., C.E. Turner, A.M. Clark, and M.A. ElSohly. 1982. Synthesis and
antimicrobial activities of certain cannabichromene and cannabigerol related compounds.
J Pharmaceut Sci 71:1319-23.
ElSohly, M.A., S. Feng, T.P. Murphy, S.A. Ross, A. Nimrod, Z. Mehmedic, and N.
Fortner. 1999. Delta-9-tetrahydrocannabivarin (delta-9-THCV) as a marker for the
ingestion of cannabis versus Marinol. J Analyt Toxicol 23(3):222-4.
Evans, A.T., E.A. Formukong, and F.J. Evans. 1987. Actions of cannabis constituents
on enzymes of arachidonate metabolism: anti-inflammatory potential. Bioch Pharmacol
Evans, F.J. 1991. Cannabinoids: the separation of central from peripheral effects on a
structural basis. Planta Med 57(Suppl 1):S60-7.
Fairbairn, J.W., and J.T. Pickens. 1981. Activity of cannabis in relation to its delta1-
trans-tetrahydro-cannabinol content. British J Pharmacol 72:401-9.
Falk, A.A., M.T. Hagberg, A.E. Lof, E.M. Wigaeus-Hjelm, and Z.P. Wang. 1990. Uptake,
distribution and elimination of alpha-pinene in man after exposure by inhalation.
Scand J Work Envir Health 16(5):372-8.
Falk-Filipsson, A., A. Löf, M. Hagberg, E.W. Hjelm, and Z. Wang. 1993. d-Limonene
exposure to humans by inhalation: uptake, distribution, elimination, and effects on
the pulmonary function. J Toxicol Envir Health 38:77-88.
John M. McPartland and Ethan B. Russo 125
Faubert, B.L., and N.E. Kaminski. 2000. AP-1 activity is negatively regulated by
cannabinol through inhibition of its protein components, c-fos and c-jun. J Leukocyte
Fenselau, C., and G. Hermann. 1972. Identification of phytosterols in red oil extract of
cannabis. J Forens Sci 17(2):309-12.
Foletta, V.C., D.H. Segal, and D.R. Cohen. 1998. Transcriptional regulation in the immune
system: all roads lead to AP-1. J Leukocyte Biol 63:139-52.
Formukong, E.A., A.T. Evans, and F.J. Evans. 1988. Inhibition of the cataleptic effect
of tetrahydrocannabinol by other constituents of Cannabis sativa L. J Pharm
Franchomme, P. and Pénoël. 1990. L’aromathérapie exactement. Limoges, France:
Fournier, G., C. Richez-Dumanois, J. Duvezin, J.P. Mathieu, and M. Paris. 1987. Identification
of a new chemotype in Cannabis sativa: cannabigerol-dominant plants,
biogenetic and agronomic prospects. Planta Med 53:277-80.
Fuhr, U. 1998. Drug interactions with grapefruit juice. Extent, probable mechanism
and clinical relevance. Drug Safety 18:251-72.
Gadow, A von, E. Joubert, and C.G. Hansmann. 1997. Comparison of the antioxidant
activity of aspalathin with that of other plant phenols of rooibos tea (Aspalathus
linearis), α-tocopherol, BHT, and BHA. J Agricult Food Chem 45:632-8.
Gallily, R., A. Yamin, Y. Waksmann, H. Ovadia, J. Weidenfeld, A. Bar-Joseph, A.
Biegon, R. Mechoulam, and E. Shohami. 1997. Protection against septic shock and
suppression of tumor necrosis factor alpha and nitric oxide production by dexanabinol
(HU-211), a nonpsychotropic cannabinoid. J Pharm Exper Therap 283(2):
Gerritsen, M.E., W.W. Carley, G.E. Ranges, C.-P. Shen, S.A. Phan, G.F. Ligon, and
C.A. Perry. 1995. Flavonoids inhibit cytokine-induced endothelial cell adhesion
protein gene expression. Am J Path 147:278-92.
Gieringer, D. 1996. Marijuana research: waterpipe study. MAPS [Multidisciplinary
Association for Psychedelic Studies] Bull 6(3):59-66.
Gieringer, D. 2001. NORML study shows vaporizers reduce marijuana smoke toxins.
California NORML Reports 25(1):2.
