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Hemp is less toxic than alcohol or tobacco

Excerpts from the Roques report, ordered by
B. Kouchner, released in June 1998

Chapter 10 - Cannabis
Cannabis is the most used of all drugs for its psychoactive properties, particularly among 15-30 years old people, in almost every country. It is also the most discussed drug with positions often opposed on its dangerousness, and on the laws to enforce regarding its use (Zimmer and Morgan, 1997; Pecle, 1989; Nahas, 1993). Many questions are usually raised concerning its use, mainly: is cannabis a gateway to hard drugs, such as heroin and cocaine? What are the long-term risks of cannabis use (central nervous system, cardiovascular, respiratory, reproduction and immune system, etc.). Does cannabis use lead to risks in terms of road traffic? What are the therapeutic properties of cannabis? This chapter offers a quick and critical review of arguments presented, taking into account the most recent results obtained, particularly in human.

10.1 Presentation of cannabinoids
Used for millennia for recreational or therapeutic uses, cannabis was listed in many pharmacopoeias until the 30-40’s, when it was progressively removed because of its psychoactive effects. Since a few years, there is a call for re-introducing THC in therapeutics - which is in line with today’s trend to privilege the medical use of natural compounds (especially plant extracts). Currently, THC is used in therapeutics as an oily solution (dronabinol) mainly in the USA, and nabilone, the synthetic analog, is used in the United Kingdom. Obtained from secretions (resin, hashish) of Cannabis sativa blossoms, the cannabinoid substances found in the leaves are very hydrophobic heterocycles. The most abundant compound is D9-tetrahydrocannabinol (THC), which concentration has increased these last years, reaching up to 20% of the resin weight in the "Netherweed". Numerous chemical studies have been conducted in order to inhibit the psychic effects of cannabinoids, while keeping the therapeutic effects (analgesic, antiemetic, etc.), without real success (Mechoulam and Feigenbaum, 1987; WHO Report, 1997). Various modifications of THC (as with 11-OH-D8-THC-dimethylheptyl), or the simplification of the structure, have led to compounds 100 to 800 times more active in behavioral tests. Several pharmaceutical companies have developed THC analogs, particularly CP 55.490 and WIN 55.212, in order to obtain new analgesic drugs (review in Adams and Martin, 1996). The structure of these molecules is more complex than THC, they bind to the same brain sites and their activity is 4 to 25 times stronger, including at the antinociceptive level. However, they have not been clinically developed, essentially because none of them could inhibit the psychic effects of THC while keeping its therapeutic properties (Pertwee, 1992). Some, like CP 55.940 are aversive at high doses in rats, as it is also observed with THC in human (Mc Gregor et al., 1996). Cannabinoids are mainly inhaled from "joints" or "reefers". More or less pure THC can also be injected intravenously, and, more rarely, it is used in pills or mixed with different cooked preparations. A recent study involving 65,171 people showed that the mortality risk associated with cannabis use is lower than the risk associated with tobacco use (Sidney et al., 1997).

10.2 Analysis of biological data - Biochemical aspects
Cannabinoids, particularly THC, induce numerous behavioral responses, which suggests the existence of multiple central and peripheral targets (Hall et al., 1994). In human, an euphoric and relaxing effect, an easiness to interindividual contacts, and an increase in visual and auditive perceptions, which can be modified with high doses, may be observed. The synthesis of titrated derivatives of previous molecules, including THC, has allowed showing the existence of specific binding sites in the rat brain (Howlett et al., 1990). The affinity of molecules tested for the so-called CB1 receptor (Matsuda et al., 1990) is well correlated with pharmacological responses (Compton et al., 1993). The distribution of CB1 receptors (Herkenham et al., 1991) shows a very high density in the limbic system, including the N.Accumbens, and the cerebellum, and high in the hippocampus and the cortex. Their distribution covers in many areas the distribution of dopaminergic receptors, but cannabinoid receptors are not located on dopaminergic neurons. There are also sites in the amygdala. In the periphery, the CB1 receptor is located in the genitourinary tract, and in the embryo (rodents), whereas CB2 sites (Munro et al., 1993) have been found in the immune system (ganglions, spleen, thymus, lymphocytes, hematopioetic cells). These receptors seem slightly different from the central sites (40% homology), but they are also able to bind to THC with high affinity. The presence of at least two binding sites shows that it is possible to develop specific ligands (agonist and antagonist) to each receptor in the future. At the surface of the hematopioetic cells, CB2 receptor could play a role in the division of these cells in conjunction with growth factors. The potentialisation effect from the latter seems to be very selective to anandamide endogenous effector, as it is not observed with other cannabinoids. The mechanism of the stimulating effect on progenitor cells’ division is unknown (activation of the RAS route?). However, it is of great interest (Bouaboula et al., 1995; Valk et al., 1997).
Cultures of cerebellum neurons are often used in biochemical studies. CB1 and CB2 receptors belong to the group of transmembrane receptors with seven helix associated to G proteins. CB1 and CB2 receptors are coupled in a negative way to the adenylate cyclase system through a Gi protein. Other transduction systems (phospholipase C) could also be coupled to CB1 receptor, and, in this case, the stimulation would lead to an increase in the intracellular levels of calcium. Results in this field are often contradictory, the problem being that they are generally obtained on cell cultures and thus are not necessarily reproducible in vivo.

