Content uploaded by Satoshi Yamaori
Author content
All content in this area was uploaded by Satoshi Yamaori on Mar 22, 2014
Content may be subject to copyright.
1 3
ORIGINAL ARTICLE
Forensic Toxicol (2007) 25:16–21
DOI 10.1007/s11419-007-0021-y
K. Watanabe (*) · Y. Itokawa · S. Yamaori · T. Funahashi ·
T. Kimura
Department of Hygienic Chemistry, Faculty of Pharmaceutical
Sciences, Hokuriku University, Ho-3 Kanagawa-machi,
Kanazawa 920-1181, Japan
e-mail: k-watanabe@hokuriku-u.ac.jp
T. Kaji
Department of Environmental Health, Faculty of
Pharmaceutical Sciences, Hokuriku University, Kanazawa,
Japan
N. Usami · I. Yamamoto
Department of Hygienic Chemistry, School of Pharmaceutical
Sciences, Kyushu University of Health and Welfare, Nobeoka,
Japan
Conversion of cannabidiol to ∆9-tetrahydrocannabinol and related
cannabinoids in artifi cial gastric juice, and their pharmacological effects
in mice
Kazuhito Watanabe · Yuka Itokawa · Satoshi Yamaori
Tatsuya Funahashi · Toshiyuki Kimura · Toshiyuki Kaji
Noriyuki Usami · Ikuo Yamamoto
sleeping time by 1.8 to 8.0 times as compared with the
control solution with 1% Tween 80-saline. The ED50
values (mg/kg, i.v.) of 9α-OH-HHC and 8-OH-iso-HHC
for the antinociceptive effect were 14.1 and 39.4, respec-
tively. The present study demonstrated that CBD can be
converted to ∆9-THC and its related cannabinoids, 9α-
OH-HHC and 8-OH-iso-HHC, in artifi cial gastric juice,
and that these HHCs show ∆9-THC-like effects in mice,
although their pharmacological effects were less potent
than those of ∆9-THC.
Keywords Cannabidiol · ∆9-Tetrahydrocannabinol ·
9α-Hydroxyhexahydrocannabinol · 8-Hydroxy-iso-
hexahydrocannabinol · Acid-catalyzed cyclization ·
Antinociceptive effect
Introduction
Cannabidiol (CBD), which is one of the major cannabi-
noids in marijuana, is known to be devoid of psychoac-
tivity in humans [1–3]. In chemical reactions, the
acid-catalyzed conversion of CBD to other cannabinoids
is well documented. Many years ago, Adams et al. [4,5]
reported that CBD was converted to cannabinoids
possessing marijuana-like pharmacological effects under
various acidic conditions; at that time, however, a pre-
cise structure of CBD was not established [4]. Thereafter,
Gaoni and Mechoulam [6,7] reported that CBD was
easily isomerized in a number of acidic reagents includ-
ing hydrochloric acid and p-toluenesulfonic acid to give
various cannabinoids. It is very important to know
whether CBD is converted to ∆9-tetrahydrocannabinol
(∆9-THC) during the handling of marijuana and in bio-
logical systems. However, there are few reports on the
Received: 9 January 2007 / Accepted: 29 January 2007 / Published online: 20 March 2007
© Japanese Association of Forensic Toxicology and Springer 2007
Abstract Cannabidiol (CBD), a nonpsychoactive can-
nabinoid, was found to be converted to 9α-hydroxy-
hexahydrocannabinol (9α-OH-HHC) and 8-hydroxy-
iso-hexahydrocannabinol (8-OH-iso-HHC) together
with ∆9-tetrahydrocannabinol (∆9-THC), a psychoactive
cannabinoid, and cannabinol in artifi cial gastric juice.