Gil, M.L., J. Jimenez, M.A. Ocete, A. Zarzuelo, and M.M. Cabo. 1989. Comparative
study of different essential oils of Bupleurum gibraltaricum Lamarck. Pharmazie
Gill, E.W., W.D.M. Paton, and R.G. Pertwee. 1970. Preliminary experiments on the
chemistry and pharmacology of Cannabis. Nature 228:134-6.
Gomez, M.A., M.T. Saenz, M.D. Garcia, and M.A. Fernandez. 1999. Study of the topical
anti-inflammatory activity of Achillea ageratum on chronic and acute inflammation
models. Zeitscrift fur Naturforsch [C] 54 (11):937-41.
Greene-McDowelle, D.M., B. Ingber, M.S. Wright, H.J. Zeringue, D. Bhatnagar, and
T.E. Cleveland. 1999. The effects of selected cotton-leaf volatiles on growth, development
and aflatoxin production of Aspergillus parasiticus. Toxicon 37: 883-93.
Greenspan, H.C. 1993. The role of reactive oxygen species, antioxidants and phytopharmaceuticals
in human immunodeficiency virus activity. Med Hypoth 40:85-92.
126 CANNABIS THERAPEUTICS IN HIV/AIDS
Grinspoon, L., J.B. Bakalar. 1997. Marihuana, the forbidden medicine, revised edition.
New Haven, CT: Yale University Press.
Guenther, E. 1948. The essential oils: Individual essential oils of the plant families.
New York: D. Van Nostrand.
Gwanzura, L., W. McFarland, D. Alexander, R. L. Burke, and D. Katzenstein. 1998.
Association between human immunodeficiency virus and herpes simplex virus type
2 seropositivity among male factory workers in Zimbabwe. J Infect Dis 177(2):
Hammerschmidt, F.J., A.M. Clark, F.M. Soliman, E.S. el-Kashoury, M.M. Abd el-Kawy,
and A.M. el-Fishawy. 1993. Chemical composition and antimicrobial activity of essential
oils of Jasonia candicans and J. montana. Planta Med 59(1): 68-70.
Hampson, A.J., M. Grimaldi, J. Axelrod, and D. Wink. 1998. Cannabidiol and ()
Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci
Hardcastle, I.R., M.G. Rowlands, A.M. Barber, R.M. Grimshaw, M.K. Mohan, B.P.
Nutley, and M. Jarman. 1999. Inhibition of protein prenylation by metabolites of
limonene. Biochem Pharmacol 57:801-9.
Hatoum, N.S., W.M. Davis, M.A. ElSohly, and C.E. Turner. 1981. Cannabichromene
and of Δ9-tetrahydrocannabinol: interactions relative to lethality, hypothermia, and
hexobarbital hypnosis. Gen Pharmacol 12:357-62.
Herring, A.C., N.E. Kaminski. 1999. Cannabinol-mediated inhibition of nuclear factor-
κB, cAMP response element-binding protein, and interleukin-2 secretion by activated
thymocytes. J Pharmacol Exp Therap 291:1156-63.
Heyser, C.J., R.E. Hampson, and S.A. Deadwyler. 1993. Effects of Δ9-tetrahydrocannabinol
on delayed match to sample performance in rats: alterations in shortterm
memory associated with changes in task specific firing of hippocampal cells.
J Pharmacol Exp Therap 264:294-307.
Hollister, L.E. 1974. Structure-activity relationships in man of cannabis constituents,
and homologs and metabolites of delta-9-tetrahydrocannabinol. Pharmacol 11(1):
Hudson, B.J.F., and S.E.O. Mahgoub. 1981. Synergism between phospholipids and
naturally-occurring antioxidants in leaf lipids. J Sci Food Agricult 32:208-10.
Jones, C.L.A. 1999. Monoterpenes: Essence of a cancer cure. Nutr Sci News 4 (4):190.
Kapeghian, J.C., A.B. Jones, J.C. Murphy, M.A. Elsohly, and C.E. Turner. 1983. Effect
of cannabichromene on hepatic microsomal enzyme activity in the mouse. Gen
Klein, T.W., C. Newton, and H. Friedman. 1987. Inhibition of natural killer cell function
by marijuana components. J Toxicol Envir Health 20:321-32.
Klein, T.W., H. Friedman, and S. Specter. 1998. Marijuana, immunity and infection.
J Neuroimmunol 83:102-5.
