the toxicology of cannabis and cannabis prohibition · effects is lower (a single dose of ca.2–3...

REVIEW

The Toxicology of Cannabis and Cannabis Prohibition

by Franjo Grotenhermen

nova-Institut, Goldenbergstraße 2, D-50354 H�rth(phone: þ49-2247-9159222; fax: þ49-2247-9159223; e-mail: [email protected])

The acute side effects caused by cannabis use are mainly related to psyche and cognition, and tocirculation. Euphoria, anxiety, changes in sensory perception, impairment of memory and psychomotorperformance are common effects after a dose is taken that exceeds an individually variable threshold.Cannabis consumption may increase heart rate and change blood pressure, which may have seriousconsequences in people with heart disease. Effects of chronic use may be induction of psychosis anddevelopment of dependency to the drug. Effects on cognitive abilities seem to be reversible afterabstinence, except possibly in very heavy users. Cannabis exposure in utero may have negativeconsequences on brain development with subtle impairment of cognitive abilities in later life.Consequences of cannabis smoking may be similar to those of tobacco smoking and should be avoided.Use by young people has more detrimental effects than use by adults. There appear to be promisingtherapeutic uses of cannabis for a range of indications. Use of moderate doses in a therapeutic context isusually not associated with severe side effects. Current prohibition on cannabis use may also haveharmful side effects for the individual and the society, while having little influence on prevalence of use.Harm is greatest for seriously ill people who may benefit from a treatment with cannabis. This makes itdifficult to justify criminal penalties against patients.

1. Introduction. – Because the prevalence of cannabis use has in recent years beenon the rise in Europe and North America, and because the potency of cannabispreparations has increased in the past decades, there is growing concern aboutpotentially harmful effects of this drug, and an ongoing debate on the policyimplications of these developments and of our scientific knowledge on the healtheffects of cannabis [1]. During the past decade, the literature on adverse effects ofcannabis and cannabinoids in humans had focused on effects that are thought to bemediated by the CB1 receptor, including effects on cognitive function, psychiatriceffects, and dependence and decline of psychomotor performance that may result intraffic accidents [2]. In addition, there is a discussion on the pulmonary and cancer-causing effects of smoking cannabis. These are not attributed to any inherent cannabiscompounds but to combustion products generated when dried plant material is smokedrather than taken orally or through other advisable modes of administration [3].Scientists generally agree on the acute and short-lasting effects of cannabis, whilequestions and controversy remain on possible chronic and long-term effects.

The primary CB1 receptor agonist and psychoactive compound in botanicalcannabis (Cannabis sativa L.) is dronabinol ((�)-trans-D9-tetrahydrocannabinol, D9-

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B 2007 Verlag Helvetica Chimica Acta AG, Z�rich

THC, THC). Consumption of isolated THC, whose concentrations in the floweringtops and upper leaves of the female plant range from 2 to 30%, produces similarpsychological effects as whole plant drug cannabis in healthy volunteers [4] [5] andpatients [6– 8]. This review will focus on the toxicity of cannabis and dronabinol(THC), leaving adverse effects of other cannabinoids that do not activate the CB1

receptor aside. This restriction is justified by the fact that, both with recreational andmedicinal use of cannabis products, the main problems concerning adverse effects areassociated with CB1 receptor activation. Acute psychological side effects, the causationof psychosis and depression, as well as the fear of dependency are among the mainreasons for reservation and scepticism towards the therapeutic application of cannabisproducts by some authors who assign cannabis an unfavourable risk/benefit ratio[9] [10]. Also, most of the studies conducted on the toxicity of cannabis have focussedon THC and on some synthetic CB1 receptor agonists (nabilone, WIN55,212-2, etc.) ,while much less evidence is available for other cannabinoids of interest.

One cannot easily draw a clear line between desired medicinal and undesirable sideeffects of cannabis and THC, and this line may vary with the indication. Desirableeffects in one case may be unwanted in another. This is not only the case forpsychological effects, such as euphoria and sedation, but also for somatic effects such asincrease in appetite or muscle relaxation, which are regarded as therapeutic in mostcases but may be unwanted in others. For example, some patients find sedation orsomnolence desirable under certain circumstances, e.g., during chemotherapy [10]. Insevere illness such as AIDS and cancer, not only the physical effects (analgesia,appetite enhancement, and anti-emetic effects) but also psychological effects (moodenhancement and anxiolytic action) may be of great value [11].

2. Acute Adverse Effects. – The acute toxicity of THC is low. Acute lethal humantoxicity for cannabis has not been substantiated. The median lethal dose (LD50) of oralTHC in rats was 800 –1900 mg/kg depending on sex and strain [12]. There were nocases of death due to toxicity following the maximum THC dose in dogs (up to3000 mg/kg THC) and monkeys (up to 9000 mg/kg THC) [12].

Above a personJs individual threshold, consumption of cannabis and isolated THCmay cause adverse effects on the central nervous system and peripheral organ systems,of which possible unwanted effects on psyche and circulation are the most relevant forthe health of the user. The large intra-individual variation of this threshold is illustratedby the different daily doses tolerated by patients in clinical studies. In a study by Wadeet al. with 160 multiple sclerosis patients who received an oral cannabis extract, themaximum daily doses varied between 2.5 and 120 mg of THC [13]. Hagenbach et al.studied the effects of THC in 25 patients with spinal cord injury; maximum daily oraldoses varied between 15 and 60 mg. With inhalation, the threshold for psychologicaleffects is lower (a single dose of ca. 2– 3 mg of THC) compared to oral intake (a singledose of usually ca. 5 – 20 mg of THC) [14].

Since tolerance develops to THC in the central nervous system and regardingseveral other effects, regular cannabis users may tolerate considerably higher doses. Ina study by Bowman and Phil on cognitive performance of cannabis users in Jamaica,participants reported a mean daily intake of ca. 24.5 g of cannabis, corresponding to ca.1000 mg of THC [15].

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2.1. Psyche, Cognition, and Psychomotor Performance. Consumer self-reports ofacute clinical effects of cannabis in low-to-medium doses (2 – 10 mg of inhaled THC)mostly point to qualitative changes in sensory perception with a heightened externaland internal sensitivity, especially with regard to visual stimuli, and to distortions of thesubjective perception of time. Further effects comprise feelings of well-being, of mildeuphoria (the LhighJ), of relaxation, anxiolysis, and sedation [16]. However, theindividual response to cannabinoids varies between subjects [17].

Inhaled doses of medium strength (10 –20 mg of THC) may lead to anintensification of emotional responses and reactivity, and to more prominent changesin perception and transient hallucinatory experiences [18]. But these effects are usuallyavoidable if users inhale cannabis, whereby the fast bioavailability gives the consumergood individual control of these responses. In a therapeutic context, users should slowlyincrease the oral dose to avoid overdosing.

Serious unwanted effects generally occur at high single inhaled doses of more than20 mg of THC, but due to the high inter-individual variability, some persons may alsoexperience such effects at lower doses. The most frequent unwanted psychic response isan acute panic reaction that occurs most often in inexperienced users or at high doses ofcannabis [19]. The most prominent sign of a panic reaction is the userJs concern oflosing control. It usually remits spontaneously. In a small number of cases, longerlasting or recurrent experiences of depersonalization have been observed. However, asfor the more frequent panic reaction and because of their generally mild severity,experiences of depersonalization in acute cannabis intoxication rarely require furtherpharmacological intervention [17].

