96
Industrial hemp is not marijuana:
Comments on the drug potential of fiber Cannabis
Franjo Grotenhermen and Michael Karus
nova-Institute, Hürth, Germany
Introduction
Since 1996, the cultivation of industrial hemp (Cannabis
sativa L.) varieties with a THC content of 0.3% or less in the upper third
of the leaves has again been allowed in Germany for the production of fiber and
seeds. In the last few years, several countries around the world have
rediscovered hemp as a versatile renewable raw material. Others never
discontinued growing this crop. Today, farmers in about 30 countries, including
Canada, Australia, China, Spain, Great Britain and France, are cultivating hemp.
Prior to the re-introduction of
industrial hemp in various countries, there were general discussions about its
drug potential, due to its botanical closeness to Cannabis varieties with
high THC content. In Germany, the argument of those who felt that there may be a
drug potential for hemp concluded that, "as long as there are neither
clinical experiments about the smoking of fiber hemp, nor the lowest effective
dose of THC in humans" one has still to assume a drug potential (Schinkel
1994).
Today, there is still no explicit
scientific research about the pharmacological effects of fiber hemp. But several
people, both habitual marijuana smokers and non-users, have made their own
experiments. Psychoactive effects have never been observed, and in the countries
where industrial hemp is cultivated today, there are no problems in this
respect. Furthermore, there is some scientific knowledge that already allows a
good assessment of the problem. In countries with a hemp cultivation tradition,
differentiation of Cannabis varieties is generally well accepted, even by
scientists who underscore the health problems they claim are caused by marijuana
and who assume a high toxicity for THC in their publications: "One should
still distinguish two principal large groups of Cannabis sativa
varieties, the drug type and the fiber type" (Nahas 1984).
Chemotype | Designation, products |
Leading cannabinoids |
THC content | Psychoactivity | |
---|---|---|---|---|---|
Drug type | marijuana, hashish, Cannabis tincture |
THC | >1-20% | yes | |
Intermediate type |
THC, CBD | > 0.3-1.0% | yes | ||
Fiber type |
industrial
hemp, fiber, oil |
CBD | < 0.3% | no | |
THC = Δ9-tetrahydrocannabinol; CBD = cannabidiol |
Industrial Hemp vs. Marijuana
Botanically, both industrial hemp
and marijuana (Cannabis sativa L.) belong, along with hop (Humulus
lupulus and associated wild species), to the family Cannabaceae (Frohne
1992). In former times, many other species of the genus Cannabis were
described, among them C. chinensis Delile, C. indica Lam., C.
lupulus Scop., C. americana Pharm. ex Wehmer, C. generalis
Krause, C. ruderalis Janischevskij (Schultes 1974).
Today, it is generally accepted that
the genus Cannabis consists of only one species, namely Cannabis
sativa L. (Frohne 1992). This conception is justified by the high
variability of characteristics used for the classification of species and the
unlimited cross-breeding within the genus (interfertility). But Cannabis
sativa L. is often divided into sub-species or varieties, according to their
composition of cannabinoids, so-called ‘chemotypes’, or according to
appearance, so-called ‘phenotypes’. Varieties used for the production of
fiber and seeds are often called "sativa" (Cannabis sativa L.
var. sativa), while those suitable for the production of drugs are often called
"indica" (Hänsel 1992).
A common classification is the
chemotypical division into a drug type, an intermediate type and a fiber type (Brenneisen
1987). The content of the most important psychotropic compound, the cannabinoid
THC, is high in Cannabis of the drug type and low in the fiber hemp
(Table 1). The THC content in industrial hemp that farmers may cultivate for
subsidy in the European Union, and are permitted to grow in Canada, is
restricted to a maximum of 0.3% with CBD:THC ratio of >2:1. Australia has
recently raised this level to 1%. Cannabidiol, a non-psychotropic compound, is
the predominant cannabinoid in these hemp varieties. The median THC
concentration of confiscated marijuana in the USA in 1997 was 4.2% (ElSohly
1998). Hemp with a THC-content lower than 1%, and also with a CBD-content higher
than it’s THC, was not classified as marijuana in this analysis of 35,312
samples confiscated in the USA between 1980 and 1997, but as "ditchweed"
(ElSohly 1998). Ditchweed is feral hemp, wild-growing and weedy descendants of
the fiber crops once cultivated in the Midwest of the United States.