10.3 Pharmacokinetic data
Almost all cannabis compounds, including those resulting from cannabinoid metabolism, can be evaluated by very accurate analytical methods (Huetis et al., 1992). Due to their strong hydrophobia, cannabinoids, and particularly THC, quickly penetrate in the systemic circulation, then in the brain after inhalation. Doses of 2mg THC in a cigarette can have behavioral effects, probably by recruiting enough receptors. The accuracy of dosing techniques in urine enables the detection of such a dose during the three following days.
Psychic effects of THC in na?ve users appear approximately 15-20 minutes after inhalation, and later in frequent users which is a sign of a slight tolerance. These effects appear 4-5 hours after ingestion by oral route. The plasma concentration decreases very quickly with the appearance of active (11-OH THC) or inactive (THC-COOH) metabolites, the latter being very abundant in plasma and urine. Elimination through the bile route is higher than urinary excretion. These pharmacokinetic data are obviously changed according to people or induced factors (hepatic metabolism naturally altered or not, alcoholism, induction of P450 by drugs, etc) and by the route of administration. One of the characteristics of THC is its non-specific affinity for the lipid tissue, where cannabinoids are slowly eliminated (up to six days after administration of high doses). Here again, there are differences according to people and products used in combination. The main incidence of the complex pharmacokinetics of cannabinoids is that it is extremely difficult to settle an "acceptable" level of THC in plasma or urine, as it is the case with alcohol. The quick dosing techniques by immunology (Elisa) EZ-CREEN (Jenkins et al., 1993), although powerful and reliable, cannot be used or should only be used in association with a questionnaire with regard to the time of cannabis use, which reliability would no doubt be very low. It is admitted that approximately four hours after inhalation of usual doses of cannabis (< 20 mg THC) physiological and behavioral effects have completely disappeared.

10.4 Endogenous ligands of CB1 and CB2 receptors
The first one was isolated by Devane et al. in 1992. Called anandamide, it is a fatty acid derivative that binds to CB1 receptors, moves THC, and produces pharmacological responses, usually similar to those produced by cannabinoids in animals (analgesia, hypothermia, catalepsy) (Fride et Mechoulam, 1993). However, anandamide is 4 to 20 times less active, and its time of action is shorter than THC. Anandamide could be generated from constitutive fatty acids by enzymatic route, and enzymes, including a peptidase (Devane et Axelrod, 1994) also inactivate it. Nevertheless, anandamide metabolism, its release and its inactivation must be clarified (Schmid et al., 1997 and ref. quoted). Indeed, there are other phospholipid analogs to anandamide, with the ability to bind to CB1 site, which can be (or not) intermediate of anandamide metabolism (Mechoulam et al., 1944). They are all derived from fatty acids, such as palmitoyl-ethanolamide and 2-arachidonyl-glycerol. The latter is 170 times more abundant than anandamide in the brain. It is formed by action of phospholipase C and diacyglycerol lipase under the influence of calcium. It acts like an agonist, and inhibits induction of long-term potentialisation phenomena involved in mnesic processes (Stella et al., Nature 1997). The question of the physiological role of anandamide is still unanswered, as it is for its profile (neurotransmitter, neuromodulator?) and its routes. Cannabinoids have the ability to modulate the action of almost all neurotransmitter systems (DA, 5HT, GABA, Ach, opiates), which makes these molecules close to barbiturates or local anesthesia drugs, very lipophilic, with a strong affinity for nervous tissues. Besides, these compounds are also diverted from their medical use for recreational purposes. We know little about endogenous ligands in the periphery of CB2 receptors. The development of the antagonist SR141716A (Rinaldi-Carmana et al., 1994), and of mice which coding gene for CB1 and CB2 receptors has been deleted, should clarify quite a few questions.