Psychotic symptoms following acute cannabis consumption have been described.Their severity, duration, and frequency heavily depended on cultural and personality-related factors, as well as on the frequency and intensity of previous cannabisconsumption [20]. Nevertheless, even a single intake of THC has been shown to causeso-called short substance-induced psychotic disorders that mimic complex schizophre-niform psychotic disorders. These psychotic states generally remit completely, eithershortly after subsidence of the acute THC effect, or after a few days [21] [22]. Hall andDegenhardt performed a review on the frequency of acute toxic cannabis psychosis andconcluded that true cannabis psychosis, if it exists, must be very rare [23]. On the otherhand, Johns concluded in his review that an appreciable proportion of cannabis usersreport short-lived adverse effects, including psychotic states following heavy con-sumption [24].

A toxic delirium due to cannabis has been observed hitherto only after ultra-highdosages. It becomes manifest by disturbances of memory function, orientation, andconsciousness [25]. Such a delirium has to be regarded as a non-specific reaction thatcan be triggered by a variety of substances, and whose origins cannot yet beconclusively explained. However, deliriant reactions to cannabis are self-limited, andthus do not call for any special intervention.

Among acute cognitive impairments caused by cannabis are difficulties withconcentration, disturbances of short-term memory, and stimulation of associations thatmight impede goal-directed mental activities. For example, an increased error rate insimple visual or auditory tasks has been demonstrated that suggest an inversely dose-related decrease in attention [26] [27]. Other reported effects of THC include


disturbances of fine motor control and co-ordination, a reduction in psychomotoractivity, and prolonged, but also unaffected reaction times [26] [28]. In addition, theclinically reported aberrations in visual perception [21] [29] and the subjectiveoverestimation of the duration of a given time period [30] have been replicated underexperimental conditions. In summary, easy learning and remote memory are probablyunaffected by cannabis, simple reaction time, disinhibition, and vigilance were affectedin some studies and not in others, whereas complex reaction time, perception, readingaloud, arithmetic performance, recall and intrusions in recognition memory wereaffected in all studies [31]. Acute cannabis smoking produced minimal effects oncomplex cognitive task performance in experienced cannabis users who used anaverage of 24 cannabis cigarettes per week, a clear indication of tolerance [32]. As withconventional hypnotics, cannabis decreases REM sleep time in a dose-dependentfashion [33].

2.2. Physical Effects. THC produces reversible and dose-dependent tachycardiawith increased cardiac labor and oxygen demand, and increased diastolic bloodpressure (in horizontal position) associated with a decreased parasympathetic tone[34]. Due to tolerance to these effects, chronic use can lead to bradycardia [35]. Athigher dosages, orthostatic hypotension may occur due to a dilation of blood vessels,which may result in dizziness and syncope. Myocardial infarction may be triggered byTHC due to these effects on circulation [36] [37]. Dilation of blood vessels also causesconjunctival reddening.

THC has a cholinergic effect on the salivary glands leading to hyposalivation anddry mouth. This effect is mediated by both CB1 and CB2 receptors [38]. Concerningophthalmic effects, the use of cannabis may disturb accommodation and the pupilsJreaction to light is slowed. Tear flow is decreased [17]. Hyposalivation and decreasedtear flow may potentially increase the risk of infections of the upper respiratory tractand the eye (keratitis, conjunctivitis).

Rare adverse effects are headache or nausea and vomiting. The relaxation ofmuscles may be accompanied by a reduction in strength and impaired coordination,leading to possible falls. Cannabis rarely causes allergies. In most cases, they are notcaused by the plant material itself but by contamination with other substances [39].

Reports on the effects of cannabinoids on platelet aggregation are conflicting.While Formukong et al. reported an inhibition by cannabigerol, cannabidiol, THC, andcannabinol in in vitro studies, Deusch et al. observed procoagulatory effects of THC inhuman platelets in vitro [40] [41]. The clinical significance of these observations isunclear. In clinical studies, laboratory investigations did not reveal any trends of clinicalsignificance in haematological parameters, including parameters relevant for coagu-lation [42].

In one study, the THC derivative nabilone deteriorated choreatic movements inHuntingtonJs disease [43]. Thus, cannabinoid receptor agonists may be contraindicatedin HuntingtonJs disease.

Gastric activity is slowed by THC [44]. Results of THC effects on the transit of foodin the bowel are somewhat conflicting. While one group found no significant effect inhumans [44], THC produced an inhibition in rats of small intestinal transit and, tolesser extent, of large bowel transit [45]. This difference may be explained by lowerdoses used in the study with humans.


2.3. Adverse Effects of Cannabis and THC in Clinical Studies. The most frequentadverse effects of cannabis and THC in clinical studies comprise effects on psyche andcognition (euphoria, dizziness, anxiety, sedation, depression etc.) and dry mouth. Inaddition, nausea may be observed in a considerable number of patients, but it is unclearwhy it is observed in some studies (see Table 1) but nearly absent in others (Tables 2and 3). Other acute effects, including spasms and pain, differed much as a function ofdisease and showed no relevant difference between verum and placebo. This supportsthe assumption that these effects are often not caused by the treatment but theunderlying disease (Tables 1–3).

Tables 2 and 3 show adverse drug events for THC (MarinolO) observed incontrolled clinical studies. Adverse events from oral cannabis preparations arepresented in Table 1 (SativexO) and Table 2 (CannadorO). Sativex is applied as anoro-mucosal spray and Cannador as well as Marinol in capsules. Events from smoked

Table 1. Side Effects of the Cannabis Extract SativexO According to the Product Information of theApproval in Canada [42]a). Data were taken from clinical studies with 166 patients treated with Sativexand 162 patients treated with placebo. The table lists all side effects that were observed in 2% of the cases

or more.

Adverse event Cannabis (n¼166) Placebo (n¼162)

Dizziness 41.6% 13.0%Fatigue 11.4% 5.6%Nausea 10.2% 7.4%Somnolence 8.4% 3.1%Dry mouth 7.8% 1.9%Application site pain 7.8% 6.8%Feeling drunk 7.2% 0.6%Oral pain 6.6% 6.8%Disturbance in attention 6.6% 0.0%Diarrhoea 6.0% 3.1%Euphoric mood 5.4% 0.6%Disorientation 4.8% 0.0%Dysgeusia (abnormal taste) 4.2% 2.5%Weakness 3.6% 1.2%Appetite increased 3.6% 1.9%Pharyngitis 3.6% 1.9%Mouth ulceration 3.0% 0.6%Fall 3.0% 1.2%Lethargy 3.0% 0.6%Thirst 3.0% 0.0%Dissociation 3.0% 0.0%Vomiting 2.4% 0.6%Sensation of heaviness 2.4% 0.6%Cough 2.4% 1.9%

a) In addition to the adverse events reported in these controlled acute studies, the following adverseevents were observed in patients (> 2%) on long-term treatment with SativexO: headache (8.7%),impaired balance (5%), depressed mood (4%), memory impairment (3.1%), and oral mucosal disorder(3.1%).


cannabis are presented in Table 3. Comparisons between cannabis and THC arepresented in Tables 2 and 3. Table 2 also compares the frequency of side effects causedby cannabis, THC, and a placebo observed in a short study of 15 weeks and a follow-upstudy of 52 weeks in duration.