Klingeren, B.V., and M.T. Ham. 1976. Antibacterial activity of Δ9-tetrahydrocannabinol
and cannabidiol. Antonie van Leeuwenhoek 42:9-12.
Komori, T., R. Fujiwara, M. Tanida, J. Nomura, and M.M. Yokoyama. 1995. Effects of
citrus fragrance on immune function and depressive states. Neuroimmunomod
John M. McPartland and Ethan B. Russo 127
Komori, T., R. Fujiwara, M. Tanida, J. Nomura, and M.M. Yokoyama. 1995. Effects of
citrus fragrance on immune function and depressive states. Neuroimmunomod
Kovar, K.A., B. Gropper, D. Friess, and H.P. Ammon. 1987. Blood levels of
1,8-cineole and locomotor activity of mice after inhalation and oral administration
of rosemary oil. Planta Med 53(4):315-8.
Kubena, R.K., and H. Barry. 1972. Stimulus characteristics of marihuana components.
Lawless, J. 1995. The illustrated encyclopedia of essential oils: the complete guide to
the use of oils in aromatherapy and herbalism. Shaftesbury, Dorset, UK: Element.
Liu, S.L. 1990. [Therapeutic effects of borneol-walnut oil in the treatment of purulent
otitis media]. Chung Hsi I Chieh Ho Tsa Chih 10(2):93-5, 69.
Lorenzetti, B.B., G.E.P. Souza, S.J. Sarti, D. Santos Filho, and S.H. Ferreira. 1991.
Myrcene mimics the peripheral analgesic activity of lemongrass tea. J Ethnopharmacol
Malfait, A.M., R. Gallily, P.F. Sumariwalla, A.S. Malik, E. Andreakos, R. Mechoulam,
and M. Feldman. 2000. The nonpsychoactive cannabis constituent cannabidiol is an
oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad
Malingré, T., H. Hendriks, S. Batterman, R. Bos, and J. Visser. 1975. The essential oil
of Cannabis sativa. Planta Med 28:56-61.
Marcihac, A., N. Dakine, N. Bourhim, V. Guillaume, M. Grino, K. Drieu, and C. Oliver.
1998. Effect of chronic administration of Ginkgo biloba extract or kinkgolide
on the hypothalamic-pituitary-adrenal axis in the rat. Life Sci 62:2329-40.
Martin, L., D.M. Smith, and C.G. Farmilo. 1961. Essential oil from fresh Cannabis
sativa and its use in identification. Nature 191:774-6.
Mathew, R.J., and W.H. Wilson. 1993. Acute changes in cerebral blood flow after
smoking marijuana. Life Sci 52:757-67.
McPartland, J.M., and P.L. Pruitt. 2000. Benign prostatic hyperplasia treated with saw
palmetto: a literature search and an experimental case study. J Amer Osteopath
McPartland, J.M. 1984. Pathogenicity of Phomopsis ganjae on Cannabis sativa and
the fungistatic effect of cannabinoids produced by the host. Mycopathologia 87:
McPartland, J.M. 1996. Viral hepatitis treated with Phyllanthus amarus and milk thistle
(Silybum marianum): a case report. Complement Med Internat 3(2):40-2.
McPartland, J.M. 1997. Cannabis as a repellent crop and botanical pesticide. J Internat
Hemp Assoc 4(2):89-94.
McPartland, J.M., R.C. Clarke, and D.P. Watson. 2000. Hemp diseases and pests:
Management and biological control. Wallingford: UK. CABI.
McPartland, J.M., and P.P. Pruitt. 1999. Side effects of pharmaceuticals not elicited by
comparable herbal medicines: the case of tetrahydrocannabinol and marijuana.
Altern Therap 5(4):57-62.
McPartland, J.M., and P.P. Pruitt. 1997. Medical marijuana and its use by the immunocompromised.
Altern Therap 3(3):39-45.
128 CANNABIS THERAPEUTICS IN HIV/AIDS
Mechoulam, R., and S. Ben-Shabat. 1999. From gan-zi-gun-nu to anandamide and
2-arachidonoylglycerol: The ongoing story of cannabis. Nat Prod Rep 16(2):
Mechoulam, R., and Y. Gaoni. 1967. Recent advances in the chemistry of hashish.
Fortschritte der Chemie Organischer Naturstoffe 25:175-213.
Mechoulam, R., and Y. Gaoni. 1965. Hashish–IV. The isolation and structure of
cannabinolic, cannabidiolic, and cannabigerolic acids. Tetrahedr 21:1223-9.