These cannabinoids were identifi ed by gas chromatogra-
phy-mass spectrometry (GC-MS) by comparison with
the spectral data of the authentic compounds. Pharma-
cological effects of 9α-OH-HHC and 8-OH-iso-HHC in
mice were examined using catalepsy, hypothermia, pen-
tobarbital-induced sleep prolongation, and antinocicep-
tion against acetic acid-induced writhing as indices. The
ED50 values (effective dose producing a 50% reduction
of control; mg/kg, i.v.) of 9α-OH-HHC and 8-OH-iso-
HHC for the cataleptogenic effect were 8.0 and 30.4, re-
spectively. 8-OH-iso-HHC (10 mg/kg, i.v.) produced a
signifi cant hypothermia from 15 to 90 min after admin-
istration, although 9α-OH-HHC failed to induce such
an effect at the same dose. However, both HHCs (10 mg/
kg, i.v.) signifi cantly prolonged pentobarbital-induced
Forensic Toxicol (2007) 25:16–21 17
1 3
conversion of CBD to other cannabinoids in biological
systems. Quarles et al. [8] reported that CBD did not
form ∆9-THC when marijuana cigarettes were smoked
either by human subjects or by a smoking machine. We
previously reported that CBD was biotransformed to a
THC derivative, 6β-hydroxymethyl-∆9-THC, via an ep-
oxy intermediate with guinea pig hepatic microsomes [9].
6β-Hydroxymethyl-∆9-THC exhibited some THC-like
effects, although its effects were much less active than
those of ∆9-THC. In biological systems, there have been
no reports on the conversion of CBD to ∆9-THC itself.
Marijuana can be ingested with foods or drinks, and
reach the stomach, which is under strong acidic condi-
tions containing gastric juice. For better understanding
of whether CBD is converted to other cannabinoids, it
is important to investigate the cyclization of CBD under
conditions similar to those in biological systems. In the
present study, we describe the conversion of CBD to
∆9-THC, cannabinol (CBN), and hexahydrocannabinols
(HHCs) in artifi cial gastric juice and their pharmacologi-
cal effects in mice.
Materials and methods
Materials
∆9-THC, CBD, and CBN were isolated and purifi ed
from cannabis leaves by the methods of Aramaki et al.
[10]. 8-Hydroxy-iso-HHC (8-OH-iso-HHC) and 9α-
hydroxy-HHC (9α-OH-HHC) were prepared by the
methods of Gaoni and Mechoulam [7] and Petrzilka et
al. [11], respectively. The purities of these cannabinoids
were checked to be more than 98% by gas chromatogra-
phy (GC). Other chemicals and solvents used were of the
highest purity commercially available.
Conversion of CBD in artifi cial gastric juice
CBD (250 µg) was incubated in 5 ml of a modifi ed artifi -
cial gastric juice without pepsin (2 mg/ml NaCl solution,
pH 1.2) (Japanese Pharmacopoeia 14th Edn, 2001) at
37°C for 20 h. The mixture was extracted twice with
20 ml of ethyl acetate after addition of 5α-cholestane
(5 µg) as internal standard (IS). After evaporation of the
organic solvent, the residue was dissolved in 250 µl of
ethyl acetate and a 5-µl aliquot was subjected to thin-
layer chromatography (TLC) with a solvent system of
benzene/n-hexane/diethylamine (25 : 10 : 1). The cannabi-
noids formed from CBD were visualized by spraying
0.1% Fast Blue BB salt. Another portion (1 µl) of the
ethyl acetate solution was injected into a gas chromatog-
raphy-mass spectrometry (GC-MS) system.
GC-MS conditions
We used two types of GC-MS instruments. For a JEOL
JMS 06 gas chromatograph coupled with a JEOL JMS
DX-300 GC mass spectrometer and a JEOL DA mass
data system, the conditions 1 were: column, 5% SE-30
on Chromosorb W (60–80 mesh, 3 mm × 2 m); column
temperature, 260°C; ionization, 70 eV; ionizing current,
300 µA; carrier gas, He at 40 ml/min.
For a Shimadzu GCMS-QP2010 instrument, the con-
ditions 2 were: column, DB-1 (0.25 mm × 30 m, fi lm
thickness, 0.25 µm); column temperature program, 50°C
(1 min), 25°C/min (6 min), 10°C/min (10 min), and 300°C
(5-min hold); ion source temperature, 250°C; interface
temperature, 280°C; ionization, 70 eV; emission current,
60 µA; carrier gas, He at 2.04 ml/min.
