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Cannabis and Cannabis Extracts: Greater Than the Sum of Their Parts?



. 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 syn-ergy. Other herbal constituents may mitigate the side effects of dominant active ingredients. We reviewed the literature concerning medical can-nabis and its primary active ingredient, ∆ 9 -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 activ-ity. [Article copies available for a fee from The Haworth Document Delivery Service: and: Cannabis Therapeutics in HIV/AIDS (ed: Ethan Russo) The Haworth Integrative Healing Press, an imprint of The Haworth Press, Inc., 2001, pp. 103-132. Single or multiple copies of this arti-cle are available for a fee from The Haworth Document Delivery Service [1-800-342-9678, 9:00 a.m. -5:00 p.m. (EST). E-mail address:].
Cannabis and Cannabis Extracts:
Greater Than the Sum of Their Parts?
John M. McPartland
Ethan B. Russo
SUMMARY. 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 syn-
ergy. Other herbal constituents may mitigate the side effects of dominant
active ingredients. We reviewed the literature concerning medical can-
nabis and its primary active ingredient, 9-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 activ-
ity. [Article copies available for a fee from The Haworth Document Delivery
Service: 1-800-342-9678. E-mail address: <>
Website: <> 2001 by The Haworth Press, Inc.
All rights reserved.]
John M. McPartland, DO, MS, is affiliated with GW Pharmaceuticals, Ltd., Porton
Down Science Park, Salisbury, Wiltshire, SP4 0JQ, UK.
Ethan B. Russo, MD, is affiliated with Montana Neurobehavioral Specialists, 900
North Orange Street, Missoula, MT 59802 USA.
Address correspondence to: John M. McPartland, DO, Faculty of Health & Environ-
mental Science, UNITEC, Private Bag 92025, Auckland, New Zealand (E-mail: jmcpartland
The authors thank David Pate and Vincenzo Di Marzo for pre-submission reviews.
[Haworth co-indexing entry note]: “Cannabis and Cannabis Extracts: Greater Than the Sum of Their
Parts?” McPartland, John M., and Ethan B. Russo. Co-published simultaneously in Journal of Cannabis Ther-
apeutics (The Haworth Integrative Healing Press, an imprint of The Haworth Press, Inc.) Vol. 1, No. 3/4,
2001, pp. 103-132; and: Cannabis Therapeutics in HIV/AIDS (ed: Ethan Russo) The Haworth Integrative
Healing Press, an imprint of The Haworth Press, Inc., 2001, pp. 103-132. Single or multiple copies of this arti-
cle are available for a fee from The Haworth Document Delivery Service [1-800-342-9678, 9:00 a.m. - 5:00
p.m. (EST). E-mail address:].
2001 by The Haworth Press, Inc. All rights reserved. 103
KEYWORDS. Cannabis, marijuana, THC, cannabinoids, phytocanna-
binoids, cannabidiol, cannabichromene, cannabibigerol, tetrahydrocanna-
bivarin, terpenoids, essential oils, flavonoids, herbal medicine, medicinal
plants, herbal synergy
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 com-
pounds, 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(9-tetrahydrocannabinol, THC), a syn-
thetic, 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 ex-
pected from their THC content.” Similarly, Fairbairn and Pickens (1981) de-
tected 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 reac-
tions, and paranoia (Grinspoon and Bakalar 1997). This difference in side ef-
fect 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 metab-
olism, so less 11-hydroxy THC is formed. Thus, “smoking cannabis is a satis-
factory 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 ben-
eficial THC activity and reduce side effects are relatively unknown. The pur-
pose of this paper is to review the biochemistry and physiological effects of
those other compounds.
MEDLINE (1966-2000) was searched using MeSH keywords: cannabin-
oids, marijuana, tetrahydrocannabinol. AGRICOLA (1990-1999) was searched
using the keywords cannabis, hemp, and marijuana. Phytochemical and ethno-
botanical databases were searched via the Agricultural Research Service
webpage <>. 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.
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 activ-
ity 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 defini-
tion, as has the discovery of endogenous cannabinoids (e.g., anandamide), de-
fined as “endocannabinoids” by DiMarzo and Fontana (1995). Thus, Pate
(1999) proposed the term “phytocannabinoids” to designate the C21 com-
pounds produced by cannabis. Phytocannabinoids exhibit very low mamma-
lian 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 para-
doxical, 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 clini-
cal 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 ago-
nist (Petitet et al. 1998), (2) CBD may modulate signal transduction by per-
turbing 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 unmetabo-
lized THC (Browne and Weissman 1981), and four times more immuno-
suppressive (Klein et al. 1987).
CBD provides antipsychotic benefits (Zuardi et al. 1995). It increases dopa-
mine activity, serves as a serotonin uptake inhibitor, and enhances norepin-
ephrine 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 con-
solidation. 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 Moersch-
baecher 1997).