The ratio of the different
cannabinoids are rather stable through genetic determination, but absolute
content can vary according to climate and other external factors (Brenneisen
1987, Turner 1984, Pitts 1992). Brenneisen and colleagues conducted extensive
breeding experiments in Switzerland in the 1980s (Brenneisen 1987). The
cannabinoid content of Cannabis remained relatively constant, although
some had more THC content in years with a hot summer. Only after six to eight
generations were there symptoms of inbreeding and a reduction of cannabinoid
content.
Practical experiences
According to reports to the
Association for Cannabis as Medicine, a number of persons have tried to obtain
medicinal effects through external and internal use of fiber hemp (ACM 1998).
There were some positive reports of antiasthmatic effects through pillows filled
with hemp, which also could have been due to terpenoid or placebo effects.
According to these reports, there occurred none of the spasmolytic, analgetic,
or other cannabinoid effects these persons had recognized from the ingestion of
marijuana.
In Great Britain, the media reported
about a hemp-growing farmer, who had tried to sell fiber hemp on the illegal
market. It was absolutely unsalable and the farmer was mocked in the media for
some weeks (O’Connell 1993). In Germany, similar attempts have not been
reported.
On the other hand, in Switzerland,
news had appeared of farmers who sold Cannabis at high prices, giving
reason for action by the police in several cases. However, in Switzer-land, Cannabis
for fiber and seed production is grown without any restriction on its THC
content, and varieties with high THC concentrations are common. The use of this Cannabis
for medicinal and recreational purposes is not allowed, but well-known.
So there have been, to some extent,
practical answers to the question of the drug potential of industrial hemp.
Independent of theoretical considerations, there will always be individual
experiments by curious youngsters. Where there is a drug potential be-cause of a
cannabinoid content that is adequate to produce the desired effects, it cannot
be hidden for long. Where there is no effect because of inadequate cannabinoid
content, there will be no such results, despite per-haps some placebo effect.
Pharmacokinetics
The pharmacokinetics of the
cannabinoids, especially that of THC, has been reviewed extensively (Agurell
1986, Harvey 1991). The pharmacokinetics of CBD largely corresponds to that of
THC.
For medical or recreational purposes,
Cannabis products are usually burned and the smoke inhaled (cigarette,
pipe, etc.), and to a lesser extent taken orally (tea, cookies, etc.).
In various studies, the efficiency of THC transfer from a marijuana cigarette
ranged between 2 and 56%, and generally between 10 and 30%, with a lower THC
availability for inexperienced users (Agurell 1986, Lindgren 1981). Smoking a
marijuana cigarette containing 10-20 mg of THC results in a maximum plasma
concentration of about 100 ng/ml within about five minutes. There is a
time-shifted correlation between THC plasma concentration and intensity of
pharmacological effects (Perez-Reyes 1982), the maximum effect being reached
within 15-30 minutes, when the plasma-level is already decreasing. This
time-shift is due to the time THC needs to penetrate the blood-brain barrier.
After one hour, the THC -plasma-level has declined to about 10 ng/ml.
Psychoactive effects last about 2-3 hours.
After oral intake, the
bioavailability of Cannabis products in a lipophilic base generally
ranges between 10 and 20%, a little below the efficiency of THC transfer that
one observes for smoking. Between 10-20 mg of orally ingested THC results in a
maximal plasma concentration of about 3-10 ng/ml, reached after 1 to 3 hours (Ohlsson
1980, Frytak 1984 Brenneisen 1996). Psychoactive effects start within 30-60
minutes and last about 4-6 hours, and depending on the dose, even longer.