There was little difference in side-effect profiles between an oral cannabis extract(Cannador) and THC (Marinol) (Table 2), and smoked cannabis vs. THC (Table 3).Compared to a short-term study in patients with multiple sclerosis a long-term therapywith cannabis and THC over a course of 12 months resulted in a dramatic reduction ofadverse effects (Table 2). This may be due to the development of tolerance for somesymptoms and to the establishment of an individual tolerable dose for every patient.Many clinical acute studies with cannabis or THC start with low doses and slowlyincrease the dose until side effects appear, or a maximum daily dose is reached. Thus,one expects to observe side effects frequently in acute studies. However, they areusually mild or moderate in intensity [6]. In the long-term study by Zajicek et al. with502 patients, the incidence of side effects was no longer higher in the verum groups(THC and cannabis) compared to the placebo group except for the events Ldizzy orlightheadednessJ and LfallsJ (Table 2) [7]. In studies with THC taken by patients withHIV, similar observations of a reduction in frequency of side effects were made. Whileca. 25% of patients reported a minor CNS-related adverse drug event during the first


Table 2. Adverse Events Observed in a 15-Week study [6] and in a 12-Month Follow-up Study [7] in MSPatients Who Received Either THC (MarinolO) the Cannabis Extract CannadorO, or Placebo. In the short-term study, 611 patients and in the long-term study 502 patients were evaluated. In the short-term study,doses were slowly increased up to the occurrence of side effects or until the maximum dose (10 –25 mg

THC depending on body weight daily) was reached.

Adverse event Short-term study (15 weeks) Long-term study (52 weeks)

THC Cannabis Placebo THC Cannabis Placebo

Dizzy or light-headedness 59% 50% 18% 8% 10% 2%Sleep 35% 40% 33% 8% 8% 9%Spasms or stiffness 34% 33% 33% 14% 15% 14%Gastrointestinal tract 30% 37% 20% 9% 12% 7%Miscellaneous 28% 30% 22% 7% 7% 7%Pain 26% 24% 32% 10% 17% 10%Dry mouth 26% 20% 7% 2% 1% 1%Weakness or reduced mobility 25% 23% 20% 10% 12% 16%Bladder 24% 26% 23% 10% 12% 15%Infection 15% 16% 17% 9% 11% 11%Tremor or lack of coordination 12% 10% 8% 5% 2% 2%Depression or anxiety 10% 9% 8% 6% 6% 5%Numbness or paraesthesia 9% 7% 7% 5% 4% 4%Vision 6% 8% 2% 2% 2% 0%MS-relapse or exacerbationa) – – – 5% 6% 6%Fallsa) – – – 4% 7% 3%Memory or concentrationa) – – – 2% 2% 1%Other skin problemsa) – – – 1% 5% 6%Pressure soresa) – – – 0% 1% 3%

a) Not measured in the short-term study.

two weeks, only ca. 4% reported such an event during each of the following six weeks[46].

2.4. Cannabis and Accidents. THC impairs perception, psychomotor performance,and cognitive and affective functions, which all may contribute to a driverJs increasedrisk of causing a traffic accident. A fatal accident is the most serious acute adverseconsequence of cannabis use, which may not only harm the user but also other subjectsinvolved. After alcohol, cannabis and benzodiazepines are the drugs most frequentlyfound in impaired drivers and in drivers involved in accidents [47] [48]. The detectionof THC or THC metabolites in a driverJs body usually results from illegal use and rarelyfrom medicinal use. In clinical studies with low doses of THC or nabilone, psychomotorand cognitive performance were not reduced, suggesting that driving skills may not beimpaired by these doses [49] [50]. The effects of cannabis are dose-related, rangingfrom no relevant to strong effects. The review by Tunbridge et al. for the EUJsCERTIFIED project categorized the overall traffic safety risk caused by a particulartype of drug as Lhigh riskJ for alcohol and benzodiazepines, Lhigh-to-moderate riskJ forcocaine, Lmoderate riskJ for cannabis and amphetamines, and Llow-to-moderate riskJ foropiates and antihistamines [48]. It is estimated that acute cannabis use doubles the riskof causing an accident [47], while regular users who are not acutely intoxicated seem tohave no increased risk [51] [52]. The combined use of cannabis and alcohol or otherdrugs may increase accident risk considerably [48] [53] [54]. However, chronic cannabisuse (in the absence of acute administration) did not per se potentiate the effects ofalcohol [55]. In fact, regular cannabis users showed lower scores for dizziness and asuperior tracking accuracy compared to infrequent users after alcohol.

Simulator and experimental on-road studies have demonstrated that cannabis mayimpair some driving skills at smoked THC doses of as low as 6.25 mg [56]. However,results varied considerably between the skills tested and among studies, and some of thetested skills were not impaired at doses as high as 18 mg. Some of the impairmentcaused by cannabis is mitigated, since subjects appear to perceive that they are indeedimpaired. Where they can compensate, they do, for example, by not overtaking, by


Table 3. Side Effects Observed in a State Clinical Trial on Oral THC and Smoked Cannabis Conducted inCalifornia in the 1970s (cited according to [8])

Adverse event Smoked cannabis (n¼98) Oral THC (n¼257)

Dry mouth 56.5% 44.8%Sedation 52.1% 64.0%Dizziness 33.1% 26.8%Ataxia 27.1% 12.8%Elated mood 26.6% 24.4%Confusion 26.6% 31.6%Anxiety 20.2% 18.8%Depressed 18.1% 13.2%Perceptual 15.9% 22.8%Fantasizing 10.7% 11.6%Orthostatic 7.5% 12.8%Panic/Fear 7.5% 7.6%Tachycardia 6.4% 10.0%

slowing down, and by focusing their attention when they know a response will berequired. Such compensation is not always possible, however, where drivers are facedwith unexpected events.

Epidemiological evaluations of accident data using culpability analysis yieldedsomewhat conflicting results (Table 4). Drivers with low THC blood concentrationsmay not have a higher accident risk than drug-free controls, but THC bloodconcentrations above 5 ng/ml may be associated with an increased accident risk.Responsibility or culpability studies analyze the responsibility assigned to driversinvolved in accidents as a function of drug levels found in samples taken after anaccident. In this kind of studies, the drivers responsible for an accident serve as casesand drivers not responsible as controls.

The two major responsibility studies conducted so far underline the importance ofalcohol as the major causal factor in traffic accidents [53] [54]. The responsibility studyby Drummer et al., conducted in Australia and using information on 3398 fatallyinjured drivers, showed an odds ratio (OR) of 6.0 for alcohol above a blood alcoholconcentration (BAC) of 0.05% with an OR of 3.7 for the BAC range of 0.1 – 0.15% andof 25 for a BAC of more than 0.2% [53]. THC was associated with an increased overallrisk of 2.7. A THC blood concentration of less than 5 ng/ml was associated with an ORof 0.7 [62], while a blood concentration above 5 ng/ml was associated with an OR of 6.6.The French study by Laumon et al. with 9772 drivers involved in an accident, in whichat least one subject was fatally injured, found an OR of 8.5 for all alcohol-positivedrivers and an OR of 1.8 for all THC-positive drivers after adjustment for substances,

Table 4. Results of Culpability Studies on Drivers with THC or THC-COOH (a metabolite) in WholeBlood or Urine

Authors Drivers (n) Specimen Percentage of driverswith cannabinoids only

Odds ratio

Terhune (1982) [57] 497 blood 3.4% 2.1Williams et al. (1985) [58] 440 blood 4.3% 0.2Terhune et al. (1992) [59] 1882 blood 1.0% 0.7Drummer (1994) [60] 1045 blood 4.1% 0.7Longo et al. 2000 [61] 2500 blood 7.1% 0.9 (all)

0.36 (< 1 ng/ml)0.52 (1–2 ng/ml)1.8 (> 2 ng/ml)

Lowenstein, Koziol-McLain(2001) [51]

414 urine 8.2% 1.1

Drummer et al. (2004) [53] [62] 3398 blood 1.7% 2.7 (all)0.7 (< 5 ng/ml)6.6 (> 5 ng/ml)

Laumon et al. (2005) [54] 9772 blood not given 1.78 (all)1.57 (< 1 ng/ml)1.54 (1–2 ng/ml)2.13 (3–4 ng/ml)2.12 (� 5 ng/ml)


age, time of accident, and vehicle type [54]. A BAC of below 0.05% was associated withan OR of 2.7 and a BAC of above 0.2% with an OR of 39.6. A THC blood concentrationof below 1 ng/ml was associated with an OR of 1.6 and a THC blood concentrationabove 5 ng/ml with an OR of 2.1, which is a considerably lower dose –effect relationshipthan in the study by Drummer [60].