Consroe (1998) presented an excellent review of CBD in neurological dis-
orders. 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 anti-
epileptic drug).
CBD demonstrated a synergistic benefit in the reduction of intestinal motil-
ity in mice produced by THC (Anderson, Jackson, and Chesher 1974). This
may be an important component of observed benefits of cannabis in inflamma-
tory bowel diseases.
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-
imum inhibition than THC, and it blocks lipoxygenase (the enzyme that pro-
duces 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 clin-
ical improvement, and the treatment effectively blocked progression of the ar-
thritis (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 In-
terferon-gamma (IFN-γ), which are two immunomodulatory cytokines de-
scribed 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 impor-
tant 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 in-
creases 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 CB1receptors (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 effi-
cacy of THC; when CBN is added to THC, the effects are not significantly ad-
ditive. CBN has a three-fold greater affinity for CB2receptors (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 re-
sponse element-binding protein (CREB), nuclear factor κB (NF-κB), and
interleukin-2 (IL-2). IL-2 is regulated by activator protein-1 (AP-1) transcrip-
tion 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 activa-
tion of ERK MAP kinases (Faubert and Kaminski 2000).
Cannabichromene (CBC) is the fourth major cannabinoid, found predomi-
nantly 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 in-
flammation (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 ac-
tivity 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 en-
zymes (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 mea-
sured. In mice, CBC causes hypothermia, sedation, and synergizes the depres-
sant effects of hexobarbital (Hatoum et al. 1981). CBC also sedates dogs and
decreases muscular coordination in rats, but causes no cannabimimetic activ-
ity 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 “inac-
tive” when compared to THC, but CBG has slight affinity for CB1receptors,
approximately the same as CBD (Devane et al. 1988). In rat brains, CBG in-
hibits the uptake of serotonin and norepinephrine, less effectively than CBD
and THC, but CBG inhibits GABA uptake more 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 (8-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 8-THC is
126 nM (Compton et al. 1993), and this loosely correlates with human studies,
which show 8-THC is less psychoactive than 9-THC (Hollister 1974). The
chemical stability of 8-THC and its relative ease of synthesis compared to
9-THC, have made 8-THC the template for the development of two impor-
tant synthetic derivatives, the extremely potent psychoactive CB1agonist,
HU-210 (Mechoulam and Ben-Shabat 1999), and the non-psychoactive anti-
emetic and neuroprotectant, HU-211 (dexanabinol) (Achiron et al. 2000;
Biegon and Joseph 1995; Gallily et al. 1997). 8-THC was employed clini-
cally 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/m2to treat chemotherapy-associated
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
(2-13 years).
Tetrahydrocannabivarin (THCV) is a propyl analogue of 9-THC, primar-
ily 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 9-THC (Hollister 1974). It has a
quicker onset of action than 9-THC (Gill et al. 1970), and is of briefer dura-
tion (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 hypothe-
size 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 Enforce-
ment Act of 1986 (Public Law 99-570). THCV is of interest from a medical-le-
gal 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 skele-
tons), 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 es-
sential 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 Kash-
mir. 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). Pre-
venting 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 com-
position 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 mem-
branes. 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 affin-
ity for CB1receptors (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 in-
hibitors (as does Prozac), enhance norepinephrine activity (as do tricyclic
antidepressants), increase dopamine activity (as do monoamine oxidase inhib-
itors and bupropion), and augment GABA (as do baclofen and the benzodiaz-
epines). Recently, strong serotonin activity at the 5-HT1A and 5-HT2a receptors
has been demonstrated (Russo et al. 2000; Russo 2001) that may support syn-
ergistic contributions of terpenoids on cannabis-mediated pain and mood ef-
fects. Further studies are in progress to identify the most active terpenoid
components responsible, and whether synergism of the components is demon-
The essential oil of cannabis is traditionally employed as an anti-inflamma-
tory 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 sup-
ports this contention based on terpene content and its activity. A recent study
has shown that inhalation of black pepper essential oil vapor significantly re-
duced withdrawal symptoms and anxiety in tobacco smokers (Rose and Behm
1994). Interestingly, the authors posited not a central biochemical mechanism,
John M. McPartland and Ethan B. Russo 111
FIGURE 1. Phytocannabinoids
Structure* Concentration
(% dry weight) Boiling
Point °C§Properties
-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
52 Antiinflammatory
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 dem-
onstrated 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-caryo-
phyllene, 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-
FIGURE 1 (continued)
Structure* Concentration
(% dry weight) Boiling
Point °C§Properties
-8-tetrahydrocannabinol (-8-THC) 0.0-0.1% 175-178 Resembles
Less psychoactive
More stable
tetrahydrocannabivarin (THCV) 0.0-1.36% < 220 Analgesic
*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.
from various sources, primarily Buckingham, 1992; Guenther, 1948; Parry, 1918; and Mechoulam (personal com-
munication, April 2001).