To achieve a comparable intensity of
effects, much higher doses are required with the oral route than with
inhalation. This observation is com-parable to the differences in drug
pharmacokinetics between the intra-venous and oral routes for medications, with
a faster and stronger action after injection.
THC-threshold for cannabimimetic effects
Lucas and Laszlo (1980) found marked
psychological reactions (anxiety, visual disturbances etc.) after oral
application of single doses of about 25 mg THC in three out of nine cancer
patients receiving chemo-therapy. A dose of 7.5 to 10 mg resulted in only mild
reactions. In another study, none of the six patients receiving single oral
doses of 15 mg THC as an antiemetic showed mood alterations (Frytak et al.
1984). Brenneisen et al. (1996) administered single oral doses of 10 or
15 mg THC to two patients. No changes of physiological (heart rate) or psycho-
logical parameters (concentration, mood) were noted. In a study with healthy
volunteers, Chesher et al. (1990) found no difference between 5 mg of
oral THC and placebo with regard to all measured pharmacological parameters.
Single doses of 10-15 mg caused slight differences in comparison to placebo,
while 20 mg caused perceptible differences in subjective experience.
There seems to be a threshold for
psychoactive effects of 0.2-0.3 mg THC per kg of body weight for a single oral
dose in lipophilic base, corresponding to 10-20 mg THC in an adult. Higher doses
are required to achieve the effects desired by marijuana users. A single dose of
5 mg oral THC can be considered as a placebo dose.
The threshold for acute
pharmacological effects after smoking is lower than after oral administration
because of a higher systemic bio-availability and, most of all, because of a
faster assimilation of THC. In various studies, marijuana users smoked about
10-16 mg THC to achieve the desired state of effect (Ohlsson 1980, Perez-Reyes
1982). The thresh-old for a minor psychoactive effect is somewhere in the range
of 5 mg.
The threshold concentration for the
discrimination of smoking marijuana from smoking placebo seems to be somewhere
in the order of 0.8-1.0% THC. Chait et al. (1988) studied the
discriminate stimulus between the effect of marijuana containing 2.7% THC and
marijuana containing 0.0% THC in experienced marijuana users. Their research
showed that 0.9% THC marijuana produced primarily placebo- appropriate
responding, while 1.4% THC marijuana produced drug appropriate responding.
However, when a low THC content material is smoked, the expectancy of the user
plays a more important part than the pharmacological effects. Even the typical
marijuana-taste of placebo cigarettes may produce some of the expected
psychological effects (Jones 1970).
Impact of assimilation speed
The comparison between the oral and
inhalative routes has shown that the speed of assimilation is an important
factor for the intensity of effects. Corrected for THC transfer, about twice as
much THC is needed after oral administration of THC than after fast inhalation
of THC. Speed of onset is the third factor besides bioavailability and quantity
for determining strength of action after the ingestion of THC.
If the whole amount of THC is inhaled
within a few minutes, as with THC-rich marijuana, the doseresponse profile
resembles that of an intravenous injection, with its characteristically fast peak
of plasma drug concentration (Agurell 1986). In this case, relatively little THC
is needed to obtain the desired effect. If the whole amount of THC is inhaled
over a longer period of time, inevitable in case of fiber hemp, the maximum
plasma peak will be much lower and will more resemble the one evident after oral
administration, resulting in higher doses being necessary to achieve the same
effects.
Impact of smoking patterns
A marijuana cigarette is smoked within
about 10-20 minutes, with high inter-individual variability resulting from
different individual smoking habits. To a certain degree, it is possible to
compensate for a relatively low THC content through intensification of smoking
patterns. Herning et al. (1986) studied the smoking behavior of ten
experienced Cannabis users in response to variation in THC content.
Marijuana cigarettes containing 1.2 or 3.9% THC were smoked on different days.