Mechoulam, R., Z. Ben-Zvi, A. Shani, H. Zemler, and S. Levy. 1972. Cannabinoids
and Cannabis activity. In: Cannabis and its derivatives. Paton WDM, Crown J, eds.
London: Oxford University Press, pp. 1-13.
Mediavilla, V., and S. Steinemann. 1997. Essential oil of Cannabis sativa L. strains.
J Internat Hemp Assoc 4(2):82-4.
Meier, C., Mediavilla, V. 1998. Factors influencing the yield and the quality of hemp
(Cannabis sativa L.) essential oil. J Internat Hemp Assoc 5(1):16-20.
Merkus, F.W.H.M. 1971. Cannabivarin and tetrahydrocannabivarin, two new constituents
of hashish. Nature 232:580-1.
Meschler, J.P., and A.C. Howlett. 1999. Thujone exhibits low affinity for cannabinoid
receptors but fails to evoke cannabimimetic responses. Pharmacol Biochem Behav
Misner, D.L., and J.M. Sullivan. 1999. Mechanism of cannabinoid effects on longterm
potentiation and depression in hippocampal CA1 neurons. J Neurosci 19(16):
Miyazawa, M., H. Watanabe, and H. Kameoka. 1997. Inhibition of acetylcholinesterase
activity by monoterpenoids with a p-methane skeleton. J Agricult Food Chem
Musonda, C.A., and J.K. Chipman. 1998. Quercetin inhibits hydrogen peroxide-induced
NF-κB DNA binding activity and DNA damage in HepG2 cells. Carcinogen
Musty, R.E., I.G. Karniol, I. Shirakawa, N. Takahshi, and E. Knobel. Interactions of
Δ9-THC and cannabinol in man. In: Pharmacology of marihuana, MC Braude and
S. Szara, eds. Raven Press, NY. Vol. 2:559-63.
Nasel, C., B. Nasel, P. Samec, E. Schindler, and G. Buchbauer. 1994. Functional imaging
of effects of fragrances on the human brain after prolonged inhalation. Chem
Nigam, M.C., K.L. Handa, I.C. Nigam, and L. Levi. 1965. Essential oils and their constituents.
XXIX. The essential oil of marihuana: composition of the genuine Indian
Cannabis sativa L. Canad J Chem 43:3372-6.
O’Neil, J.D., W.S. Dalton, and R.B. Forney. 1979. The effect of cannabichromene on
mean blood pressure, heart rate, and respiration rate responses to tetrahydrocannabinol
in the anesthetized rat. Toxicol Appl Pharmacol 49:265-70.
Offord, E.A., K. Macé, O. Avanti, and A.M.A. Pfeifer. 1997. Mechanisms involved in
the chemoprotective effects of rosemary extract studied in human liver and bronchial
cells. Cancer Lett 114:275-81.
Ohlsson, A., J.E. Lindgren, A. Wahlen, S. Agurell, L.E. Hollister, and H.K. Gillespie.
1980. Plasma Δ9-tetrahydrocannabinol concentrations and clinical effects after oral
and intravenous administration and smoking. Clin Pharmacol Therap 28:409-16.
John M. McPartland and Ethan B. Russo 129
Onawunmi, G.O., W.A. Yisak, and E.O. Ogunlana. 1984. Antibacterial constituents in
the essential oil of Cymbopogon citratus (DC.) Stapf. J Ethnopharmacol 12(3):
Ortiz de Urbina, A.V., M.L. Martin, M.J. Montero, A. Moran, and L. San Roman.
1989. Sedating and antipyretic activity of the essential oil of Calamintha sylvatica
subsp. ascendens. J Ethnopharmacol 25(2):165-71.
Paris, R.R., E. Henri, and M. Paris. 1976. Sur les c-flavonoïdes du Cannabis sativa L.
Plantes Médicinales et Phytothérapie 10:144-54.
Parry, E.J. 1918. The chemistry of essential oils and artificial perfumes. 2 vols. London:
Scott, Greenwood and Son.
Pate, D. 1994. Chemical ecology of cannabis. J Internat Hemp Assoc 2:32-7.
Pate, D. 1999. Anandamide structure-activity relationships and mechanisms of action
on intraocular pressure in the normotensive rabbit model. PhD thesis, University of
Kuopio, Finland, 99 pp.