Under the above conditions, the retention times
(min; conditions 1 and 2) of cannabinoids were: CBD
(3.7, 13.6), ∆9-THC (4.7, 14.3), CBN (5.4, 14.9), 9α-OH-
HHC (5.6, 15.0), 8-OH-iso-HHC (6.0, 15.2), and 5α-
cholestane (11.2, 17.2).
Pharmacological experiments
Male ddY mice (20–25 g body weight) were used for
pharmacological experiments. They were kept in an air-
conditioned room (22.0° ± 2°C) with a 12-h light and
dark cycle with automatically controlled lighting, and
given food and water ad lib. Each cannabinoid was sus-
pended in saline containing 1% Tween-80 and injected
into mice intravenously. The pharmacological effects
of the cannabinoids were evaluated by the following
criteria [12,13].
1. Catalepsy: mice were separated into three groups,
each of 8 animals. They were injected with dif-
ferent amounts of each cannabinoid, and the cata-
leptogenic effect was assessed by the simple bar test
[12].
2. Hypothermia: fi ve groups of mice (n = 8) were in-
jected with each cannabinoid (10 mg/kg), and the
rectal temperature of each mouse was measured
using a thermister thermometer up to 120 min after
the administration.
3. Pentobarbital-induced sleep: fi ve groups of mice (n =
8–24) were injected with each cannabinoid (5 or
10 mg/kg) and challenged with sodium pentobarbital
(40 mg/kg, i.p.) 15 min later. The time between the loss
and the regaining of the righting refl ex was recorded
as the sleeping period.
4. Antinociception: antinociceptive effect was also as-
sessed by the blockade of 0.7% acetic acid (10 ml/kg,
i.p.)-induced writhing [13].
18 Forensic Toxicol (2007) 25:16–21
1 3
Statistical analysis
The statistical signifi cance of difference between the con-
trol and the test groups was analyzed by use of the
Bonferroni test. Differences were accepted as being sig-
nifi cant at P < 0.05 or P < 0.01. The ED50 values (effec-
tive dose producing a 50% reduction of control) and
their 95% confi dence limits in the cataleptogenic and
antinociceptive effects of cannabinoids were calculated
by the method of Litchfi eld and Wilcoxon [14].
Results and discussion
CBD was converted to ∆9-THC and HHCs when incu-
bated in the artifi cial gastric juice. TLC analysis indi-
cated that four Fast Blue BB salt-positive spots were
visualized (Rf values, 0.04, 0.18, 0.28, and 0.35). Rf val-
ues and the colors of two less polar spots (Rf values, 0.35
and 0.28) were identical to those of CBD and ∆9-THC,
respectively. Two other compounds (Rf values, 0.18 and
0.04) were more polar than CBD or ∆9-THC, and a red
color was developed with Fast Blue BB salt, suggesting
that these compounds were the ring-cyclization products
of CBD. The GC-MS analysis indicated that CBD was
converted to at least four cannabinoids (peaks 1–4) (Fig.
1). Mass spectra and retention times of peak 1 and peak
2 were identical to those of ∆9-THC and CBN, respec-
tively (Figs. 1, 2). Peak 3 and peak 4 showed the same
molecular ion at m/z 332 and similar fragmentation pat-
terns (the fragment ions at m/z 314, 299, 271, and 231),
IS
CBD
(1) Peak-1
(2) Peak-2
(3) Peak-3
(4) Peak-4
(1)
(2)
(4)
TIC
231
295
299
310
314
332
372
Rt (min)
*
(3)
Fig. 1 Typical mass chromatograms of cannabinoids formed from
cannabidiol (CBD) in artifi cial gastric juice obtained under condi-
tions 2. Asterisk indicates a background peak that appeared in the
control incubated without CBD
(m/z)
Relative intensity (%)
Peak-1
Peak-2
Peak-3
Peak-4
Fig. 2 Mass spectra of cannabinoids
formed from CBD in artifi cial gastric
juice, labeled as peaks 1–4 in Fig. 1
Forensic Toxicol (2007) 25:16–21 19
1 3
indicating that the molecules were larger than CBD by
18 mass units and were isomers of each other (Fig. 2).