The less potent cigarettes were inhaled with longer puffs, shorter intervals
between puffs and with less of the inhaled air volumes that dilute the marijuana
smoke.
However, in a study by Perez-Reyes et
al. (1982) there was only little adaptation by smokers. Six subjects were
asked to smoke marijuana cigarettes containing 1.32%, 1.97%, and 2.54% THC at
weekly intervals in a double-blind cross-over design until obtaining a
"high". Due to their very similar smoking habits, there was a positive
correlation between the amount of assimilated THC, the maximum plasma
concentration, the achieved "high" and the potency of the cigarettes.
"The results indicate that, irrespective of the potency of the marijuana,
the pattern of smoking was much the same. The magnitude of the subjective high,
heart rate acceleration, THC, and THC carboxylic acid plasma concentrations were
proportional to potency. This dose response was particularly clear between the
1.32% and the 2.54% cigarettes."
Similar relationships between THC
concentration of the marijuana cigarette and the obtained effects were reported
by other authors (Cappell 1973, Chait 1989, Chait 1994). There is some
adaptation of smoking pattern to the THC content, but especially in the case of
large differences in THC concentrations, this is not adequate compensation for
lack of potency. High THC concentrations in Cannabis smoke allow drug
ingestion within a short period of time resulting in high maximum plasma
concentrations achieved with-in few minutes and therefore a strong effect.
"Thus, not only the dose of THC smoked is important, but also the time used
for smoking" (Agurell 1986).
Studies with different
marijuana-potencies have demonstrated that "the reinforcing effects of
marijuana, and possibly its abuse [sic] liability, are positively related to THC
content" (Chait 1994). This observation implies that with decreasing
content, the THC-concentration will finally reach a critical threshold under
which its consumption is not reinforcing.
Chemotype | THC content | THC/CBD ratio | CBD/THC ratio | |
---|---|---|---|---|
Drug type | > 1-20% | 2.3-7.4 | 0.14-0.4 | |
Intermediate
type Fiber type |
> 0.3-1.0% < 0.3% |
0.5-2.0 0.06-0.5 |
0.5-2.0 |
|
THC = Δ9-tetrahydrocannabinol; CBD = cannabidiol |
Impact of cannabidiol content
"Marijuana is not simply Δ9-tetrahydrocannabinol"
(Musty 1997). CBD antagonizes the psychotropic effects of THC and is found in
industrial hemp in a much higher concentration than THC. While in Cannabis
of the drug type, the THC/ CBD ratio is about 2-7 or more, there is an opposite
ratio in fiber hemp, with a CBD content of at least twice that of THC (De Meijer
1992). In practice, we find THC/CBD ratios of 0.06-0.5 in industrial hemp (Table
2).
CBD shows no psychotropic effects,
but some clinically relevant effects have been found. Among them are
anticonvulsant effects in epileptics (Cunha 1980) and antidystonic effects in
movement disorder patients (Consroe 1986). Some properties resemble those of
THC, e.g., some effects on the immune system (Watzl 1991), other
properties differ from THC, e.g., the electrophysiological properties
(Turkanis
1981), others show distinct contrary effects, e.g. some effects on the
heart (Nahas 1985).
Of interest in this context is the
action of CBD on the psyche. There are sleep-inducing (Carlini 1981), anxiolytic
and anti-psychotic effects, as well as an antagonism of the psychotropic effects
of THC. High doses of THC can induce anxiety, panic reactions and functional
psychotic states. Zuardi et al. (1997) found a significant reduction of
anxiety in a model of speech simulation, with 300 mg CBD comparable to 10 mg of
the sedative diazepam. The same working group treated a young schizophrenic man
who was admitted to a hospital because of aggressive behavior, self-injury,
incoherent thoughts and hallucinations, for four weeks with doses up to 1,500 mg
CBD. All symptoms improved impressively with CBD, so that the improvement could
not solely be attributed to an anxiolytic effect. These studies were inspired by
the observation that CBD antagonized the psychotropic effects of THC in animal
and man.