10.5 Psychopharmacology of cannabinoids
Absorption of cannabis produces a feeling of light euphoria and relaxation, along with amplified auditive and sight perceptions, as it has been reported. Slight disturbances may be observed in the ability to perform more or less complex usual tasks. This is interpreted by a slight impairment of psychomotor and mnesic performances (review in Hall et al., 1994) , possibly connected to the reduction of LTP resulting from the activation of CB1 receptors (Stella, 1997 and ref. quoted). These effects are dose related, and with high concentration (> 40 g THC) sedation syndromes, feeling of heaviness and sometimes depression may be observed. It is important to note that the effects of somnolence produced by cannabis are the result of the combined action of the various cannabinoids, which explains why they are different according to the source of cannabis (hashish vs. marijuana). Although criticizable in their methodology, several studies showed that during the period of administration of high doses of THC, training skills were slightly impaired with cannabis use, especially because of a lack of attention. However, results are rather contradictory, the heaviest consumers being the less affected (Adams and Martin, 1996, and ref. quoted). On the opposite, no modification of abstraction abilities and use of vocabulary was observed. It is rather an impairment of the short-term memory, with apparently no effect on the long-term retention (Schwartz et al., 1989). Although these effects seem modest, and should be confirmed by more extensive studies, they must be taken into account for teenagers attending school (Block et al., 1992, 1993; Solowij et al., 1991, 1996; Pope and Zurgelam, 1995, 1996; Fletcher et al., 1996). Nevertheless, it should be noted that despite a possible impairment of mnesic processes, and altered time perception often noticed by cannabis users, no modification of the quality of the task performed is observed (Hollister, 1986).
In the same way, daily use of high doses of cannabis for many years does not seem to induce neither amotivational nor absence of motivation behaviors well established. Impairment of the short-term memory due to chronic use of cannabis would result from disturbances in the organisation and integration of complex information. They involve the frontal cortex where THC induces blood flow and metabolism variations observed by neuro-imaging (Mathew et al., 1992). Behavioral effects of cannabis, in particular somnolence, and psychomotor slowdown led to study their repercussion in terms of vehicle driving (Simpson, 1986). Numerous studies or surveys were carried out (viz. White Paper, G Lagier). The results are uneasy to interpret because of a practically constant combination of several products, most frequently with alcohol, among drivers responsible for accidents who were tested. Used alone, cannabis does not seem to be a major risk factor for accident (Scherman, 1992; Robbe, 1994; Drummer et al, 1994; Chescher, 1995), which is not the case when associated with alcohol, psychostimulants or tranquillizers. Current studies carried out on a more important number of cases could contradict these results. In presence of hallucinogens, which can be used by accident mixed with ecstasy, the psychic effects are such as car driving is almost impossible.
Laboratory research made it possible to assess more directly the effects of cannabis on vehicle driving (review in Robbe et al., 1994). Cannabis users, tested using driving simulators or during controlled driving in town, do not seem very different from the control groups. However, it showed that the first ones have delayed responses when starting, overtaking, etc... (Smiley, 1986). Moreover, there is an awareness to compensate attention’s impairment (Mercier-Guyon, 1994), which however could failed in the event of an unexpected situation or when over consuming. Nevertheless, it is necessary to put the risk into perspective compared to alcohol (Robbe, 1994), which remains much more frightening in terms of traffic accidents, particularly because of its desinhibiting effects.

Cannabis and psychopathological states.
Using cannabis for the first time can involve, in rare cases, effects of severe anxiety, close to those felt during crises of panic in vulnerable people. They are reversible when stopping use, and do not seem to reproduce thereafter. No mental pathology directly connected to the over consumption of cannabis was observed, which makes this drug different from psycho stimulants such as MDMA, cocaine or alcohol, which excessive and repeated use can lead to specific psychotic syndromes. In the same way, cannabis does not seem to accelerate the onset of pre-existing mental disorders (schizophrenia, bipolar depression, etc...). However, it is possible that, as this is the case for all drug abuse, the repeated use of cannabis is more often found in people with psychic disorders, in particular schizophrenic (Allebeck, 1993; Allebeck et al., 1993; Williams et al., 1996). Finally, no amnesia syndrome comparable to the Wernicke and Korsakov syndrome observed in chronic alcoholics, was observed in heavy cannabis users.

Cannabis and cerebral functions - Neurotoxicity.
Addiction to cannabis does not involve neurotoxicity such as it was defined in chapter 3 by neuroanatomical, neurochemical and behavioral criteria. Thus, former results suggesting anatomic changes in the brain of chronic cannabis users, measured by tomography, were not confirmed by the accurate modern neuro-imaging techniques. Moreover, morphological impairment of the hippocampus of rat after administration of very high doses of THC (Langfield et al., 1988) was not shown (Slikker et al., 1992). Thus, the post-mortem anatomical analysis of baboon brains, treated with high doses of cannabis for 8 months, do not show signs of neuronal injury or morphological activation of nervous tissue (Ames et al., 1979). However, the death of an animal due to meningitis led to questions on the risk of encephalopathy induced by cannabis. No epidemiological data has confirmed this possibility (Castle and Ames, 1996). Several studies aimed at showing the effects of cannabis on the mentioned potentials, and on the electroencephalogram in human. Irregular use produces reversible changes in the alpha waves profiles in the frontal cortex, probably in connection with the states of somnolence induced by THC. In the very long term (more than 15 years), and with heavy daily use, an increase in the frontal activity theta, and a hyperfrontality alpha were observed (Struve et al., 1990, 1994). The possible relation with behavioral changes or in neuropsychological tests is not discussed nor the possible relation with the anticonvulsant effects of THC. Several studies showed variations of cerebral and metabolism circulation in some cerebral areas, particularly in the cerebellum, and in the prefrontal cortex by PET Scan or FMRI (Volkow et al., 1996), what is however often observed with psychoactive agents. It would certainly be very interesting to study more in details the distribution of filled CB1 sites, by quantitative FART scan, with respect to: I) the dose of THC administered; ii) the period between administration and the measure (kinetic dissociation in the different cerebral areas); iii) to link these parameters with the effects observed. This requires the development of selective ligands marked with radioactive isotopes, with a short life, and an appropriate bioavailability. Besides, taking into account the multitude of neuronal routes potentially recruited by THC, it would be interesting to systematically examine them in PET scan, using appropriate ligands.