The retention times and mass spectra of peak 3 and
peak 4 were identical to those of 9α-OH-HHC and 8-
OH-iso-HHC, respectively, prepared by the chemical
syntheses described in Materials and methods. These
results show that CBD can be converted to 9α-OH-HHC
and 8-OH-iso-HHC together with ∆9-THC and CBN in
the artifi cial gastric juice (Fig. 3). The conversion rates
for ∆9-THC, CBN, 9α-OH-HHC, and 8-OH-iso-HHC
from CBD were 2.9%, 1.1%, 1.4%, and 10.0%, respec-
tively, under the conditions in the present study.
Gaoni and Mechoulam [7] reported that CBD was
readily converted to ∆9-THC and iso-THC in a number
of acidic reagents. They also reported that treatment of
CBD with sulfuric acid in methanol gave a mixture of
methoxy-iso-HHCs and methoxy-HHCs [7], and that
the boiling of CBD with diluted HCl in ethanol gave two
stereoisomers of 9-ethoxy-HHCs [6].
A number of investigators have insisted that ∆9-THC
is the only psychoactive component of marijuana. Little
attention has been paid to the pharmacological effects
of HHCs, although some HHC derivatives were report-
ed to have THC-like pharmacological effects [15–17]. In
the present study, pharmacological effects of 9α-OH-
HHC and 8-OH-iso-HHC have been assessed in mice by
catalepsy, hypothermia, pentobarbital-induced sleep
prolongation, and antinociception as indices, and have
been compared with those of CBD or ∆9-THC. 9α-OH-
HHC and 8-OH-iso-HHC exhibited cataleptogenic ef-
fects in mice, although their activities were much lower
than that of ∆9-THC (Table 1). In the present study, the
ED50 (mg/kg, i.v.) of ∆9-THC was 1.9 (1.3–2.7) and com-
parable with the data previously reported [18]. CBD
failed to induce the cataleptogenic effect at doses up to
30 mg/kg i.v. The results indicate that, for the catalepto-
genic effect, both HHCs are more active than the precur-
sor CBD, but less active than ∆9-THC in mice.
∆9-THC is known to produce hypothermia, which is
one of the typical pharmacological effects of cannabi-
noids in experimental animals [19–21]. In the study using
CB1 receptor knockout mice, it was shown that the hy-
pothermic effect of ∆9-THC was mediated through the
CB1 receptor [22]. Confl icting data were reported for the
effects of CBN and CBD on the body temperature of
animals, depending on the experimental conditions used
OH
HO C
5
H
11
Cannabidiol
(CBD)
Artificial gastric
juice
9-OH-HHC
OH
O
OH
C
5
H
11
OH
OC
5
H
11
9
-THC CBN
OC
5
H
11
OH
8-OH-iso-HHC
HO
O
OH
C
5
H
11
Fig. 3 Conversion of CBD to
∆9-tetrahydrocannabinol (∆9-
THC) and related cannabinoids
in artifi cial gastric juice. CBN,
cannabinol; 9α-OH-HHC, 9α-
hydroxyhexahydrocannabinol;
8-OH-iso-HHC, 8-hydroxy-
iso-hexahydrocannabinol
Table 1 Cataleptogenic effects of 9α-hydroxyhexahydrocanna-
binol (9α-OH-HHC) and 8-hydroxy-iso-hexahydrocannabinol
(8-OH-iso-HHC) in mice
Cannabinoid ED50 (mg/kg, i.v.)