Perry, N.S., P. J. Houghton, A. Theobald, P. Jenner, and E. K. Perry. 2000. In-vitro inhibition
of human erythrocyte acetylcholinesterase by salvia lavandulaefolia essential
oil and constituent terpenes. J Pharm Pharmacol 52(7):895-902.
Perry, N., G. Court, N. Bidet, J. Court, and E. Perry. 1996. European herbs with
cholinergic activity: potential in dementia therapy. Internat J Geriatr Psych 11:
Petitet, F., B. Jeantaud, A. Imperato, and M.C. Dubroeucq. 1998. Complex pharmacology
of natural cannabinoids: evidence for partial agonist activity of Δ9-tetrahydrocannabinol
and antagonist activity of cannabidiol on rat brain cannabinoid
receptors. Life Sci 63:PL1-6.
Pitts, J.E., J.D. Neal, and T.A. Gough. 1992. Some features of Cannabis plants grown
in the United Kingdom from seeds of known origin. J Pharm Pharmacol 44(12):
Poddar, M.K., and W.L. Dewey. 1980. Effects of cannabinoids on catecholamine uptake
and release in hypothalamic and striatal synaptosomes. J Pharmacol Exper
Poirier, J., M.C. Delisle, R. Quirion, et al. 1995. Apolipoprotein E4 allele as a predictor
of cholinergic deficits and treatment outcome in Alzheimer’s disease. Proc Natl
Acad Sci 92:12260-4.
Raman, A., U. Weir, and S.F. Bloomfield. 1995. Antimicrobial effects of tea-tree oil
and its major components on Staphylococcus aureus, Staph. epidermidis and
Propionibacterium acnes. Lett Appl Microbiol 21(4):242-5.
Rao, V.S.N., A.M.S. Menezes, and G.S.B. Viana. 1990. Effect of myrcene on nociception
in mice. J Pharm Pharmacol 42:877-8.
Rodríguez de Fonseca, F., P. Rubio, F. Menzaghi, E. Merlo-Pich, J. Rivier, G.F. Koob,
and M. Navarro. 1996. Corticotropin-releasing factor (CRF) antagonist (D-Phe12,
Nle21, CαMeLeu37) CRF attenuates the acute actions of the highly potent cannabinoid
receptor agonist HU-210 on defensive-withdrawal behavior in rats. J Pharm
Exp Therap 276:56-64.
Rose, J.E., and F.M. Behm. 1994. Inhalation of vapor from black pepper extract reduces
smoking withdrawal symptoms. Drug Alcohol Dep 34(3):225-9.
130 CANNABIS THERAPEUTICS IN HIV/AIDS
Ross, S.A., and M.A. ElSohly. 1996. The volatile oil composition of fresh and air-dried
buds of Cannabis sativa. J Natl Prod 59:49-51.
Russo, E.B. 2000. Handbook of psychotropic herbs: A scientific analysis of herbal
remedies for psychiatric conditions. Binghamton, NY: The Haworth Press, Inc.
Russo, E., C.M. Macarah, C.L. Todd, R.S. Medora, and K.K. Parker. 2000. Pharmacology
of the essential oil of hemp at 5-HT1A and 5-HT2a receptors. Poster at 41st Annual
Meeting of the American Society of Pharmacognosy, July 22-26, Seattle, WA.
Russo, E.B. 2001. Hemp for headache: an in-depth historical and scientific review of
cannabis in migraine treatment. J Cann Therap 1(2):21-92.
Salgueiro, J.B., P. Ardenghi, M. Dias, M.B.C. Ferreira, I. Izquierdo, and J.H. Medina.
1997. Anxiolytic natural and synthetic flavonoid ligands of the central benzodiazepine
receptor have no effect on memory tasks in rats. Pharmacol Biochem Behav
Santos, F.A., and V.S. Rao. 2000. Antiinflammatory and antinociceptive effects of
1,8-cineole a terpenoid oxide present in many plant essential oils. Phytother Res
Sauer, M.A., S.M. Rifka, R.L. Hawks, G.B. Cutler, and D.L. Loriaux. 1983. Marijuana:
interaction with the estrogen receptor. J Pharm Exper Therap 224:404-7.
Setzer, W.N., M.C. Setzer, D.M. Moriarity, R.B. Bates, and W.A. Haber. 1999. Biological
activity of the essential oil of Myrcianthes sp. nov. “black fruit” from
Monteverde, Costa Rica. Planta Med 65(5):468-9.