Tolerance and dependence to cannabis.
It is still a very discussed topic (Jones et al., 1981). In animals, the pharmacological actions of THC and synthetic cannabinoids lead to tolerance phenomena (review in Adams and Martin; 1996). The biochemical origin of this phenomenon could be of the same type as the one found with opiates, i.e. an adaptation of the reception-transduction system, but this remains to be clarified, as is the case for all neuromodulators. Contradictory results concerning the density of receptors in certain cerebral areas show a decrease or an increase (Oviedo et al., 1993; Romero et al., 1995), measured by in-situ connection or hybridization. These changes are reversible in any case, as shown in a study with a monkey brain, 7 months after a one-year exposure of the animal to cannabis smoke (Westlake et al., 1991).
"Drugs" are generally classified with respect to their ability to generate physical and psychic dependence, and they are regarded at risk if they meet these two criteria. Cannabis was included in this group, although cannabinoids are far from producing effects similar to those induced by heroin, alcohol or tobacco. Thus, the sudden stop of a chronic treatment with THC gave contradictory results in rats, since in the case of behavioral modifications, these were not modified by administration of the agonist (Adams and Martin, 1996 and ref. quoted). Naxalone induces a slight abstinence syndrome, very different from the syndrome this opioid antagonist produces in animals addicted to morphine (Kaymakcalan et al., 1977). The recent development of the selective CB1 receptor antagonist, SR 141716A, made it possible to show in rats (Aceto et al., 1995; Tsou et al., 1995), then recently in mice (Cook et al., 1998; Hutcheson et al., 1998), the existence of a light physical dependence to THC, very different from the one induced, for instance, by opioids. Moreover, we must expect that withdrawal symptoms are even lower in the absence of antagonists’ administration. This is rather well what is observed in human when stopping cannabis use. According to Cook et al. (1998), the risk of addiction is low in occasional users. Indeed, even in the case of frequent use of high doses, no syndrome similar to that induced by heroin or alcohol withdrawal, for instance, is observed. The effects of withdrawal to THC reported in a recent study are signs of nervousness, light sleep disorders, and a reduction in appetite which quickly disappears (Wiesbeck et al., 1996). The absence of a serious withdrawal syndrome in the case of cannabinoids is undoubtedly due to its slow elimination. It would be interesting to study this phenomenon by FART Scan in monkey and human.
If the behavioral effects consecutive to the discontinuation of cannabis use remain modest, the cardiovascular and vegetative effects are more precise (tachycardia with the peak of cannabis effect, then bradycardia) with naive users (Benewitz and Jones, 1981). They are prone to tolerance.
The dangerousness of a drug is evaluated from its ability to generate a psychic dependence (addiction). It is well established that the very large majority of cannabis users only occasionally use this product, and they can definitively discontinue use without difficulty. This is clearly shown by the curves showing the evolution of use during different periods of life. It is considered that there is less than 10% of very heavy cannabis users having difficulties to give up its use, although they wish it. (Wiesbeck et al., 1996). Withdrawal effects possibly responsible for dependence are found with the same incidence (9%).
Nevertheless, the discussion on the risks of cannabis dependence was initiated again these last two years by the direct description of two parameters considered as predictive of a risk of addiction. The first is the release of dopamine in N.Accumbens induced by the administration of THC. The second is the observation that this release is antagonized by naloxone, thus seeming to be controlled by the stimulation of the opioid system (Tanda et al., 1997). Indeed, this has just been confirmed formally by the demonstration of an increase in the extra cellular rate of Met-encephalin in N.Acc by microdialyse after treatment with THC (Valverde et al., under press). Nevertheless, this release is low, approximately 4 times lower than that produced by RB 101 (Daug? et al., 1996) which does not produce any physical or psychic dependence (Roques et al., 1993). Besides, the release of CRF is induced by the administration of SR 141716A in rat chronically treated with THC, a phenomenon also produced by alcohol withdrawal or any form of stress. Acting on the amygdala receptors, the CRF could increase feelings of anxiety, thus potentiating the vulnerability to the resumption of use (Rodriguez de Fonseca et al., 1997).
Acute administration of the CB1 agonist, HU-210, in rats produces an increase in the release of CRF, as it happens when the animal is under stress conditions (forced swimming or open field). The antagonist D.Phe-CRF12-41, which also reduces stressing action of H-210, blocks reactions of the rat’s adaptation to this stress conditions. However, the release of corticosterone induced by the CB1 agonist is not antagonized by SR 141.716A (Rodriguez de Fonseca, 1996). Responses obtained in rats would report anxiety effects that sometimes happen to human after use of a heavy dose of cannabis. However, another explanation could come from the release of dynorphine under the action of THC (Rowen et al., 1997) We have already mentioned the absence of direct relation between DA release in the N.Acc., induced by different drugs or natural stimuli, and the power of reinforcing effects, as well as the dependence to them. Thus, it is to be reminded that THC does not seem able to induce a self-administration behavior (Mansbach et al., 1994 and ref. quoted). A very recent result obtained in mice with a synthetic cannabinoid, WIN 55212-2, seems to show the opposite, however with an aversive effect with high doses (Martellota et al., 1998). In the same way, in many cases, a preference to chronic THC is not observed, (McMillan et al., 1971), and a slight aversive effect is even measured (Hutcheson et al., 1998). Nevertheless, a positive response in this test has been reported (Lepore et al., 1995). In the same way, THC has the ability to facilitate electrical self-stimulation of the "reinforcing" DA route (Leporte et al., 1996).
The "drift" towards hard drugs, the "gateway theory" (Nahas, 1993; Cohen and Sas, 1997) after chronic use of THC does not seem supported by the results of recent experiments in animals. Thus, chronic treatment with THC does not modify the preference induced by morphine (Valverde et al., 1998; under press). The heterosensibilisation, which corresponds to the activation of the answer induced by a drug (heroin for instance) at the time of administration of another drug (alcohol for instance), is a phenomenon which does not seem to have been studied in detail with THC (Balster et al., 1992). However, it should be noted that anandamide (V?la et al., 1995) and THC (Hine et al., 1975) have the ability to decrease the severity of opioid withdrawal, which suggests that cannabis could lessen withdrawal symptoms in heroin addicts. In human, epidemiological studies give very contradictory results according to the way the results are presented and interpreted. Zimmer and Morgan (1997) discuss this in detail in their recent review. According to surveys carried out in the USA, 1% of cannabis users could use cocaine, which does not mean that they would thus become addicted (S.A.M.H.S.A. U.S. Department of Health and Human Services, 1996, page 36). Other studies show that the use of hard drugs, following the use of cannabis is especially found in a minority of young people from disadvantaged backgrounds, living in unstable social and family environments, in school failure and in relation with cocaine and heroin dealers (Johnson et al., 1997). These results, coupled to those of many epidemiological studies, seem to show that the use of hard drugs following THC use would mainly have psycho sociological causes (Zimmer and Morgan, 1997, and ref. quoted).
Nevertheless, although all criteria retained to define a drug as addictive are unmet with cannabis, there is a certain pressure in the USA so that programs are implemented to totally stop its use. This leads to companies requesting analysis in order to show the existence or not of such a use, and to the possible requirement for abstinence.
It is certain that the removal of the CB1 receptor gene, which has just been achieved, will make it possible to clarify a certain number of questions about the pharmacology of cannabinoids, including the problem of the possible existence of a heterosensibilisation, as it was made with other genetically modified mice. This work is going on. Nevertheless, it will be necessary to remain careful on a direct extrapolation to human for obvious reasons of species, and the possible adaptation (probable) inherent to any gene modification.