John M. McPartland and Ethan B. Russo 113
FIGURE 2. Terpenoid essential oil components of cannabis.
Cannabis Constituent Structure* ConcentrationBoiling
Point °C§Properties
β-myrcene 0.47% 166-168 Analgesic
β-caryophyllene 0.05% 119 Antiinflammatory
(gastric mucosa)
d-limonene 0.14% 177 Cannabinoid agonist?
Immune potentiator
linalool 0.002% 198 Sedative
Immune potentiator
pulegone 0.001% 224 Memory booster?
AChE inhibitor
1,8-cineole (eucalyptol) > 0.001% 176 AChE inhibitor
Increases cerebral
blood flow
α-pinene 0.04% 156 Antiinflammatory
AChE inhibitor
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 analge-
sic, 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,
FIGURE 2 (continued)
Cannabis Constituent Structure* ConcentrationBoiling
Point °C§Properties
α-terpineol 0.02% 217-218 Sedative
AChE inhibitor
terpineol-4-ol 0.0004% 209 AChE inhibitor
-cymene 0.0004% 177 Antibiotic
AChE inhibitor
borneol 0.008% 210 Antibiotic
-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 indi-
vidual constituents, suggesting synergy (Evans et al. 1987).
Myrcene also synergizes the antibiotic potency of other essential oil com-
ponents, against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeru-
ginosa, and a specific strain of Escherichia coli (Onawunmi et al. 1984).
Myrcene inhibits cytochrome P450 2B1, an enzyme implicated in the meta-
bolic activation of promutagens (De Oliveira et al. 1997). Aflatoxin B1is a
promutagen produced by Aspergillus flavus and Aspergillus parasiticus, two
fungal contaminants of moldy marijuana (reviewed by McPartland and Pruitt
1997). After aflatoxin B1is 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-in-
flammatory 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 se-
cretion. The authors suggested this agent as clinically safe, and potentially use-
ful. 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 occur-
rence and application, its biological activity is well known. Limonene is highly
absorbed by inhalation and quickly appears in the bloodstream (Falk-Flilips-
son 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 fra-
grance (predominately limonene) have demonstrated inhibition of thymic in-
volution 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 em-
ployed 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 an-
tidepressant drugs.
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 inhibit-
ing 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 canna-
bis. Thus, this terpenoid may reduce the harm caused by inhaling cannabis
smoke. Limonene blocks carcinogenesis by multiple mechanisms. It detoxi-
fies 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 re-
differentiation 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 can-
nabis, such as citronellol and α-terpineol, are also deeply sedating upon inha-
lation, even in low concentrations. 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
corticosterone secretion by attenuating corticotropin-releasing factor (CRF)
expression (Marcihac et al. 1998). CRF not only induces corticosterone secre-
tion 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 re-
lease 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-in-
duced 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 de-
creased in individuals carrying the E4 subtype of the apolipoprotein E gene,
ApoE E4 (Poirier et al. 1995). Pulegone has also demonstrated significant sed-
ative 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 inhala-
tion 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
Wilson 1993).
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 corre-
lated 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 (Car-
son and Riley 1995). In a rat study, 1,8-cineole prevented the sexual transmis-
sion 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 lavan-
dulaefolia containing 1,8-cineole and other terpenoids produced a synergistic
inhibition of acetylcholinesterase that suggested utility in the clinical treat-
ment 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 vari-
ety 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 mono-
terpenoids. 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 (Car-
son and Riley 1995). Campbell et al. (1997) have demonstrated a moderate
antimalarial effect against two strains of Plasmodium falciparum by an essen-
tial 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
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% ef-
fective (P < 0.001), to a greater degree than neomycin, and without toxicity.
3-Carene, a bicyclic monoterpenoid, was effective in prevention of acute
inflammation in a carrageenan-induced plantar edema model (Gil et al.
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 mecha-
nism 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 cal-
cium 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, shield-
ing healthy cells from the activation of benzo[α]pyrene and aflatoxin B1
(Offord et al. 1997), which are two procarcinogens potentially found in canna-
bis 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 GABAAreceptors (Salgueiro et al. 1997); this anxio-
lytic activity is not associated with the unwanted side effects caused by syn-
thetic 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-αinduces and maintains inflammation, a pathological condition
in rheumatoid arthritis and multiple sclerosis. THC decreases TNF-α, proba-
bly 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). Al-
though apigenin has a high affinity for estrogen receptors (especially β-estrogen
receptors), it has low estrogenic activity; apigenin actually inhibits estradiol-
induced proliferation of breast cancer cells (Wang and Kurzer 1998).