9α-OH-HHC 8.0 (4.0–16.2)a
8-OH-iso-HHC 30.4 (6.3–147)
∆9-THC 1.9 (1.3–2.7)
The bar test was carried out 15 min after the injection of cannabi-
noids (i.v.) by placing the front paws of the mouse on a bar. If
the mouse maintained in this position for more than 30 s, the
ca taleptogenic effect was regarded as positive. ED50, effective
dose producing a 50% reduction of control; ∆9-THC, ∆9-
tetrahydrocannabinol
a 95% Confi dence limits shown in parentheses
20 Forensic Toxicol (2007) 25:16–21
1 3
[23–27]. The hypothermic effects of these cannabinoids
were far less potent than that of ∆9-THC. 9α-OH-HHC
and 8-OH-iso-HHC did not show any signifi cant hypo-
thermia at a dose of 5 mg/kg i.v. (data not shown), but
the latter cannabinoid at the dose of 10 mg/kg i.v. exhib-
ited a signifi cant hypothermia from 15 to 90 min after
administration with the maximum temperature differ-
ence of −0.6°C in comparison with each level of the
controls. CBD (10 mg/kg, i.v.) failed to produce signifi -
cant hypothermia under the same conditions (Fig. 4).
∆9-THC and CBD are known to potentiate barbitu-
rate-induced sleeping time [28–30], although their mech-
anisms are different from each other. ∆9-THC prolongs
sleeping time by direct action on the central nervous
system, possibly through the CB1 receptor, while CBD
potentiates the barbiturate effect by the inhibition of
hepatic cytochrome P450 [31,32]. 8-OH-iso-HHC (5 mg/
kg, i.v.) signifi cantly prolonged pentobarbital-induced
sleeping time by 1.8 times as compared with the control
level (mean sleeping time 22.0 min) (Fig. 5). Both HHCs
(10 mg/kg, i.v.) signifi cantly prolonged pentobarbital-
induced sleeping time by 1.9 to 2.8 times. However, such
effects of 9α-OH-HHC and 8-OH-iso-HHC were much
less active than those of ∆9-THC and CBD.
In addition to catalepsy, hypothermia, and barbitu-
rate synergism, ∆9-THC possesses antinociceptive effects
in experimental animals [13,33,34]. Although 9α-OH-
HHC and 8-OH-iso-HHC also exhibited an antinocicep-
tive effect against the acetic acid-induced writhing test,
their effects were much weaker than those of ∆9-THC
(Table 2). CBD did not show any signifi cant effect at
10 mg/kg i.v. in these experiments.
The present study demonstrated that CBD was con-
verted to two HHCs together with ∆9-THC and CBN in
the artifi cial gastric juice. Marijuana is sometimes in-
gested together with candies, cakes, or alcoholic drinks,
and, therefore, CBD in marijuana can be converted to
∆9-THC and HHCs under the acidic conditions in the
stomach before absorption into the body, thus contrib-
uting to potentiation of the effects of ∆9-THC originally
present in marijuana.
Acknowledgments A part of this work was supported by the “Aca-
demic Frontier” Project for Private Universities from the Ministry
of Education, Culture, Sports, Science, and Technology of Japan
(2005–2009).
References
1. Mechoulam R, Shani A, Edery H, Grunfeld Y (1970) The
chemical basis of hashish activity. Science 169:383–393
2. Hollister LE (1973) Cannabidiol and cannabinol in man.
Experientia 29:825–826
Fig. 4 Effects of intravenous administration of CBD-derived
cannabinoids (10 mg/kg each) on rectal temperature of mice. The
data are shown as means ± SE obtained from eight mice. Asterisk,
signifi cant difference from controls at P < 0.05; double asterisk,
P < 0.01
Sleeping time (min)
Control
0
20
40
60
80
100
CBD
**
**
510
9-THC
**
**
510
8-OH-iso-
HHC
*
**
510
9 -OH-
HHC
**
510
Dose
(mg/kg, i.v.)
Fig. 5 Effects of intravenous administration of CBD-derived can-
nabinoids on pentobarbital-induced sleeping time in mice. The ef-
fects were determined under the conditions described in Materials
and methods. The data are shown as means ± SE obtained from
8–24 mice. Asterisk, signifi cant difference from controls at P <
0.05; double asterisk, P < 0.01
Table 2 Antinociceptive effects of 9α-OH-HHC and 8-OH-iso-
HHC in mice
Cannabinoid ED50 (mg/kg, i.v.)