These findings on the impact of cannabis on driving skills and accident risk suggestthat the use of cannabis or THC at low doses that do not cause psychotropic effects isalso not associated with an increased accident risk. Regular users of cannabis have noincreased risk, if they are not acutely impaired by the drug, but acute use may increasethe risk by more than twofold, depending on the dose and the time passed betweencannabis use and driving. Low THC concentrations in the blood were not associatedwith increased culpability rates, while higher concentrations were. Cannabis use incombination with alcohol may considerably increase accident risk.

The results from studies on the correlation between cannabis use and injuries from arange of accidents and requiring hospitalization are somewhat conflicting. Vinsonfound no increased risk for cannabis users in 2,161 injured subjects requiringemergency-room treatment and 1,856 controls [63]. Among the cases, 27% wereinjured in a fall, 19% were struck by an object, 18% were in a motor vehicle crash, andthe rest were injured by a variety of mechanisms. Self-reported cannabis use in theprevious seven days was associated in this study with a decreased risk of injury, whilethe use of other illicit drugs and recent use of alcohol was associated with an increasedrisk. In contrast, a study by Gerberich et al. found a small risk increase of hospitalizedinjury in cannabis users. In their retrospective study with 64,657 subjects whocompleted a questionnaire about health behaviors including cannabis use, that use wasindependently associated in the follow-up with an increased risk for injury hospital-izations of 1.28 for men and for women of 1.37 [64].

3. Chronic Adverse Effects. – The long-term use of cannabis was not associated withan increased mortality in animals [65] and humans [66]. Chan et al. administered 50 mg/kg of THC to rats for a period of two years. At the end of the observation, overallsurvival was higher in the treated animals (70%) than in the untreated controls (45%)[65]. The higher survival rate in the THC group was ascribed to the lower incidence ofcancer. No relationship between cannabis use and mortality has been discovered in alongitudinal epidemiological study with 65171 citizens of the USA [66], although thismay be due to methodic limitations.

A multitude of chronic effects of cannabis use on the immune and endocrinesystems, respiratory tract (when inhaled), psyche, cognition, and psychomotorperformance have been described. Adverse effects of medical cannabis use are withinthe range of effects tolerated for other medications [11] [67]. Long-term medical use ofcannabis for more than 15 years is reportedly well-tolerated without significant physicalor cognitive impairment [68]. Side effects observed in acute clinical studies diminishconsiderably with longer medicinal use [7].

3.1. Risks of Smoking. The risks of cannabis smoking are often regarded as inherentrisks of cannabis use resulting in an unfavorable risk/benefit ratio in a therapeuticcontext [9]. However, as with the use of other drugs, the risks caused by an inherentlyunsafe method of administration must be distinguished from the risks of the drug itself.


For example, the risks of needle sharing or of overdose in a recreational context cannotbe used as an argument against the use of opioids in pain therapy.

One of the greatest concerns about chronic effects of recreational cannabis usepertains to the inhalation of combustion products that may damage the mucousmembranes, if the drug is smoked as a cannabis cigarette (LjointJ) or in a pipe. Incontrast, during the 19th century, oral cannabis use was common for medical andrecreational use. The cannabis plant contains ca. 500 chemical compounds, most ofwhich are also found in other organisms such as hydrocarbons (50 compoundsdetected), terpenes (120), amino acids (18), flavonoids (21), fatty acids (22), andsugars and related compounds (34), among others [69]. These compounds themselvesgenerally have a very low toxic potential. Pyrolysis creates at least 200 thermaldegradation products in smoke not found in cannabis, including mutagenic polycyclichydrocarbons such as benz[a]anthracene, benzo[a]pyrene, naphthalene, and severalcresols and phenols [70]. The composition of these combustion products is at leastqualitatively similar to that of tobacco smoke or that of the smoke generated fromother dried plant material, despite some minor differences [71]. Thus, one wouldexpect similar damage to the mucosa by cannabis smoke as following the use oftobacco. Indeed, signs of airway inflammation (vascular hyperplasia, submucosaloedema, inflammatory cell infiltrates, and goblet cell hyperplasia) were found inbronchial biopsies of cannabis smokers similar to the changes in tobacco smokers[72]. Regular cannabis smoking in young adults was associated with wheezing,shortness of breath during exercise, and the production of sputum, as it is known fortobacco smokers [73]. Another group found that heavy cannabis smokers had asignificantly higher prevalence of chronic cough (18 vs. 0%, resp.), chronic sputumproduction (20 vs. 0%), wheeze (25 vs. 3.5%), and episodes of acute bronchitis (13 vs.2%) than nonsmokers, while the prevalence of symptoms of chronic and acutebronchitis were not significantly different between cannabis and tobacco smokers[74].

Biopsies from cannabis smokers have also yielded a higher rate of precancerouspathological changes compared to non-smokers [75] [76], which is suggestive of anincreased cancer risk of the respiratory tract and other cancers. So far, theepidemiological data is inconclusive. A review of two cohort studies and 14 case-control studies by the International Agency for Research on Cancer (IARC) did not finda clear association between cannabis use and cancer [77]. Authors noted that sufficientstudies are not available to adequately evaluate the impact of cannabis smoking oncancer risk, and available studies often have limitations including too few heavycannabis users in the study samples. The largest epidemiological study conducted so farwith 1212 incident cancer cases and 1040 cancer-free controls did not find a positiveassociation between cannabis smoking and the investigated cancer types (mouth,larynx, lung, pharynx) [78]. There was no dose –effect relationship, and even heavy usewas not associated with an increased risk.

Until better data are available, it is reasonable to avoid smoking, but to use otherless risky modes of administration, i.e., inhalation with a vaporizer, which allowsinhalation of cannabinoids and terpenes without burning the plant material, oral ororo-mucosal ingestion, or other routes under investigation (rectal, transdermal,topical) [3].


3.2. Psychosis and Schizophrenia. There is some biological plausibility from the roleof the endocannabinoid system in dopaminergic actions that exogenous ligands of theCB1 receptor may play a causal role in the development of psychosis. On the otherhand, heightened levels of endocannabinoids in cerebrospinal fluid in patients withschizophrenia may reflect compensatory adaptation to the disease state [79].Anandamide levels in cerebrospinal fluid were eightfold higher in first-episodeparanoid schizophrenics than in healthy controls, and this level was negativelycorrelated with psychotic symptoms.