Quercetin is a flavonol found in nearly all vascular plants, including canna-
bis (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-
FIGURE 3. Flavonoid and phytosterol components of cannabis.
Cannabis Constituent Structure* ConcentrationBoiling
Point °C§Properties
apigenin > 0.1% 178 Anxiolytic
quercetin > 0.1% 250 Antioxidant
cannflavin A 0.02% 182 COX inhibitor
LO 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, effec-
tively recycling CBD as an antioxidant. Flavonoids block free radical forma-
tion at several steps: by scavenging superoxide anions (in both enzymatic and
non-enzymatic systems), by quenching intermediate peroxyl and alkoxyl radi-
cals, 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 in-
hibitory subunit of NF-κB called IκB (Musonda and Chipman 1998), conse-
quently 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-in-
duced 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 E2in human rheumatoid
synovial cells, with an IC50 of 31 ng/ml, about 30 times more potent than aspi-
rin 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 phe-
nols 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 ingre-
dient 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 pal-
metto have proven equivalent or superior to finasteride in treatment of benign
prostatic hyperplasia.
John M. McPartland and Ethan B. Russo 121
Does the body absorb non-cannabinoids in physiologically relevant con-
centrations? 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 approxi-
mately 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 con-
sists 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 smok-
ing 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 tis-
sue concentration of 1.3 µM. This concentration is an order of magnitude be-
low the IC50 concentration of limonene’s inhibition of AChE (Miyazawa et al.
1997). Hence, limonene must synergize with other AChE inhibitors in order to
be effective.
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 canna-
binoid-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 car-
cinogenic vapors did not appear until 200°C (392°F), and cannabis combus-
tion occurred around 230°C (446°F) (Gieringer 2001).
Concerning bioavailability, it should be mentioned that cannabis com-
pounds need not be absorbed systemically through the lungs to produce CNS
activity. Inhaled compounds may reach receptors in the olfactory bulb, send-
ing 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 peri-
odically criticized (Mechoulam et al. 1972; McPartland and Pruitt 1999; Russo
2000). We have highlighted several cannabinoids, terpenoids, and flavonoids
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 experi-
ments 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 neuro-
toxicity in mice: effects on cholinergic (muscarinic) receptors and blood brain bar-
rier permeability. Res Commun Subst Abuse 10:155-68.
Anderson, P.F., D.M. Jackson, and G.B. Chesher. 1974. Interaction of delta-9-tetra-
hydrocannabinol 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 activ-
ity of cannabigerol against human oral epitheloid carcinoma cells. Arch Pharmacol
Res 21:353-6.
Banerjee, S.P., S.H. Snyder, R. Mechoulam. 1975. Cannabinoids: influence on neuro-
transmitter 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 fla-
vones from Cannabis sativa L. Experientia 42:452-3.
Basile, A.C., J.A. Sertie, P.C. Freitas, and A.C. Zanini. 1988. Anti-inflammatory activ-
ity 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 hand-
book 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: Har-
wood Academic Publishers.
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 com-
pounds 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 9-tetrahydrocannabinol. Proc Soc Exp Biol
Med 210:64-76.
Burstein, S., C. Varanelli, and L.T. Slade. 1975. Prostaglandins and Cannabis–III. In-
hibition of biosynthesis by essential oil components of marihuana. Biochemical
Pharmacology 24:1053-4.
Burstein, S., E. Levin, and C. Varanelli. 1973. Prostaglandins and Cannabis–II. Inhibi-
tion of biosynthesis by the naturally occurring cannabinoids. Biochem Pharmacol
Burstein, S., P. Taylor, F.S. El-Feraly, C. Turner. 1976. Prostaglandins and Canna-
bis–V. Identification of p-vinylphenol as a potent inhibitor of prostaglandin synthe-
sis. 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 mari-
huana 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 re-
lease after acute and repeated 9-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 as-
pects, central and peripheral synapses, and clinical significance. New York: Ple-
num Press.
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.
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 vola-
tile 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
1999; 129:775S-8S.
Daaka, Y., W. Zhu, H. Friedman, and T.W. Klein. 1997. Induction of interleukin-2 re-
ceptor αgene by 9-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 9-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. Deter-
mination and characterization of a cannabinoid receptor in rat brain. Molecular
Pharmacol 34:605-13.
Di Marzo, V. and A. Fontana. 1995. Anandamide, an endogenous cannabinomimetic
eicosanoid: “killing two birds with one stone.” Prostagland Leukotr Essent Fatty
Acids 53:1-11.
Domino, E.F. 1976. Effect of 9-terahydrocannabinol and cannabinol on rat brain ace-
tylcholine. In Nahas G.G., Panton W.D.M., Idanpaan-Heikkila J.E., eds. Mari-
juana: chemistry, biochemistry, and cellular effects. New York: Springer-Verlag:
pp. 407-13.