9α-OH-HHC 14.1 (8.7–23.0)a
8-OH-iso-HHC 39.4 (6.8–226)
∆9-THC 1.1 (0.6–2.0)b
0.7% Acetic acid (10 ml/kg, i.p.) was administered 20 min after the
injection of each cannabinoid or the vehicle (1% Tween 80-saline,
10 ml/kg, i.v.). The numbers of abdominal constriction were
recorded for 10 min
a 95% Confi dence limits shown in parentheses
b Data taken from our previous report [13]
Forensic Toxicol (2007) 25:16–21 21
1 3
3. Hollister LE (1974) Structure–activity relationships in man of
cannabis constituents and homologs and metabolites for ∆9-
tetrahydrocannabinol. Pharmacology 11:3–11
4. Adams R, Pease DC, Cain CK, Clark JH (1940) Structure of
cannabidiol. VI. Isomerization of cannabidiol to tetrahydro-
cannabinol, a physiologically active product. Conversion of
cannabidiol to cannabinol. J Am Chem Soc 62:2402–2405
5. Adams R, Cain CK, McPhee WD, Wearn RB (1941) Structure
of cannabidiol. XII. Isomerization to tetrahydrocannabinols.
J Am Chem Soc 63:2209–2213
6. Gaoni Y, Mechoulam R (1966) Hashish-VII, the isomeriza-
tion of cannabidiol to tetrahydrocannabinols. Tetrahedron
22:1481–1488
7. Gaoni Y, Mechoulam R (1968) The iso-tetrahydrocannabi-
nols. Israel J Chem 6:679–690
8. Quarles W, Ellman G, Jones R (1973) Toxicology of mari-
huana: conditions for conversion of cannabidiol to THC upon
smoking. Clin Toxicol 6:211–216
9. Nagai K, Watanabe K, Narimatsu S, Gohda H, Matsunaga
T, Yamamoto I, Yoshimura H (1993) In vitro metabolic
formation of a new metabolite, 6β-hydroxymethyl-∆9-
tetrahydrocannabinol from cannabidiol through an epoxide
intermediate and its pharmacological effects on mice. Biol
Pharm Bull 16:1008–1013
10. Aramaki H, Tomiyasu N, Yoshimura H, Tsukamoto H (1968)
Forensic chemical study on marihuana. I. A detection method
of the principal constituents by thin-layer and gas chromatog-
raphies. Chem Pharm Bull 16:822–826
11. Petrzilka T, Demuth M (1974) Synthese von (−)-11-
hydroxy-∆8-6a,10a-trans-tetrahydrocannabinol. Helv Chim
Acta 57:121–150
12. Yoshimura H, Watanabe K, Oguri K, Fujiwara M, Ueki S
(1978) Synthesis and pharmacological activity of a phosphate
ester of ∆8-tetrahydrocannabinol. J Med Chem 21:1079–
1081
13. Watanabe K, Kijima T, Narimatsu S, Nishikami J, Yama-
moto I, Yoshimura H (1990) Comparison of pharmacological
effects of tetrahydrocannabinols and their 11-hydroxy-
metabolites in mice. Chem Pharm Bull 38:2317–2319
14. Litchfi eld JT, Wilcoxon F (1949) A simplifi ed method of eval-
uating dose–effect experiments. J Pharmacol Exp Ther 96:99–
113
15. Wilson RS, May EL, Martin BR, Dewey WL (1976) 9-Nor-9-
hydroxyhexahydrocannabinols. Synthesis, some behavioral
and analgesic properties, and comparison with the tetrahydro-
cannabinols. J Med Chem 19:1165–1167
16. Skinner WA, Rackur G, Uyeno E (1979) Structure-activity
studies on tetrahydro- and hexahydrocannabinol derivatives.