Evidence from several longitudinal studies published in the past five years suggeststhat the use of cannabis predicts an increased risk of a schizophrenia diagnosis or ofreporting symptoms of psychosis [80– 86]. A three-year longitudinal study with 4044psychosis-free persons and 59 subjects with a baseline diagnosis of psychotic disorderwas conducted in the Netherlands [85]. Baseline cannabis use predicted the presence atfollow-up of any level of psychotic symptoms (adjusted OR 2.76). There was a dose –response relationship between frequency of cannabis use and risk of psychoticsymptoms. Researchers concluded that their observations confirm previous findingsthat cannabis use increases the risk of both the incidence of psychosis in psychosis-freepersons and of a poor prognosis for persons with an established vulnerability topsychotic disorder. In the so-called Christchurch Health and Development Study with1011 New Zealanders, the association between cannabis dependence and the presenceof psychotic symptoms at ages 18 and 21 years was examined [82]. Participants werefollowed from birth into early adulthood allowing for the control for previous psychoticsymptoms and for clarifying the temporal sequence of drug use and symptoms.Individuals who met the diagnostic criteria for cannabis-dependence disorder at age 21had a 2.3 times higher risk of psychotic disorders than non-users. After adjustment forprevious psychotic symptoms and a range of other confounding factors, this associationwas still significant (rate ratio 1.8). A four-year follow-up of a cohort of 2437 youngpeople aged 14 to 24 years with and without predisposition for psychosis in Munichconfirmed a much stronger effect of cannabis use on the development of psychosis inpredisposed individuals [83]. After adjustment for age, sex, socioeconomic status,urbanicity, childhood trauma, predisposition for psychosis at baseline, and use of otherdrugs, tobacco, and alcohol, cannabis use at baseline increased the cumulativeincidence of psychotic symptoms at follow up by 1.67. The risk difference between usersand non-users of cannabis in the LpredispositionJ group was significantly greater thanthe risk difference in the Lno predispositionJ group. There was a dose – response relationwith increasing frequency of cannabis use. The results of the other longitudinal studiesare in accordance with these three studies.

In their review Arseneault et al. concluded that cannabis use confers an overalltwofold increase in the relative risk for later schizophrenia, and that it appears to beneither a sufficient nor a necessary cause for psychosis but a component cause, part of acomplex constellation of factors leading to psychosis [87]. They assume that cases ofpsychotic disorder could be prevented by discouraging cannabis use among vulnerableyouths and would reduce the incidence of schizophrenia by ca. 8% if the association iscausal. Degenhardt and Hall concluded that it is most likely that cannabis useprecipitates schizophrenia in individuals who are vulnerable because of a personal orfamily history of schizophrenia [88]. This hypothesis is consistent with the stress-


diathesis model of schizophrenia and evidence that a genetic vulnerability to psychosisincreases the risk that cannabis users will develop psychosis. Instead of being a causalfactor for schizophrenia, Weiser and Noy suggested that the pathology of thecannabinoid system in schizophrenia patients may be associated with both increasedrates of cannabis use and increased risk for schizophrenia [89]. De Irala et al. pointedout that, from a public health perspective, actions are required since a causalrelationship between cannabis use and psychosis is likely [90].

Adolescents are thought to be more susceptible to possible toxic effects of cannabisto the brain. Kumra et al. presented data at the 2005 Meeting of the RadiologicalSociety of North America according to which cannabis use may damage certain brainregions applying diffusion tensor imaging (DTI) [91]. They concluded that, in additionto interfering with normal brain development, heavy cannabis use in adolescents mayalso lead to an earlier onset of schizophrenia in individuals who are geneticallypredisposed to the disorder. In contrast to this result, Delisi et al. did not find anydifferences in brains of individuals who were frequent cannabis users in adolescenceand control subjects using magnetic resonance imaging (MRI) [92]. They concludedthat frequent cannabis use is unlikely to be neurotoxic to the normal developing brain,refuting the hypothesis that cannabis alone can cause a psychiatric disturbance such asschizophrenia by directly producing brain pathology.

It is generally agreed that cannabis use increases the incidence of psychosis in high-risk groups and worsens the course of psychosis. However, not all recent studiesconfirm this concept. Cannabis use was not associated with development of psychosis ina very high-risk group of 100 young people identified by the presence of sub-thresholdpsychotic symptoms, or a combination of a first-degree relative with a psychoticdisorder and recent functional decline [93]. In the twelve-months follow-up period,32% developed an acute psychotic episode, which was not associated with the level ofcannabis use prior to enrolment in the study. A Canadian study of 147 patients withschizophrenia-spectrum disorders, who were followed prospectively for twelve monthsdid not find an influence of substance abuse (cannabis or alcohol) on symptoms ofschizophrenia, but substance abuse was associated with higher levels of depression andanxiety in this patient group [94].

3.3. Depression and Other Psychiatric Co-Morbidity. It is well-established thatpersons with mental disorders such as schizophrenia, anxiety, and depression have ahigher rate of tobacco use, cannabis use, and alcohol dependence, and some scientistshave proposed causal relationships between these disorders, and alcohol dependencyand cannabis use [95]. Cannabis and THC may cause anxiety and depression but alsoameliorate these conditions. Cannabis is often used to alleviate psychological problems[96], especially by patients who suffer from chronic somatic diseases [11] [97]. An anti-depressive effect was also observed in clinical studies [98] [99]. A rationale for theseobservations has been offered by experimental studies, which found that endocanna-binoids may have an anti-depressive [100] and anxiolytic effect [101], and CB1 agonistsreduced blood corticosterone levels in stressed mice while a CB1 receptor antagonistincreased corticosterone levels [102].

Particularly, the use of cannabis by young people may have negative effects on theirmental and social development. In his review of 48 long-term studies on cannabis use,and psychological and social problems, Macleod et al. did not find a strong support for


an important causal relation between cannabis use by young people and psychosocialharm, but could not exclude the possibility that such an association exists [103]. Otherssee a strong support for a causal relationship [90]. 736 subjects from New York wereinterviewed at the ages of ca. 14, 16, 22, and 27 years, and psychiatric disorders wereassessed. Early alcohol use and early marijuana use were associated with majordepressive and drug-use disorders at age 27 [104]. In the so-called Dunedin study, along-term prospective study in New Zealand, a linkage between cannabis use andmental health problems was observed [105]. Mental health problems at age 15 were apredictor of cannabis use at age 18, whereas cannabis use at age 18 predicted a higherrisk of mental illnesses at age 21. Both cannabis use and mental problems were linked tolow socioeconomic status, childhood behavioral problems, and separation from theparents during adolescence. In the other New Zealand birth-cohort study, theChristchurch study, with 1265 children there was a strong correlation between at leastweekly cannabis use and several indicators of poor psycho-social outcome, includingcrime, depression, and suicide attempts [106]. Amotivational symptoms observed inheavy cannabis users during treatment were attributed to depression [107].

Cannabis use seems to have less effect on the mental health of adults than onadolescents [108– 109]. After adjusting for differences in baseline risk factors ofcannabis use and depression, past-year cannabis use did not significantly predict laterdevelopment of depression in 8759 adults (age range 29– 37 years) [108]. In a sample of6792 young adults, a small but significant increase in the risk of developing a majordepression was found among current cannabis users [109]. Green and Ritter found aweak association between adult cannabis use and depression in 1941 participants of arepresentative sample of U.S. males from the 1944– 1954 birth cohort, but theassociation disappeared after adjustment for educational attainment, employmentstatus, marital status, and other drug use, notably alcohol and tobacco use [110].Depression was associated with earlier age of first cannabis use rather than with thecurrent level of use. In an Australian twin study, Lynskey et al. found a substantialcontribution of genetic vulnerabilities to the association between cannabis use anddepression [111].

3.4. Cognitive Function. Neuropsychological studies have indicated that chronicheavy users may, depending on intensity and duration of use, show impairments ofmemory, attention, and ability to organize and integrate complex information. A partialexplanation for cognitive impairment may be the influence of cannabis use on bloodflow in the brain. Cerebrovascular resistance and systolic velocity were significantlyincreased in cannabis users compared to control subjects, and these increases persistedin very heavy users (131 joints per week on average) after a month of monitoredabstinence [112]. The clinical significance to humans, of observations that the regularuse of CB1 receptor agonists may promote neurogenesis in the hippocampus of adultrats [113], and that mice lacking CB1 receptors showed an accelerated decrease ofcognitive functions [114], is unclear.