ElSohly, H.N., C.E. Turner, A.M. Clark, and M.A. ElSohly. 1982. Synthesis and
antimicrobial activities of certain cannabichromene and cannabigerol related com-
pounds. 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 Pharm-
acol 36:2035-7.
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. Up-
take, distribution and elimination of alpha-pinene in man after exposure by inhala-
tion. 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 Leuko-
cyte Biol 67:259-66.
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 im-
mune 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
Pharmacol 40:132-4.
Franchomme, P. and Pénoël. 1990. L’aromathérapie exactement. Limoges, France:
Roger Jallois.
Fournier, G., C. Richez-Dumanois, J. Duvezin, J.P. Mathieu, and M. Paris. 1987. Iden-
tification 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 dexana-
binol (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 topi-
cal anti-inflammatory activity of Achillea ageratum on chronic and acute inflam-
mation 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, devel-
opment and aflatoxin production of Aspergillus parasiticus.Toxicon 37: 883-93.
Greenspan, H.C. 1993. The role of reactive oxygen species, antioxidants and phyto-
pharmaceuticals in human immunodeficiency virus activity. Med Hypoth 40:85-92.
Grinspoon, L., J.B. Bakalar. 1997. Marihuana,the forbidden medicine, revised edi-
tion. 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 es-
sential 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 ()
9-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 9-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 fac-
tor-κB, cAMP response element-binding protein, and interleukin-2 secretion by ac-
tivated thymocytes. J Pharmacol Exp Therap 291:1156-63.
Heyser, C.J., R.E. Hampson, and S.A. Deadwyler. 1993. Effects of 9-tetrahydro-
cannabinol on delayed match to sample performance in rats: alterations in short-
term 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. Ef-
fect of cannabichromene on hepatic microsomal enzyme activity in the mouse. Gen
Pharmacol 14:361-3.
Klein, T.W., C. Newton, and H. Friedman. 1987. Inhibition of natural killer cell func-
tion 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 9-tetrahydrocanna-
binol 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.
Nature 235:397-8.
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 Ethno-
pharmacol 34:43-8.
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
Sci 97:9561-6.
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. Oli-
ver. 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
Assoc 100(2):89-96.
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 this-
tle (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 immuno-
compromised. Altern Therap 3(3):39-45.
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 constitu-
ents 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 long-
term 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-in-
duced 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
9-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 imag-
ing of effects of fragrances on the human brain after prolonged inhalation. Chem
Senses 19:359-64.
Nigam, M.C., K.L. Handa, I.C. Nigam, and L. Levi. 1965. Essential oils and their con-
stituents. 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 tetrahydro-
cannabinol 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 bron-
chial cells. Cancer Lett 114:275-81.
Ohlsson, A., J.E. Lindgren, A. Wahlen, S. Agurell, L.E. Hollister, and H.K. Gillespie.
1980. Plasma 9-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. Lon-
don: 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 in-
hibition of human erythrocyte acetylcholinesterase by salvia lavandulaefolia essen-
tial 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 pharmacol-
ogy of natural cannabinoids: evidence for partial agonist activity of 9-tetra-
hydrocannabinol 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 up-
take and release in hypothalamic and striatal synaptosomes. J Pharmacol Exper
Therap 214:63-7.
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 noci-
ception 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,
αMeLeu37) CRF attenuates the acute actions of the highly potent canna-
binoid 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 re-
duces smoking withdrawal symptoms. Drug Alcohol Dep 34(3):225-9.
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. Pharmacol-
ogy of the essential oil of hemp at 5-HT1A and 5-HT2a receptors. Poster at 41st An-
nual 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 benzodiaz-
epine 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. Mari-
juana: 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. Bio-
logical 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. 9-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. 9-Tetrahydrocan-
nabinol (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-caryo-
phyllene. 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 9-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. Compari-
son of acute oral toxicity of cannabinoids in rats, dogs and monkeys. Toxicol Appl
Pharmacol 25:363-73.
Tisserand, R., and T. Balacs. 1995. Essential oil safety:A guide for health care profes-
sionals. 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-limo-
nene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clini-
cal 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 pal-
metto 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-in-
flammatory properties of cannabichromene. Life Sci 26:1991-5.
Zuardi, A.W., I. Shirakawa, E. Finkelfarb, and I.G. Karniol. 1982. Action of canna-
bidiol on the anxiety and other effects produced by 9-THC in normal subjects.
Psychopharmacol 76:245-50.
Zuardi, A.W., S.L. Morais, F.S. Guimarães, and R. Mechoulam. 1995. Antipsychotic
effect of cannabidiol. J Clin Psychiatr 56:485-6.