J Pharm Sci 68:330–332
17. Ganz AJ, Waser PG (1980) Prufung der pharmakologischen
wirkung einiger synthetischer Cannabinoide an der Maus.
Arzneim-Forsch 30:471–477
18. Narimatsu S, Yamamoto I, Watanabe K, Yoshimura H (1983)
9α,10α-Epoxyhexahydrocannabinol formation from ∆9-
tetrahydrocannabinol by liver microsomes of phenobarbital-
treated mice and its pharmacological activities in mice. J
Pharmacobio-Dyn 6:558–564
19. Holtzman D, Lovell RA, Jaffe JH, Freedman DX (1969)
l-∆9-Tetrahydrocannabinol: neurochemical and behavioral
effects in the mouse. Science 163:1464–1467
20. Lomax P (1971) Acute tolerance to the hypothermic effect of
marihuana in the rat. Res Commun Chem Path Pharmacol
2:159–167
21. Haavik CO, Hardman HF (1973) Evaluation of the hypother-
mic action of tetrahydrocannabinols in mice and squirrel mon-
keys. J Pharmacol Exp Ther 187:568–574
22. Zimmer A, Zimmer AM, Hohmann AG, Herkenham M,
Bonner TI (1999) Increased mortality, hypoactivity, and hy-
poalgesia in cannabinoid CB1 receptor knockout mice. Proc
Natl Acad Sci USA 96:5780–5785
23. Fernandes M, Schabarek A, Coper H, Hill R (1974) Modifi ca-
tion of ∆9-THC actions by cannabinol and cannabidiol in the
rat. Psychopharmacology 38:329–338
24. Turkanis SA, Cely W, Olsen DM, Karler R (1974) Anticon-
vulsant properties of cannabidiol. Res Commun Chem Path
Pharmacol 8:231–246
25. Chiu P, Karler R, Craven C, Olsen DM, Turkanis SA (1975)
The infl uence of ∆9-tetrahydrocannabinol, cannabinol and
cannabidiol on tissue oxygen consumption. Res Commun
Chem Path Pharmacol 12:267–286
26. Bloom AS, Johnson KM, Dewey WL (1978) The effects of
cannabinoids on body temperature and brain catecholamine
synthesis. Res Commun Chem Path Pharmacol 20:51–57
27. Yamamoto I, Watanabe K, Kuzuoka K, Narimatsu S,
Yoshimura H (1987) The pharmacological activity of canna-
binol and its major metabolite, 11-hydroxycannabinol. Chem
Pharm Bull 35:2144–2147
28. Paton WD, Pertwee RG (1972) Effects of cannabis and certain
of its constituents on pentobarbitone sleeping time and phena-
zone metabolism. Br J Pharmacol 44:250–261
29. Coldwell BB, Bailey K, Paul CJ, Anderson G (1974) Interac-
tion of cannabinoids with pentobarbital in rats. Toxicol Appl
Pharmacol 29:59–69
30. Siemens AJ, Kalant H, Khana M, Marshman J, Ho G (1974)
Effect of cannabis on pentobarbital-induced sleeping time
and pentobarbital metabolism in the rat. Biochem
Pharmacol 23:477–488
31. Borys HK, Ingall GB, Karler R (1979) Development of toler-
ance to the prolongation of hexobarbitone sleeping time
caused by cannabidiol. Br J Pharmacol 67:93–101
32. Watanabe K, Arai M, Narimatsu S, Yamamoto I, Yoshimura
H (1987) Self-catalyzed inactivation of cytochrome P-450 dur-
ing microsomal metabolism of cannabidiol. Biochem Pharma-
col 36:3371–3377
33. Buxbaum DM (1972) Analgesic activity of ∆9-tetrahydrocan-
nabinol in the rat and mouse. Psychopharmacologia 25:275–
280
34. Sofi a RD, Nalepa SD, Harakal JJ, Vassar HB (1973) Anti-
edema and analgesic properties of ∆9-tetrahydrocannabinol
(THC). J Pharmacol Exp Ther 186:646–655