Effects on the respiratory system.
The most foreseeable toxic effects of cannabis are connected to excessive use by inhalation. Indeed, the same concentrations of carcinogenic substances (phenol, nitrosamines, polyaromatic substances, etc...) are found in cigarette or joint smoke (report by the British Medical Association, 1997).
They are the most dangerous effects with very frequent cannabis use, because of the risk of lung tumor, inasmuch as its use does not reduce tobacco use. In addition, bronchial inflammations were observed in very heavy users (more than 10 cigarettes/day) as well as asthmatic disorders, and impairment of the respiratory functions (Taskin et al., 1987), although some of these effects were not shown in all studies (Gil et al., 1995). One of the dangers of inhaling cannabis is that inhalation is deeper, and the air inhaled is hotter. Nevertheless, there is no epidemiological study showing that the combination of cannabis and tobacco is a risk factor higher than tobacco alone for the incidenceoflungcancer,andchronicrespiratory insufficiency.

Cannabis and the immune system.
Studies carried out on cells and in vivo show that cannabinoids can harm the immune system with doses higher than those used for recreational use. Several studies in animals showed a reduction of resistance to microbial and viral affections after treatment with THC, which acts like an immunomodulator, probably acting on peripheral CB2 receptors (lymphoid organs, lymphocytes, macrophages; etc...). However, doses used were very high, and thus expected pathological features difficult to establish... (review in Friedman et al., 1994). Thus, it was recently shown that anandamide has the ability to stimulate the proliferation of hematopoietic cells in synergy with a cytokine, interleukin-3, (IL3) which acts by activating the glycoproteic receptors, from the hematopoietic receptors family (Valk et al., 1997). This result seems to contradict the harmful actions of THC on resistance to infection, caused particularly by the Legionella pneumophila bacterium in mice, which was connected to defects in the action of cytokines and immunocompetent cells (Smith et al., 1997). These results are discussed in a recent review (Klein et al., 1997). However, it is interesting to note that there is a great structural similarity between anandamide (and other endocannabinoids) and the family of phospholipids derivatives (arachidonic acid, prostaglandin, prostacyline, etc...). Some studies could be conducted to confirm the direct effects of cannabinoids on inflammatory and immune processes. The cannabinoid receptor found on macrophages is different from the cannabinoid receptor found in the brain, which explains the immunomodulator effects obtained with non-psychoactive THC derivatives. It is to be noted that THC and smoked cannabis were used in AIDS patients in order to reduce treatments side-effects (vomiting, wasting syndrome, etc...). No study showed worsening effects due to cannabinoids on the lymphocyte system affected by HIV-1 virus (Kaslow et al., 1989). This is one of the reasons why clinical use of THC is put forward among AIDS and cancer patients.