... 8,9 It has been suggested that cannabis extracts could provide advantages over a single phytocannabinoid (i.e., CBD), offering beneficial entourage effects. 5,10 However, more investigation about this effect is required. ...
... The entourage effect refers to the idea that multiple compounds can act in concert or synergically to produce different outcomes. 10,28 In fact, Russo and McPartland 29 and other reports proposed the entourage effect in relation to the clinical contribution of CBD, other cannabinoids, terpenoids, and flavonoids in pharmaceutical-medical cannabis. 10,30 However, our results did not support a possible synergistic or entourage effect because EPI showed similar toxicity (Fig. 2a, b) and neuroprotective action curves compared with XAL ( Fig. 3a, b). ...
... 10,28 In fact, Russo and McPartland 29 and other reports proposed the entourage effect in relation to the clinical contribution of CBD, other cannabinoids, terpenoids, and flavonoids in pharmaceutical-medical cannabis. 10,30 However, our results did not support a possible synergistic or entourage effect because EPI showed similar toxicity (Fig. 2a, b) and neuroprotective action curves compared with XAL ( Fig. 3a, b). Our findings would a priori rule out the participation of other individual substances present in EPI, highlighting the benefit of the formulation of MCT oil in the neuroprotective EPI effect. ...
... 8,9 It has been suggested that cannabis extracts could provide advantages over a single phytocannabinoid (i.e., CBD), offering beneficial entourage effects. 5,10 However, more investigation about this effect is required. ...
... The entourage effect refers to the idea that multiple compounds can act in concert or synergically to produce different outcomes. 10,28 In fact, Russo and McPartland 29 and other reports proposed the entourage effect in relation to the clinical contribution of CBD, other cannabinoids, terpenoids, and flavonoids in pharmaceutical-medical cannabis. 10,30 However, our results did not support a possible synergistic or entourage effect because EPI showed similar toxicity (Fig. 2a, b) and neuroprotective action curves compared with XAL ( Fig. 3a, b). ...
... 10,28 In fact, Russo and McPartland 29 and other reports proposed the entourage effect in relation to the clinical contribution of CBD, other cannabinoids, terpenoids, and flavonoids in pharmaceutical-medical cannabis. 10,30 However, our results did not support a possible synergistic or entourage effect because EPI showed similar toxicity (Fig. 2a, b) and neuroprotective action curves compared with XAL ( Fig. 3a, b). Our findings would a priori rule out the participation of other individual substances present in EPI, highlighting the benefit of the formulation of MCT oil in the neuroprotective EPI effect. ...
Introduction: Preclinical research supports the benefits of pharmaceutical cannabis-based extracts for treating different medical conditions (e.g., epilepsy); however, their neuroprotective potential has not been widely investigated. Materials and Methods: Using primary cultures of cerebellar granule cells, we evaluated the neuroprotective activity of Epifractan (EPI), a cannabis-based medicinal extract containing a high level of cannabidiol (CBD), components like terpenoids and flavonoids, trace levels of Δ9-tetrahydrocannabinol, and the acid form of CBD. We determined the ability of EPI to counteract the rotenone-induced neurotoxicity by analyzing cell viability and morphology of neurons and astrocytes by immunocytochemical assays. The effect of EPI was compared with XALEX, a plant-derived and highly purified CBD formulation (XAL), and pure CBD crystals (CBD). Results: The results revealed that EPI induced a significant reduction in the rotenone-induced neurotoxicity in a wide range of concentrations without causing neurotoxicity per se. EPI showed a similar effect to XAL suggesting that no additive or synergistic interactions between individual substances present in EPI occurred. In contrast, CBD did show a different profile to EPI and XAL because a neurotoxic effect per se was observed at higher concentrations assayed. Medium-chain triglyceride oil used in EPI formulation could explain this difference. Conclusion: Our data support a neuroprotective effect of EPI that may provide neuroprotection in different neurodegenerative processes. The results highlight the role of CBD as the active component of EPI but also support the need for an appropriate formulation to dilute pharmaceutical cannabis-based products that could be critical to avoid neurotoxicity at very high doses.
... The biological effects of phytocannabinoids are facilitated through the G-protein-coupled cannabinoid receptors, CB1 and CB2 [6]. CB1 receptors are predominantly located in the central and peripheral nervous systems and the liver and pancreatic islets [7], while CB2 receptors are more prominently expressed in immune cells [8]. These receptors bind endocannabinoids like anandamide (AEA) and 2-arachidonoylglycerol (2-AG), which play essential roles in regulating various physiological processes, including appetite, pain perception, mood, memory, and inflammation [9]. ...