Shen, M., and S.A. Thayer. 1999. Δ9-tetrahydrocannabinol acts as a partial agonist to
modulate glutamatergic synaptic transmission between rat hippocampal neurons in
culture. Molec Pharmacol 55:8-13.
Shimizu, E., Y.P. Tang, C. Rampon, and J.Z. Tsien. 2000. NMDA receptor-dependent
synaptic reinforcement as a crucial process for memory consolidation. Science
Shivers, S.C., C. Newton, H. Friedman, and T.W. Klein. 1994. Δ9-Tetrahydrocannabinol
(THC) modulates IL-1 bioactivity in human monocyte/macrophage cell
lines. Life Sci 54:1281-9.
Showalter, V.M., D.R. Compton, B.R. Martin, and M.E. Abood. 1996. Evaluation of
binding in a transfected cell line expressing a peripheral cannabinoid receptor
(CB2): identification of cannabinoid receptor subtype selective ligands. J Pharm
Exper Therap 278:989-99.
Small, E. 1979. The Species problem in cannabis. Volume 1: Science. Ottawa: Corpus
Information Services Limited.
Sparacino, C.M., P.A. Hyldburg, and T.J. Hughes. 1990. Chemical and biological
analysis of marijuana smoke condensate. NIDA Res Monogr 99:121-40.
Tambe, Y., H. Tsujiuchi, G. Honda, Y. Ikeshiro, and S. Tanaka. 1996. Gastric
cytoprotection of the non-steroidal anti-inflammatory sesquiterpene, beta-caryophyllene.
Planta Med 62(5):469-70.
Tashkin, D.P., S. Reiss, B.J. Shapiro, B. Calvarese, J.L. Olsen, and W. Lodge. 1977.
Bronchial effects of aerosolized Δ9-tetrahydrocannabinol in healthy and asthmatic
subjects. Am Rev Resp Dis 115:57-65.
John M. McPartland and Ethan B. Russo 131
Thompson, G.R., H. Rosenkrantz, U.H. Schaeppi, and M.C. Braude. 1973. Comparison
of acute oral toxicity of cannabinoids in rats, dogs and monkeys. Toxicol Appl
Tisserand, R., and T. Balacs. 1995. Essential oil safety: A guide for health care professionals.
Edinburgh: Churchill Livingstone.
Turner, C.E., M.A. Elsohly, and E.G. Boeren. 1980. Constituents of Cannabis sativa L.
XVII. A review of the natural constituents. J Nat Prod 43:169-304.
Veszki, P., G. Verzár-Petri, and S. Mészáros. 1980. Comparative phytochemical study
on the cannabinoid composition of the geographical varieties of Cannabis sativa L.
under the same condition. Herba Hungarica 19:95-102.
Vigushin, D.M., G.K. Poon, A. Boddy, J. English, G.W. Halbert, C. Pagonis, M.
Jarman, and R.C. Coombes. 1998. Phase I and pharmacokinetic study of D-limonene
in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical
Trials Committee. Cancer Chemother Pharmacol 42(2):111-7.
Walton, R.P. 1938. Marihuana, America’s new drug problem. J.B. Lippincott Co.,
Wang, C., and M.S. Kurzer. 1998. Effects of phytoestrogens on DNA synthesis in
MCF-7 cells in the presence of estradiol or growth factors. Nutr Cancer 31:90-100.
Wilt, T.J., A. Ishani, G. Stark, R. MacDonald, J. Lau, and C. Mulrow. 1998. Saw palmetto
extracts for treatment of benign prostatic hyperplasia: a systematic review.
J Amer Med Assoc 280(18):1604-9.
Wirth, P.W., E.S. Watson, M. ElSohly, C.E. Turner, and J.C. Murphy. 1980. Anti-inflammatory
properties of cannabichromene. Life Sci 26:1991-5.
Zuardi, A.W., I. Shirakawa, E. Finkelfarb, and I.G. Karniol. 1982. Action of cannabidiol
on the anxiety and other effects produced by Δ9-THC in normal subjects.
Zuardi, A.W., S.L. Morais, F.S. Guimarães, and R. Mechoulam. 1995. Antipsychotic
effect of cannabidiol. J Clin Psychiatr 56:485-6.
132 CANNABIS THERAPEUTICS IN HIV/AIDS