In a meta-analysis of studies on cannabis use and cognitive function Grant et al.found only a small effect of the drug on long-lasting deficits, which would offer anacceptable margin of safety if the drug is used medicinally [115]. They analyzed 15studies that met essential inclusion criteria with 704 cannabis users and 484 nonusers.Neuropsychological results were grouped into eight ability domains, and effect sizes


were calculated by domain for each study individually, and combined for the full set ofstudies. With the exception of both the learning and forgetting domains, effect sizeconfidence intervals for the remaining six domains included zero, suggesting a lack ofeffect.

Among these studies is the one by Pope et al. who compared three groups ofindividuals aged 30 to 55 years with regard to their cognitive abilities followingcessation of cannabis use: 63 current heavy users of cannabis, 45 former heavy users,and 72 nonusers [116]. Some cognitive deficits were detectable at least seven days afterdiscontinuation of heavy cannabis use. By day 28, however, there were virtually nosignificant differences among the groups on any of the test results, suggesting thatcannabis effects on cognition in heavy users appear to be reversible and related torecent cannabis exposure. However, another investigation suggests that very heavy useof cannabis may be associated with irreversible decline in cognitive performance [117].Participants were divided according to the number of joints smoked per week into lightusers (mean: 11 joints), medium users (mean: 42 joints), and heavy users (mean: 94joints). Very heavy users performed significantly worse on 5 of the 35 tests compared tolight users even after 28 days of controlled abstinence. Memory, executive functioning,psychomotor speed, and manual dexterity were affected. In a more recent study, nodifferences in the performance of moderate regular cannabis users, who were abstinentfrom the drug for one week, and non-users in tasks on working memory and selectiveattention were observed [118].

The effect of the drug on cognitive performance may be more pronounced inadolescence [82] [119]. Early-onset users who started using cannabis before age 17differed significantly from both late-onset users (onset at age 17 or later) and fromnonusing controls on several measures of cognitive function, most notably verbal IQ[119]. Few differences were found between late-onset users and controls on the testbattery. After adjustment for verbal IQ, virtually all differences between early-onsetusers and controls on test measures ceased to be significant. The authors suggestedthree alternative explanations for poorer cognitive performance in early-onsetcannabis users: 1) innate differences between groups in cognitive ability, antedatingfirst cannabis use; 2) an actual neurotoxic effect of cannabis on the developing brain; or3) poorer learning of conventional cognitive skills by young cannabis users who haveeschewed academics and diverged from the mainstream culture. In the Christchurchbirth cohort, there was a significant correlation between level of cannabis use duringadolescence and young adulthood, and failure to complete school or universityprograms, even after controlling for confounding factors [82]. According to theseauthors, it is likely that this reflects the effects of the social context within whichcannabis is used rather than any direct effect of cannabis on cognitive ability ormotivation.

3.5. Tolerance and Dependency. Humans can develop tolerance to cannabis-inducedcardiovascular and autonomic changes, decreased intraocular pressure, sleep and sleepEEG, mood, and certain behavioral changes [35]. In a number of studies, Jones andBenowitz administered daily doses of 210 mg of oral dronabinol to ca. 120 volunteersfor 11– 21 days [120]. Participants developed tolerance to cognitive and psychomotorimpairment, and to the psychological high by the end of the studies [121]. After a few


days, an increased heart rate was replaced by a normal or a slowed heart rate. Tolerancedevelops also to cannabinoid-induced orthostatic hypotension [122].

Clinical long-term studies with THC and cannabis in patients suffering frommultiple sclerosis [7] [123], spasticity and pain [124], and AIDS [125] did not findtolerance to the medicinal effects of moderate doses (usually 5 – 30 mg of THC daily)within 6 – 12 months.

As with tolerance, withdrawal symptoms are dose-dependent [126]. In experimen-tal studies, comparatively high doses were administered to volunteers (80– 120 mg and210 mg daily, resp.) [35] [120] [127]. In the study by Haney et al., abstinence from THCincreased ratings of LanxiousJ, LdepressedJ, and LirritableJ, decreased the reportedquantity and quality of sleep, and decreased food intake [127]. In the studies by Jonesand Benowitz, most of the participants (55– 89%) experienced irritability, restlessness,insomnia, anorexia, nausea, sweating, salivation, increased body temperature, alteredsleep and altered waking EEG, tremor, and weight loss after discontinuation of THCadministration [35] [120]. These withdrawal symptoms that were described as Lmild andtransientJ started within 5 – 6 h after intake of the last dose and disappeared within 4days. Sleep disturbances were observed for several weeks after discontinuing therapy.Withdrawal symptoms were alleviated by the administration of a cannabis cigarette ororal THC [120]. In another study, withdrawal symptoms, e.g., aggression, anxiety,decreased appetite, irritability, restlessness, and sleep problems, typically set in betweendays 1 –3, peaked at days 2 –6 and lasted 4 – 14 days [128]. Planned, sudden interruptionof long-term therapeutic cannabis administration for two weeks in 25 patients did notcause a consistent withdrawal syndrome, although 11 (46%) patients reported at leastone withdrawal symptom (tiredness, interrupted sleep, hot and cold flushes, moodalteration, reduced appetite, emotional liability, intoxication or vivid dreams) [123].

The U.S. National Comorbidity Study indicated that 9% of lifetime cannabis usersmet DSM-R-III criteria for dependence at some time in their life, compared to 32% oftobacco users, 23% of opiate users, and 15% of alcohol users [129]. In a representativesample of German adolescents (N¼1228), who were followed for 20 months, thecumulative life-time incidence for DSM-IV cannabis abuse was 3.5% [130]. Similardata were obtained from an Australian sample of 10.641 adults of whom 1.5% weredependent according to DSM-IV, and 0.7% were diagnosed with cannabis abuse [131].The natural course of cannabis use, abuse, and dependence is rather variable [132].Cumulative incidence and patterns of cannabis use and disorders were examined in aprospective longitudinal design (mean follow-up period 42 months) in a representativesample (N¼2446) aged 14– 24 years at the outset of the study. Cannabis use waswidespread in this sample, but the probability of developing cannabis abuse ordependence was relatively low (8%), and about half of all cannabis users sponta-neously gave up their use in their twenties [132]. In cannabis users, the percentage ofdependency may be much higher than in the general population. It was reported to beup to 50% in long-term heavy users [133].

Genetic and environmental risk factors are thought to contribute to dependency[134]. Young age at first use of cannabis is associated with an increased risk of laterdevelopment of dependency [135]. In a group of boys, early-onset of use was associatedwith earlier onset of substance use disorder symptoms and more rapid acceleration ofproblems with drugs than late-onset use [135]. In another study, adolescents were


dependent at a lower frequency and quantity of cannabis use compared to adults andtwice as many adolescents as adults who used cannabis near-daily or daily within thelast year were identified as being dependent (35 vs. 18%) [136]. There is a correlationbetween cannabis dependence, and the dependence on tobacco, alcohol, and otherdrugs [137].

3.6. Hormonal System and Fertility. Cannabis and D9-THC act on the hypothalamic-pituitary adrenal axis, and, in animal studies, a multitude of endocrine processes areinfluenced by the drug, thus affecting sexual and other hormones (ACTH, TSH, HGH,melatonin) as well as glucose metabolism [138]. Changes in human hormone levels dueto acute cannabis or THC ingestion are minor and usually remain in the normal range[17]. Tolerance develops to these effects, however, and even regular cannabis usersdemonstrate normal hormone levels. Reductions in male fertility by cannabis arereversible and only seen in animals at THC blood concentrations higher than thosefound in chronic cannabis users. After several weeks of daily smoking 8 – 10 cannabiscigarettes, a slight decrease in sperm count was observed in humans, withoutimpairment of their function [139]. In animal studies, high doses of cannabinoidsinhibited the acrosome reaction [140].