Effects of cannabis on the endocrine system and reproduction functions.
LH and FSH hypophyseals factors are responsible for the synthesis of sex hormones (estrogens and testosterone) and for the normal functioning of sex organs (menstrual cycle, ovulation, spermatogenesis, etc.). LH and FSH plasma levels are dependent of several factors, particularly prolactine which reduces their secretion. The release of prolactine is itself negatively controlled by dopamine, thus indirectly by the substances acting on this neurotransmitter. In rats, THC reduces LH and testosterone plasma levels (Fernandez-Ruiz et al., 1992), stimulates ACTH secretion, and increases the circulating level of corticosterone (Rodriguez de Fonseca et al., 1995). Anandamide gives similar results. The low increase of dopamine induced by THC in the N.Acc. could explain changes in the circulating concentration of prolactine if the same increase was observed at hypophyseal-hypothalamo level, which is not demonstrated. It is more likely that the action of THC is directly brought into effect at the level of hypothalamic neurons (Weidenfeld et al., 1993).
Effects of cannabis on the endocrine system and reproduction functions. LH and FSH hypophyseals factors are responsible for the synthesis of sex hormones (estrogens and testosterone) and for the normal functioning of sex organs (menstrual cycle, ovulation, spermatogenesis, etc.). LH and FSH plasma levels are dependent of several factors, particularly prolactine which reduces their secretion. The release of prolactine is itself negatively controlled by dopamine, thus indirectly by the substances acting on this neurotransmitter. In rats, THC reduces LH and testosterone plasma levels (Fernandez-Ruiz et al., 1992), stimulates ACTH secretion, and increases the circulating level of corticosterone (Rodriguez de Fonseca et al., 1995). Anandamide gives similar results. The low increase of dopamine induced by THC in the N.Acc. could explain changes in the circulating concentration of prolactine if the same increase was observed at hypophyseal-hypothalamo level, which is not demonstrated. It is more likely that the action of THC is directly brought into effect at the level of hypothalamic neurons (Weidenfeld et al., 1993).
In rodents, anandamide concentrations in the uterus seem very high (viz. above). It would be interesting to study if the effects of this effector obtained in sea urchins at 10-6 M are compatible with ligand and receptor concentrations with respect to their affinity for each other. In any case, we must be careful in transposing directly to human results obtained in vitro with species very different from human. Epidemiological studies (absence of fertility, abortion, premature birth, etc.) on a significant number of women not using other drugs likely to mask the particular effect of cannabis should answer these questions. In the USA, there is a 30 years experience since the beginning of cannabis use, and no study showing a decrease in fertility due to this drug has been published. Besides, it would be interesting that studies are conducted by specialists in the functioning of reproductive cells using human material (particularly sperm cells), and on tissues (uterus and placenta), which can be obtained without technical difficulties (for instance, post-operative) with the consent of patients.

Cannabis mutagenesis and carcinogenic potency
Two studies assess the situation. The first one (Berryman et al., 1992) compares the action of high doses of THC in rats during 5 weeks to the action of ethanol and a control mutagen, Trenimon. Results show that THC, alone or associated with ethanol, produces no effect on the level of embryonic pre-implantation, fetal mortality and mutations index.
More recently (Chan et al., 1996), a study was initiated by the NIH to evaluate the possible carcinogenic potential of THC in rodents (rats, mice) with daily doses up to 500 mg/kg! for periods going from 13 weeks to two years. No evidence of a tumorigenic effect of THC was shown. With very high doses, weight loss may be observed. They are associated to lowered frequencies of tumors, including testicle in male and uterus and ovary in female. An atrophy of these last organs is observed, possibly in relation with significant increases in hormonal concentrations induced by very high doses of THC.
The mutagen effects of "smoked" cannabis as observed in the test of AMES (Sparacino et al., 1990) are thus due to the existence of tar and compounds obtained from cigarettes, which contain the same molecules as tobacco. Studies on human cells in culture in presence of pure THC or of condensates of cigarette smoke should confirm these observations.

10.6 Potential use of cannabis in therapy.
In the past, cannabis was praised for its properties to relieve migraines, and to decrease allergic reactions. More recently, THC was used for its analgesic properties, in the treatment of glaucoma, and like an antiemetic. This latter effect led the FDA to introduce cannabis into the American pharmacopoeia in 1987 (Dronabinol), with indications for nauseas and vomiting not responding to other antiemetic drugs, in particular among patients treated with anti-cancer or antiviral drugs. A recovery of appetite was also observed. Few comparative clinical studies with others compounds were conducted and the psychic effects appeared when doses were increased. Thus, it certainly would be necessary to study more in detail the interest of THC or, even better, of the synthetic derivatives, comparing them with analgesic drugs currently used (viz. recent review by British Medical Association, 1997).