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Cannabis, a plant known for its recreational use, has gained global attention due to its widespread use and addiction potential. Derived from the Cannabis sativa plant, it contains a rich array of phytochemicals concentrated in resin-rich trichomes. The main cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), interact with CB1 and CB2 receptors, influencing various physiological processes. Particularly concerning is its prevalence among adolescents, often driven by the need for social connection and anxiety alleviation. This paper provides a comprehensive overview of cannabis use, its effects, and potential health risks, especially in adolescent consumption. It covers short-term and long-term effects on different body systems and mental health and highlights the need for informed decision making and public health initiatives, particularly regarding adolescent cannabis use.
... Several reviews and perspectives claiming the therapeutic potential of the 'entourage effect' and elucidating it in a primarily optimistic perspective have been published [4,5,29,51]. These papers have in common that they refer to the same few pre-clinical original research papers presented above (e.g., [2,[36][37][38]). ...
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The ‘entourage effect’ term was originally coined in a pre-clinical study observing endogenous bio-inactive metabolites potentiating the activity of a bioactive endocannabinoid. As a hypothetical afterthought, this was proposed to hold general relevance to the usage of products based on Cannabis sativa L. The term was later juxtaposed to polypharmacy pertaining to full-spectrum medicinal Cannabis products exerting an overall higher effect than the single compounds. Since the emergence of the term, a discussion of its pharmacological foundation and relevance has been ongoing. Advocates suggest that the ‘entourage effect’ is the reason many patients experience an overall better effect from full-spectrum products. Critics state that the term is unfounded and used primarily for marketing purposes in the Cannabis industry. This scoping review aims to segregate the primary research claiming as well as disputing the existence of the ‘entourage effect’ from a pharmacological perspective. The literature on this topic is in its infancy. Existing pre-clinical and clinical studies are in general based on simplistic methodologies and show contradictory findings, with the clinical data mostly relying on anecdotal and real-world evidence. We propose that the ‘entourage effect’ is explained by traditional pharmacological terms pertaining to other plant-based medicinal products and polypharmacy in general (e.g., synergistic interactions and bioenhancement).
... For its intoxicating qualities, high quantities of THC are preferred in the illegal market [83]. Terefore, standardized whole plant cannabis medical extracts (CBMEs) have recently been developed [84]. Inhalation and vaping are the most common ways to consume cannabis. ...
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Neuroimmune diseases are a group of disorders that occur due to the dysregulation of both the nervous and immune systems, and these illnesses impact tens of millions of people worldwide. However, patients who suffer from these debilitating conditions have very few FDA-approved treatment options. Neuroimmune crosstalk is important for controlling the immune system both centrally and peripherally to maintain tissue homeostasis. This review aims to provide readers with information on how natural products modulate neuroimmune crosstalk and the therapeutic implications of natural products, including curcumin, epigallocatechin-3-gallate (EGCG), ginkgo special extract, ashwagandha, Centella asiatica, Bacopa monnieri, ginseng, and cannabis to mitigate the progression of neuroimmune diseases, such as Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, depression, and anxiety disorders. The majority of the natural products based clinical studies mentioned in this study have yielded positive results. To achieve the expected results from natural products based clinical studies, researchers should focus on enhancing bioavailability and determining the synergistic mechanisms of herbal compounds and extracts, which will lead to the discovery of more effective phytomedicines while averting the probable negative effects of natural product extracts. Therefore, future studies developing nutraceuticals to mitigate neuroimmune diseases that incorporate phytochemicals to produce synergistic effects must analyse efficacy, bioavailability, gut-brain axis function safety, chemical modifications, and encapsulation with nanoparticles.
Introduction: This review aims to provide an overview of the advancements and status of clinical studies and potential permeation-enhancing strategies in the transdermal delivery of cannabinoids. Methods: A systematic and comprehensive literature search across academic databases, search engines, and online sources to identify relevant literature on the transdermal administration of cannabinoids. Results: Cannabinoids have proven beneficial in the treatment of wide-ranging physical and psychological disorders. A shift toward legalized cannabinoid products has increased both interests in cannabinoid research and the development of novel medicinal exploitations of cannabinoids in recent years. Oral and pulmonary delivery of cannabinoids has several limitations, including poor bioavailability, low solubility, and potential side effects. This has diverted scientific attention toward the transdermal route, successfully overcoming these hurdles by providing higher bioavailability, safety, and patient compliance. Yet, due to the barrier properties of the skin and the lipophilic nature of cannabinoids, there is a need to increase the permeation of the drugs to the underneath layers of skin to reach desired therapeutic plasma levels. Literature describing detailed clinical trials on cannabinoid transdermal delivery, either with or without permeation-enhancing strategies, is limited. Conclusion: The limited number of reports indicates that increased attention is needed on developing and examining efficient transdermal delivery systems for cannabinoids, including patch design and composition, drug-patch interaction, clinical effectiveness and safety in vivo, and permeation-enhancing strategies.