There is no conclusive evidence on any cannabis-associated influences on themenstrual cycle length, the number of cycles without ovulation or on the plasmaconcentrations of estrogens, progesterone, testosterone, prolactin, LH, or FSH infemale cannabis users [141– 143]. A transient cannabis-induced suppression ofprolactin and LH levels was observed if the drug was inhaled during the luteal phaseof the menstrual cycle [144].

There are few epidemiological data on influences of cannabis on fertility, and theseprovide no definitive answers. In an Indian study, 150 married male cannabis users thatinitiated cannabis use shortly before marriage were compared to an equal number ofopium users and non-users of drugs. 1% of non-users, 2% of cannabis users, and 10% ofopium users were childless [145]. Noteworthy sterility rate in bhang users (cannabisleaves) with an average daily consumption of ca. 150 mg of THC was lower (0.4%) thanin nonusers, whereas the users of ganja and charas (flowers and resin) with a dailyconsumption of ca. 300 mg of THC was clearly higher (5.7%).

Mueller et al. investigated effects on female sterility. There was a low increase ofsterility risk in association with marijuana use (rate ratio, 1.7; 95% CI, 1.0– 3.0) [146].The risk was only increased in occasional users and not in more heavy users. Joesoefet al. investigated the period of time from child wish until conception in 2817 women[147]. Regular users of cannabis became pregnant most quickly (mean 3.7 months).Tobacco smokers needed an average of 5.1 months, and drug-free women 4.3 months.

Grotenhermen reviewed the effects of cannabis and THC on other hormones [148].A single oral administration did not elevate plasma cortisol in man [149]. However,smoking two cannabis cigarettes caused a transient significant increase in plasmacortisol level [150]. Chronic heavy cannabis users did not show any significantdifferences in their cortisol levels [151]. Cannabis use does not result in measurablechanges in blood glucose level, but may influence glucose tolerance [152]. However,relatively high doses are needed. 6 mg of intravenously applied THC influencedglucose tolerance in some volunteers, while others remained unaffected [153].


3.7. Pregnancy and Foetal Development. The endocannabinoid system plays acrucial role in pregnancy. Successful pregnancy implantation and progression seem torequire low levels of anandamide [154]. At term, anandamide levels dramaticallyincrease during labor and are affected by the duration of labor, which may explain asometimes observed shorter gestation in cannabis users. For example, Fried et al. founda reduction of approximately one week in the gestational age of infants born to motherswho used cannabis six or more times per week [155]. Both, higher than normalanandamide concentrations and cannabis use disturbed normal development ofembryos, their oviductal transport and deferred on-time implantation [156].

THC rapidly crosses the placenta, and the course of THC levels in foetal bloodcoincides well with that in the maternal blood, though foetal plasma concentrations arelower than maternal level in rats [157]. It is unlikely that cannabis causes embryonic orfoetal malformations. There are inconsistent epidemiological data on its effect on birthweight. There is evidence of subtle disturbances of cerebral development resulting incognitive impairment in offspring of cannabis users from two longitudinal studiesconducted in Canada and the USA [158] [159]. This impairment might not be observedbefore preschool or school age. Thus, Jacobson et al. found poorer cognitive perform-ance in new-borns at 12 months associated with prenatal exposure to alcohol but noassociation with cannabis exposure [160]. In 13- to 16-year-old adolescents, thestrongest relationship between prenatal maternal cigarette smoking and cognitivevariables was seen with overall intelligence and aspects of auditory functioning,whereas prenatal exposure to cannabis was negatively associated with tasks thatrequired visual memory, analysis, and integration [158].

3.8. Other Organ Systems. The long-term use of cannabis may have a negativehealth impact on other organ systems, including immune system and circulation.

It has been demonstrated that THC may cause a shift in the development of Th1and Th2 cells. THC Treatment of cell cultures [161] and the use of cannabis [162] wasassociated with a decrease of pro-inflammatory Th1 cytokines, such as IFN gamma andIL 2 (interleukin 2), and an increase in anti-inflammatory Th2 cytokines, such as IL 4and IL 10. In clinical studies, no such changes were observed [163], which may be due tolower doses. These effects on the immune system may be beneficial in inflammatorydiseases such as CrohnJs disease and multiple sclerosis, but may have a negative impactin immunocompromised subjects such as AIDS and cancer patients. Studies inves-tigating the effects of cannabis or THC on the course of AIDS have yielded conflictingresults. In a prospective study by Kaslow et al., the use of cannabis in HIV-infectedpersons was not associated with the onset of AIDS [164]. Di Franco et al. also did notobserve any such influence of cannabis in HIV-infected men in a six-year epidemio-logical study [165]. In a three-week clinical study with smoked cannabis and THC inHIV-positive adults taking protease inhibitor-containing highly active antiretroviraltherapy (HAART), no relevant effects on immune parameters were detectable [166].On the other hand, Tindall et al. and Whitfield et al. found evidence for such anassociation [167] [168].

The use of cannabis may acutely increase the risk of suffering from a heart attackdue to its effect on blood pressure and heart frequency (see above). However, chronicuse was not associated with cardiovascular risk factors such as blood triglyceride levelsand blood pressure in the longitudinal CARDIA study, which began in 1986 [169].


Cannabis use was also not associated with a higher body mass index (BMI) comparedto controls [170]. In an animal model of atherosclerosis, low doses of THC inhibiteddisease progression [171]. This was associated with a decreased interferon-gammasecretion by lymphoid cells and reduced macrophage chemotaxis. There are severalcase reports of an association between arteriopathies such as BuergerJs disease andcannabis use, but it is unclear whether this relation is causal, since the study subjectsusually also smoked tobacco [172].

Daily cannabis use was a risk factor for progression of fibrosis in chronic hepatitis Cin one epidemiological study, while occasional use was not [173]. The development ofliver fibrosis may be regulated by cannabinoid receptors, and, in cirrhotic patients, CB1

receptors are markedly increased in nonparenchymal cells within and at the edge offibrous septa, while there is only a faint expression of CB1 receptors in normal liver. Onthe other hand, cannabis use improved retention and virological outcomes in patientstreated for hepatitis C with interferon and ribavirin [174].

3.9. Cannabis Prohibition. In contrast to other social activities that may be harmfulto the individual and/or society, notably alcohol use, the use of cannabis remains illegalin most countries. Advocates of cannabis prohibition believe that it reduces traffickingand use, thereby improving productivity and health. Critics believe that prohibitioncurbs trafficking and use only modestly, while causing several negative side effects, suchthat the LtoxicityJ of prohibition in fact enhances the toxicity from consumption of thedrug itself. Brief reviews of several potential benefits and cost of cannabis prohibitionfollow.

3.9.1. Medical Use. In most western countries, cannabis remains prohibited even formedicinal purposes. Where individual cannabinoids (dronabinol, nabilone) or cannabispreparations that may be prescribed legally in some countries are not available or tooexpensive, therapeutic use of cannabis may cause considerable repercussions for thepatient who requires it and has to obtain it illegally. They include criminal prosecutionor fear thereof, exposure to possible contamination in low-quality drugs, and use of anunknown concentration of THC with possible variability in dosing. Since cannabis maybe an effective painkiller, and people suffering from chronic pain are at a high risk ofcommitting suicide [175], prohibition of medical cannabis use may increase mortalityamong this group of patients. The argument that other effective painkillers areavailable is no consolation for those, whose pain is not effectively treated by these. Aperson in his 50s, bound to a wheelchair and with little social interaction, will find ithard to obtain an illegal drug. Ironically, prohibition of medical cannabis tends to affectmuch more those adult patients with chronic pain and other severe diseases thatrespond positively to cannabis treatment than adolescents, who are the main focus ofprotection from drug use by prohibition.