The first studies in humans designed
to investigate the mutual interference of THC and CBD, conducted by three
different working groups, led to contradictory results (Karniol 1974, Hollister
1975, Dalton 1976). Hollister and Gillespie (1975) found a delayed, longer and
slightly rein-forced action of 20 mg THC if the subjects had received 40 mg CBD
previously (Hollister 1975). In the other two studies, CBD antagonized the
characteristic psychotropic effects of THC when given simultaneously (Karniol
1974, Dalton 1976). Zuardi et al. (1982) offered an explanation for these
differences based on the different application methods. While a simultaneous
application of CBD antagonizes the THC effects, a CBD application before THC
might eventually potentiate the effect of the latter. This proposal was
supported by later animal re-search. The kinetics of THC is altered in mice
pretreated with CBD, probably through the inhibition of hepatic microsomal THC
metabolism (Bornheim 1995). THC blood levels were modestly elevated after CBD
pretreatment compared to untreated controls, and the area under the curve (AUC)
of THC increased 50% as a function of decreased clearance.
In a study of Zuardi et al.
(1982), eight volunteers received high oral doses of THC (0.5 mg THC per kg body
weight, about 35 mg), or this dose plus twice the dose of CBD in a double-blind
design. The study demonstrated that CBD blocked the anxiety produced by THC.
This inhibition was extended to the marijuana-like effects and other alterations
caused by THC.
Conclusion
The time period required for the
assimilation of THC plays an important role in the intensity of the psychoactive
effects. This is well-known also from other drugs; for example alcohol, or
prescribed sedatives. It is much more difficult to obtain an intoxicated state
from "non-alcoholic" beer, which contains about 0.1-0.5% alcohol, than
from drinks being considered as alcoholic, even if the same amount of alcohol is
ingested, but within a longer period of time. Also, intravenous applications of
sedatives, e.g., diazepam, result in a faster and stronger action
compared to the effects after oral application. The main reason the
counterculture breeds marijuana with a high THC content (up to 20% and more) is
to achieve high maximum plasma THC concentrations within a short period of time,
resulting in strong cannabimimetic effects.
This principle has consequences for
the smoking of industrial hemp with low THC concentrations: First, the lower the
THC content in hemp, the higher is the total amount of THC necessary to obtain
psychological effects, and there is only a partial cumulative effect. Secondly,
even after adjustment of smoking habits, the requirement for ingesting this
higher amount of THC can only partly be fulfilled. There is no strict threshold
for the lowest THC concentration in Cannabis necessary to induce
psychoactive effects, because there is inter-individual variability due to
tolerance after chronic administration, as well as inter-individual and
intra-individual variabilities due to different smoking patterns. However, this
threshold seems to approximate the upper limits (0.8-1.0% THC) for Cannabis
of the intermediate type (>0.3-1.0% THC).
Additionally, we find other
cannabinoids in Cannabis, the most important being CBD. With a decreasing
THC content, CBD gains increasing importance concerning the overall
pharmacological effects of the crude drug. A CBD/THC ratio of two or more
results in a partial inhibition of these effects. With increasing CBD/ THC
ratios, and depending on absolute THC content, a complete inhibition of the
psychoactive effects is probably achieved.
Hence, it seems reasonable and useful
to classify Cannabis into three distinct categories: drug types (>1%
THC) whose products are used recreationally and medicinally; inter-mediate types
(>0.3-1.0% THC) with only a small drug potential, depending on the CBD/THC
ratio; and fiber types (industrial hemp, fiber hemp) (<0.3% THC) used
for the production of fiber and seeds with no drug potential.
This study was supported by dupetit
natural products, Richelbach, Germany.
References
ACM 1997-1998. Personal communications from several members of the ACM.