10.7 Cannabis and analgesia
Another potential therapeutic application of THC could be related to its analgesic ability shown in animals, and which could be devoid of opioid compound µ and d, but could imply the c receptors (Pugh et al., 1997; Rowen et al., 1997). Few double blind clinical studies on a sufficient number of patients were carried out to test the analgesic properties of THC. Two more significant studies are by Noyes et al. in 1975 (36 patients suffering from cancer pain), and by Jain et al. in 1981 (56 patients suffering from post-operative pains). In both cases, significant analgesic effects were observed compared to placebo. Several studies (Consroe et al., 1992, 1997, and ref. quoted) show the analgesic effects of cannabis or THC on various types of neurogenes pain which, when confirmed under controlled conditions, could develop an interesting application because this type of pain remains often refractory to any treatment, including to the action of morphine.
Other studies give contradictory results (no analgesia for dental pains for instance). These results need that comparative studies with other opioid or non opioid analgesics are conducted to confirm the potential interest of THC, and above all the potential of analogs synthesis which have a higher affinity than the natural product. Indeed, it must be clearly shown that analgesic effects are related to the activation of CB1 receptor. This is now possible with the antagonist SR 174716. If such a research confirms the interest of CB1 agonists in analgesia, it would be then desirable to try to eliminate or at least to reduce the unwanted psychic effects. Nevertheless, it is not sure that this is possible. It must be reminded that the potent analgesic action of morphine, and the reduction of the emotional constituent of pain by recruitment of the hedonic system certainly plays an important role.

10.8 Cannabinoids and antiemetic effects.
It is probably in this field that results are the most convincing, in particular in aids patients with treatments involving nauseas, and very frequent vomiting. These effects appear not only significantly reduced with THC, but moreover a weight recovery is observed, showing the improvement of the food intake (Mattes et al., 1994; Voth et al., 1997; Dansak, 1997). The antiemetic mechanism of action of THC remains unknown, as the location of the connection sites involved. Thus, it is necessary before planning any therapeutic use of cannabinoids to better monitor the mechanism of action, and especially to compare its effects with the best current antiemetic drugs.
In any case, it would be desirable, if antiemetic and stimulating effects on appetite are exerted by the activation of CB1 and/or CB2 receptors, that synthetic compounds more potent than THC are developed, and, if at all possible, without psychic effects.
The therapeutic future of cannabinoids (agonists and/or antagonists), must be investigated through the conventional studies for a drug development before a new drug application. Thus, this requires that the possible beneficial effects of a "cannabinoid" are compared to the effects produced by drugs from the same therapeutic class, and that they prove to be better. This does reduce at all the potential interest of this class of molecule but places it, like others, in the usual evaluation strategy of therapeutic activities.

Conclusion
Despite significant results obtained these last years concerning cannabis action, there is still a lot of unknown parameters on the mechanism of action of cannabinoids, and the role of the endogenous system. In this framework, it should be important:

- to develop a selective antagonist, with a high affinity to CB2 site.
- to explore the endocannabinoid physiological system: cellular and sub-cellular location of receptors, with help of specific antibody. Tracing of routes release and in vivo measure of anandamide and its derivatives by microdyalyse, use of synthesis inhibitors and/or inactivation of these molecules.
- mechanism of formation and catabolism of anandamide.
- development (it seems under way) of ligands suited for the study in PET scan or SPECT to examine the relations between occupancy of receptors in vivo and psychic effects. Relation between occupancy and duration of effects (answer to the discussion on cannabis actions in the long term).
- use of suited animal models (rats, monkeys) and tests really adapted to explore the effects of cannabinoids on memory. Idem in human (see legislation).
- use of human cells and tissue models to study the possible perturbations caused by cannabis on reproduction functions, the immune system, etc. before transposing the results obtained in vivo or in other species.
- to conduct experiments with mice which coding genes for CB1 or CB2 receptors have been deleted, and examine again problems of selective, crossed dependence, etc. to use mice without Krox 24 factor hyper-expressed under chronic treatment with THC to study its role in the possible development of addiction.

