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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).

Table 1. Chemotypes of Cannabis (modified according to Brenneisen et al. 1987).
  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.

Table 2. Ratio of THC and CBD (according to analyses of De Meijer 1992).
  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
2-17
  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