Agurell, S., et al. 1986. Pharmacokinetics and metabolism of delta-1-tetrahydrocanna-binol and other cannabinoids with emphasis on man. Pharmacol. Rev. 38(1): 21-43.
Ames, F. R. and S. Cridland 1986. Anti-convulsant effect of cannabidiol [letter]. S. Afr. Med. J. 69(1): 14.
Bornheim, L. M. et al. 1995. Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain. Drug Metab. Dispos. 23(8): 825-831.
Brenneisen, R. et al. 1996. The effect of orally and rectally administered delta-9-tetra-hydro cannabinol on spasticity: a pilot study with 2 patients. Int. J. Clin. Pharmacol. Ther. 34(10): 446-452.
Brenneisen, R. and T. Kessler 1987. Psycho-trope Drogen. V. Die Variabilitat der Cannabinoidführung von Cannabispflanzen aus Schweizer Kulturen in Abhängigkeit von genetischen und ökologischen Faktoren [Psychotropic drugs. V. Variability of cannabinoid liberation from Cannabis plants grown in Switzerland in relation to genetic and ecological factors]. Pharm. Acta Helv. 62(5-6): 134-139.
Cappell, H., E. Kuchar and C. D. Webster 1973. Some correlates of marihuana self-administration in man: a study of titration of intake as a function of drug potency. Psychopharmacologia 29(3): 177-184.
Carlini, E. A. and J. M. Cunha 1981. Hypnotic and antiepileptic effects of cannabidiol. J. Clin. Pharmacol. 21(8-9 Suppl): 417-427.
Chait, L. D. and K. A. Burke 1994. Preference for high- versus low-potency marijuana. Pharmacol. Biochem. Behav. 49(3): 643-647.
Chait, L. D. 1989. Delta-9-tetrahydrocanna-binol content and human marijuana self-administration. Psychopharmacology (Berl) 98 (1): 51-55.
Chait, L. et al. 1988. Discriminative stimulus and subjective effects of smoked marijuana in humans. Psychopharmacology (Berl) 94(2): 206-212.
Chesher, G. B. et al. 1990. The effects of orally administered delta-9-tetrahydrocannabinol in man on mood and performance measures: a dose-response study. Pharmacol. Biochem. Behav. 35(4): 861-864.
Cocchetto, D. M. et al. 1981. Relationship between plasma delta-9-tetrahydrocanna-binol concentration and pharmacologic effects in man. Psychopharmacology (Berl) 75(2): 158-164.
Consroe, P., R. Sandyk and S. R. Snider 1986. Open label evaluation of cannabidiol in dystonic movement disorders. Int. J. Neurosci. 30(4): 277-282.
Cunha, J. M. et al. 1980. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 21(3): 175-185.
Davis, K.H. et al. 1984. Some smoking characteristics of marijuana cigarettes. in Agurell, S., W. L. Dewey and R. E. Willette (Eds.). The Cannabinoids: Chemical, Pharmacologic and Therapeutic Aspects. Academic Press, New York. pp. 245-261.
Dalton, W. S. et al. 1976. Forney influence of cannabidiol on delta-9-tetrahydrocannabi-nol effects. Clin. Pharmacol. Ther. 19(3): 300-309.
De Meijer, E. P. M. et al. 1992. Characterisation of Cannabis accessions with regard to cannabinoid content in relation to other plant characters. Euphytica 62: 187-200.
ElSohly, M. A., et al. 1998. Delta-9-THC and other cannabinoids content of confiscated marijuana: potency trends, 1980-1997. in 1998 Symposium on the Cannabinoids. International Cannabinoid Research Society, Burlington, Vermont.
Frohne, D. 1992. Systematik des Pflanzenreichs [Systematics of Plants]. Stuttgart, Fischer. [in German]
Frytak, S., C. G. Moertel and J. Rubin 1984. Metabolic studies of delta-9-tetrahydro-cannabinol in cancer patients. Cancer Treat. Rep. 68(12): 1427-1431.