Recommendations

- Cannabis does not have any neurotoxicity, such as defined in chapter 2. From this point of view, cannabis is completely different from alcohol, cocaine, ecstasy and psychostimulants, as well as certain drugs used for addiction. In addition to their neurotoxicity, these drugs induce very severe behavioral impairment, and a social dangerousness in the case of alcohol and cocaine, which are practically never found with cannabis. On the opposite, THC and some derived agonists could decrease the frequency of epileptic seizures, and protect from neuronal impairment by ischaemia, although this requires to be confirmed.
- Toxicity of "smoked" cannabis, with respect to respiratory function and cardiovascular system, should not be neglected although it undoubtedly remains low compared to tobacco, for the only reason of amounts used, at least for occasional users, i.e. 90% of the population.
- The results of many works conducted both in animals and human show a temporary impairment of mnesic performances, a lack of attention and a state of somnolence induced by cannabis. These effects are dose-related. It is desirable that behavioral studies in suitable animal models (rat and monkey) are conducted to objectivize these impairments, and to measure them during the development, and in adults and old animal. This would complement electrophysiological studies, which remain necessary to study the mechanisms of reduction in the mnesic performances.
- Taking into account the frequent use of cannabis at the time when attending school or university, and although this use does not seem to lead to more school failures or a loss of motivation, it is desirable that the population attending school is informed of these specific effects of cannabis. Here again, this is the decrease, induced by cannabis, of free choice capabilities, critical spirit, authenticity and spontaneousness, which could be used as dissuasive arguments against use at school.
- Current studies do not accredit the existence of a psychiatric syndrome specific to cannabis. It is the same for the possible "discovery" of a subjacent schizophrenic state. However, frequent use of cannabis highly concentrated in THC could lead to schizoid states (Williams et al., 1996).
- Impairment of the reproduction functions observed on cells or in rodents should lead to assess the effects of cannabis on human cells (and tissues) before any conclusion. Studies in this direction should be initiated quickly.
- The chemical structure of the endogenous effectors of the cannabinoids receptors let foresee a possible role (physiological?, pharmacological?) in the mechanisms of inflammation. This could give an account of often contradictory effects of THC on immunizing cells, bronchial inflammation, reduction of painful inflammatory processes, etc. Here again, epidemiological studies are necessary.
- Dangerousness of a compound in terms of addiction is measured not only by the efforts made to get the product, but by the considerable energy spent to try to escape dependence. Cannabis generates hedonic effects, it is thus likely to induce dependence. Less than 10% of heavy users become addicted to cannabis, which is not negligible but much lower than the risk induced by excessive alcohol or tobacco use. It should be added that this percentage is lower than 2% of the whole population of THC users (" 90% being occasional users). No epidemiological study was conducted to compare the difficulties of giving-up mono-consumption of cannabis, alcohol and tobacco but their evolution according to the age show that cannabis is less addictive. This is why NIDA did not consider it useful to recommend research on the development of substitutive treatments to cannabis.
- The interest to study the effects of THC for its therapeutic use was the topic of a very recent report by the experts of the British Medical Association. They write that research on the medical use of THC remains anecdotal, and do not give undeniable scientific results, in particular when comparing studies conducted with studies required for the marketing of a new drug. Nevertheless, they observe that cannabinoids, used for a very long time by a very high number of users, did not lead to major toxic effects and thus they act as "remarkably safe drugs with side-effects profiles superior to many drugs used for the same indications" (Therapeutic uses of cannabis, British Medical Association, 1997, Hardwood Academic Publishers The Netherlands). We also think that the potential therapeutic future of (synthetic) cannabinoids goes through an evaluation of their properties according to the usual standards of a new drug application.

Facteurs de dangerosité des drogues / Auswirkungen der Drogen - ein Vergleich

 
Alcool
Alkohol
Héroïne
(opioïdes)
Heroin
(Opiate)
Cocaïne
Kokain
MDMA
Ecstasy
Benzodia
z-épines
Valium
Cannabis
Hanf
Tabac
Tabak
Dépendance physique
Körperliche Abhängigkeit
Trés forte
Sehr stark
Trés forte
Sehr stark
Faible
Schwach
Trés faible
Sehr Schwach
Moyenne
Mittel
Faible
Schwach
Forte
Stark
Dépendance Psychique
Psychische Abhängigkeit
Trés forte
Sehr stark
Trés forte
Sehr stark
Forte
Stark
?
Forte
Stark
Faible
Schwach
Trés forte
Sehr stark
Toxité général
Giftigkeit
Forte
Stark
Forte (1)
Stark (1)
Forte
Stark
Trés forte
Sehr stark
Trés faible
Sehr Schwach
Trés faible
Sehr Schwach
Trés forte (Cancer)
Sehr stark(Krebs)
Dangerosité sociale
Gesellschafts-gefährlichkeit
Forte
Stark
Trés forte
Sehr stark
Trés forte
Sehr stark
Faible (?)
Schwach (?)
Faible (2)
Schwach (2)
Faible
Schwach
0
Traitements substituifs ou autres existants
Behandlung
smöglichkeit
Oui
Ja
Oui
Ja
Oui
Ja
Non
Nein
Non recherchés
Nicht Untersucht
Non recherchés
Nicht Untersucht
Oui
Ja
by Chanvre-Info, Les echos du chanvre et Nova institut
Artikel modifiziert Thursday 17 July 2003 16:42, Erscheinungsdatum Thursday 17 July 2003 16:40

Forum des Artikels

I totally agree
Hemp is definitely less toxic than alcohol or tobacco, no doubt.

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Die Webseite besuchen : Cannabis Seeds : http://www.canaseed.com
6 April 2007 von Ari
  I totally agree
 
Not to mention a lot more fun!

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  Die Webseite besuchen : Shiva Head Shop : http://www.shivaheadshop.co.uk/
  9 03 2009
 
  I totally agree
 
It’s also much less harmful to society. No one gets stoned and then starts a bar fight, do they?

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  Die Webseite besuchen : Cannabis Seeds : http://www.coffeesh0p.com
  29 06 2010
 

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