Cannabinoids (CBDs) represent a group of C21 or C22 terpenophenolic compounds predominantly produced by Cannabis but have also been found in plants from the Radula and Helichrysum genera. There are about 100 different cannabinoids, although some of them are metabolites. They are generally classified into ten subclasses [1–3].
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Introduction: We measure for the first time the associations between subjective patient experiences of feeling “high” and treatment outcomes during real-time Cannabis flower consumption sessions. Methods: Our study uses data from the mobile health app, Releaf App™, through which 1,882 people tracked the effects of Cannabis flower on a multitude of health conditions during 16,480 medical cannabis self-administration sessions recorded between 6/5/2016 and 3/11/2021. Session-level reported information included plant phenotypes, modes of administration, potencies, baseline and post-administration symptom intensity levels, total dose used, and real-time side effect experiences. Results: Patients reported feeling high in 49% of cannabis treatment sessions. Using individual patient-level fixed effects regression models and controlling for plant phenotype, consumption mode, tetrahydrocannabinol (THC) and cannabidiol (CBD) potencies, dose, and starting symptom level, our results show that, as compared to sessions in which individuals did not report feeling high, reporting feeling high was associated with a 7.7% decrease in symptom severity from a mean reduction of −3.82 on a 0 to 10 analog scale (coefficient = −0.295, p < 0.001) with evidence of a 14.4 percentage point increase (p < 0.001) in negative side effect reporting and a 4.4 percentage point (p < 0.01) increase in positive side effect reporting. Tetrahydrocannabinol (THC) levels and dose were the strongest statistical predictors of reporting feeling high, while the use of a vaporizer was the strongest inhibitor of feeling high. In symptom-specific models, the association between feeling high and symptom relief remained for people treating pain (p < 0.001), anxiety (p < 0.001), depression (p < 0.01) and fatigue (p < 0.01), but was insignificant, though still negative, for people treating insomnia. Although gender and pre-app cannabis experience did not appear to affect the relationship between high and symptom relief, the relationship was larger in magnitude and more statistically significant among patients aged 40 or less. Discussion: The study results suggest clinicians and policymakers should be aware that feeling high is associated with improved symptom relief but increased negative side effects, and factors such as mode of consumption, product potency, and dose can be used to adjust treatment outcomes for the individual patient.
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A screening study was performed on/by essential oils of Nepeta viscida Boiss and Nepeta italica L. using tail‐flick and tail immersion (52.5°C) methods. N. italica samples were collected from three different­localities of Turkey. Surprisingly, only one of the essential oils showed significant activity, which was blocked by naloxone, indicating the involvement of opioid receptors. This was seen only with the mechanical but not the thermal algesic stimulus, suggesting a specific activity on opioid receptors, excluding mu receptors. The same, active essential oil also exhibited a non‐competitive inhibition of acetylcholine contractions of isolated rat ileum but it was inactive on the isolated rat aorta. Furthermore, a correlation between the analgesic activity and the amount of 1,8‐cineole was noticed. Copyright © 1999 John Wiley & Sons, Ltd.
The essential oil of black cumin seeds, Nigella sativa L., was tested for a possible antioxidant activity. A rapid evaluation for antioxidants, using two TLC screening methods, showed that thymoquinone and the components carvacrol, t-anethole and 4-terpineol demonstrated respectable radical scavenging property. These four constituents and the essential oil possessed variable antioxidant activity when tested in the diphenylpicrylhydracyl assay for non-specific hydrogen atom or electron donating activity. They were also effective ·OH radical scavenging agents in the assay for non-enzymatic lipid peroxidation in liposomes and the deoxyribose degradation assay.
The essential oil obtained by hydrodistillation of freshly harvested Indian Cannabis sativa L. was found to contain the following constituents that have not previously been reported: α-pinene, camphene, β-pinene, α-terpinene, β-phellandrene, γ-terpinene, linalool, trans-linalool oxide, sabinene hydrate, α-bergamotene, terpinene-4-ol, β-farnesene, α-terpineol, α-selinene, curcumene, and caryophyllene oxide. The presence of trace amounts of two alcohols and of an α,β-unsaturated ketone, for which gas chromatographic and spectral characteristics are recorded, was also detected.
It is well documented that Δ9-tetrahydrocannabinol (Δ9-THC) in man has a biphasic effect of initial elation and the feeling of being “high” followed by sedation and sleepiness [7,12]. Studies in animals also tend to bear out a “stimulant” action, although a “depressant” effect is far more readily apparent. Whether the “stimulation” is merely due to behavioral disinhibition is not known. Neurochemical studies in animals that bear on these behavioral effects have been sparse. There is evidence that the mono-aminergic systems are affected, especially with large doses of Δ9-THC[11].