Hänsel, R. (Ed.) 1992. Cannabis. In: Bruchhausen, F. von (Ed.). Hagers Handbuch der pharmazeutischen Praxis [Hager’s Handbook of the Pharmaceutical Practice]. Vol. 4 (Drogen [Drugs]), Springer, Berlin. [in German]
Harvey, D. J. 1991. Metabolism and pharmacokinetics of the cannabinoids. In: Watson, R. R. (ed.). Biochemistry and physiology of substance abuse. Volume III. Boca Raton, Florida: 279-365.
Herning, R. I., W. D. Hooker and R. T. Jones 1986. Tetrahydrocannabinol content and differences in marijuana smoking behavior. Psychopharmacology (Berl) 90(2): 160-162.
Hollister, L. E. and H. Gillespie 1975. Inter-actions in man of delta-9-tetrahydrocan-nabinol. II. Cannabinol and cannabidiol. Clin. Pharmacol. Ther. 18(1): 80-83.
Jones, R. T. and G. C. Stone 1970. Psycho-logical studies of marijuana and alcohol in man. Psychopharmacologia 18(1): 108-117.
Karniol, I. G. et al. 1974. Cannabidiol interferes with the effects of delta -9- tetrahydrocannabinol in man. Eur. J. Pharmacol. 28(1): 172-177.
Lindgren, J. E. et al. 1981. Clinical effects and plasma levels of delta-9-tetrahydrocanna-binol (delta-9-THC) in heavy and light users of cannabis. Psychopharmacology (Berl) 74(3): 208-212.
Lucas, V. S., Jr. and J. Laszlo 1980: Delta 9-Tetrahydrocannabinol for refractory vomiting induced by cancer chemotherapy. JAMA 243(12): 1241-1243.
Musty, R. E. 1997. Marijuana is not simply delta-9-Tetrahydrocannabinol. 1997 Symposium on the Cannabinoids, International Cannabinoid Research Society, Burlington, Vermont.
Nahas, G. G. (Ed.) 1984. Marihuana in Science and Medicine. Raven Press, New York. p. 31.
Nahas, G. and R. Trouve 1985. Effects and interactions of natural cannabinoids on the isolated heart. Proc. Soc. Exp. Biol. Med. 180(2): 312-316.
O’Connell, F. 1993. Personal communication.
Ohlsson, A. et al. 1980. Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin. Pharmacol. Ther. 28(3): 409-416.
Perez-Reyes, M. et al. 1982. Comparison of effects of marihuana cigarettes to three different potencies. Clin. Pharmacol. Ther. 31(5): 617-624.
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): 947-951.
Schinkel 1994. Personal communication about an internal paper of the Bundesinstitut für Arzneimittel und Medizinprodukte [Federal Institute for Drugs and Medical Products]. Letter of November 15.
Schultes, R. E. et al. 1974. Cannabis: an example of taxonomic neglect. Harvard Bot. Mus. Leaflets 23: 337-367.
Turkanis, S. A. and R. Karler 1981. Electro-physiologic properties of the cannabinoids. J. Clin. Pharmacol. 21(8-9 Suppl): 449-463.
Turner, J. C. et al. 1984. A temporal study of cannabinoid composition in continual clones of Cannabis sativa L. (Cannabaceae). Bot. Gaz. 146: 32-38.
Watzl, B., P. Scuderi and R. R. Watson 1991. Marijuana components stimulate human peripheral blood mononuclear cell secretion of interferon-gamma and suppress interleukin-1 alpha in vitro. Int. J. Immuno-pharmacol. 13(8): 1091-1097.
Zuardi, A. W. and F. S. Guimarães 1997. Cannabidiol as an anxiolytic and antipsychotic. in Mathre, M. L. (Ed.): Cannabis in medical practice: a legal, historical and pharmacological overview of the therapeutic use of marijuana. McFarland & Co., Jefferson, NC: 133-141.