The medical benefits of cannabis for some indications and the problems caused bycontinued prohibition of its medical use, recently prompted several medical journals toendorse reconsideration and reclassification of medical cannabis. In 2005, the editors ofMedGenMed and the Journal of the American Medical Association pleaded for areclassification of cannabis in the USA, so that its medical use would be allowed underfederal law [176] [177].

3.9.2. Individual and Societal Cost of Prohibition. The Editors of the Journal of theCanadianMedical Association not only advocated the legal medical use of cannabis but


also the general decriminalization of cannabis for personal use. They argued that thesocial and legal consequences of being arrested for cannabis possession and obtaining acriminal record far outweigh the minimal health effects of moderate cannabis use [178].Since most of todayJs regular cannabis users are young adults [179], over-reactivelaws on cannabis may be regarded as a modern version of the generational conflict[180].

Aside from having a criminal record, loosing oneJs driverJs license may be anotherserious consequence of cannabis use. In the large French epidemiological study ondrugs and traffic safety cited above, the risk of causing an accident increased 1.8-fold ifTHC was present in blood. Yet, it increased even more for drivers with a blood alcoholconcentration of less than 0.05% and for drivers older than 70 years of age. In bothcases, the risk increased by a factor of 2.7 [54]. To date, these findings only broughtabout heavier sanctions in France for drivers testing positive for THC, while nosanctions for drivers with a blood alcohol concentration of less than 0.05% or olderdrivers have been proposed. This suggests that sanctions against cannabis and drivingare not necessarily based on a rational assessment of potential risks to traffic safety.

Cannabis prohibition may cause several other undesirable social and health effects.They include the need for cannabis users to interact with a criminal milieu and anerosion of the credibility of governments that created laws considered by many to beunjust and unenforceable. Cannabis prohibition also may have disrupted small-scaleoutdoor production, drove commercial growers indoors, and likely contributed to theobserved increase in the potency of illegal cannabis, as its producers tried to maximizeprofits and minimize their risks [1].

These and other consequences of cannabis prohibition, such as the need to buildand maintain a growing criminal system, including courts and prisons, also generateconsiderable costs to society. Based on a report on the economics of cannabisprohibition, the late Nobel Prize-winning economist Milton Friedman and more than500 of his colleagues released an open letter to President Bush calling for Lan open andhonest debate about marijuana prohibitionJ. They added, LWe believe such a debate willfavor a regime in which marijuana is legal but taxed and regulated like other goodsJ. Thereport estimated that replacing cannabis prohibition with a system of taxation andregulation, similar to that used for alcoholic beverages, would generate combinedsavings and tax revenues of between 10 and 14 billion US Dollars per year in the USAalone [181].

Currently, the profits from drug trafficking only benefit the traffickers and are oftenused to finance criminal activities, including terrorist acts. On the forty-sixth session ofthe Commission on Narcotic Drugs of the United Nations in April 2003, 142representatives approved a joint statement which expressed deep concern for theLthreats posed by continuing links between illicit drug trafficking and terrorism and other. . . criminal activities, such as trafficking in human beingsJ. [182].

3.9.3. Decriminalization and Prevalence of Cannabis Use. There is no agreementamong scientists on how decriminalization or legalization of cannabis would affect keyparameters, such as the prevalence of cannabis use by adults and adolescents, pricetrends, and the extent of unregulated home production. Effects will vary betweencountries and their socio-cultural settings. Decriminalization and legalization wouldcertainly increase availability of cannabis, and there is great concern that this will also


increase use [183]. Other authors fear that legalization of cannabis could trigger noisyadvertising campaigns for its use, some of which might be directed towards adolescents[183].

The developments following decriminalization of cannabis in some states orcountries, and the comparison between countries with different drug laws offer someindication on how decriminalization may affect prevalence of use in other jurisdictions.When comparing cannabis prevalence statistics from the USA, Australia, the Nether-lands, and other European nations, MacCoun and Reuter found that depenalization ofsmall-scale possession of cannabis in some U.S. and Australian states, and in someEuropean countries did not increase cannabis prevalence [184]. However, the authorsconcluded from the Dutch experience that commercial promotion and public sale ofcannabis might significantly increase cannabis prevalence. Currently, the prevalence ofcannabis use in the 15 – 34-year-age bracket in the Netherlands, which decriminalizedcannabis more than 20 years ago, is higher than in Norway, Sweden, Ireland, Bulgaria,Portugal, Poland, and Greece, but lower than in Austria, Italy, Germany, the UnitedKingdom, France, and Spain [185]. Most studies on the effects of decriminalization ofcannabis, including a report by the U.S. Institute of Medicine, conclude thatdecriminalization and increased availability will have no significant impact on use(e.g., [11] [186] [187]). Recent experience in the UK confirmed this experience. There,cannabis was moved in 2004 from a Class-B to a Class-C drug, making its possession amisdemeanor, which did not increase cannabis use.

Instead, several studies found that social background, emotional, and other psycho-social factors were more reliable predictors of cannabis use and generally problematicdrug use than the availability of the drug or its legal status. These factors includedchildhood behavioral problems [105], Lqualitative aspects of family life, particularlyattachment to mothersJ [188], peer-oriented lifestyle and Lpatterns of antisocial behaviorand truancyJ [189], and separation from parents during adolescence [105] [188].

4. Conclusions. – As Hollister already found in 1986, cannabis is now firmlyestablished as another social drug in Western countries [17]. The recently observedincrease in cannabis use, particularly among younger people, poses potential harm toindividuals and society at large, and must clearly be attended to by society. The extentof the risks associated with cannabis use depend on several factors. According to theabove review, young age among users, regular and heavy use, and the smoking ofcannabis cigarettes are factors most likely to increase the negative effects of cannabisuse. The greatest concerns should be associated with minimizing cannabis use by youngadolescents. Potentially negative long-term effects of cannabis use, including depend-ency, induction of psychosis, effects on cognition and academic achievement are moresevere in young people than in adults. Factors that tend to protect users fromundesirable effects of cannabis are adult age, low-to-moderate use, and consumption ofsingle cannabinoids and whole plant preparations in a therapeutic context.

This review of the toxicology of cannabis and the effects of currently used controlstrategies suggests that cannabis is a drug of moderate toxicity, particularly when usedby adults. Because it may create undesirable effects on personal development andhealth, cannabis use by adolescents should be discouraged effectively. The medical useof cannabis appears to offer some persons benefits for a wide range of indications.


Cannabis prohibition appears to have only moderate success in reducing cannabisconsumption. At the same time, it may have side effects resulting in harm to theindividual and society, particularly with people who suffer from severe illnesses andmay benefit from the therapeutic properties of the drug. Thus, unless it can be shownthat decriminalizing personal use and regulating medical of cannabis will increase theharmful effects of the drug itself, it is difficult to see what society gains from continuedprohibition [183]. If their shared objective is to minimize the negative effects ofcannabis use to society as a whole and the youth in particular, both critics andproponents of cannabis prohibition must be open to assessing and balancing the risksassociated with the use of the drug, particularly for adolescents, and the costs incurredby any approach to damage control.

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Received December 9, 2006


the toxicology of cannabis and cannabis prohibition · effects is lower (a single dose of ca.2–3...

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