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Major Studies of Drugs and Drug Policy
Canadian Senate Special Committee on Illegal Drugs
Volume I - General Orientation

Chapter 5 - Cannabis: From Plant to Joint

Pharmacokinetics [1][41]

Upon inhalation, and depending on the smoker's way of smoking and smoking experience, between 15% and 50% of the D9THC present in the smoke is absorbed into the bloodstream. The percentage also depends on the D9THC concentration in the smoked product. The substance is absorbed very quickly, and maximum blood concentrations are achieved in less than 15 minutes after the start of inhalation. The effects felt almost immediately after absorbing the smoke diminish gradually over the next 60 minutes and generally last a maximum of three hours after inhalation. In other words, THC levels in the blood plasma are highest immediately after absorption, whereas maximum effects are felt approximately 30 to 40 minutes later. The following table reproduced from the ISERM collective assessment, shows the time to appearance and duration of detection of cannabinoids in the blood.[2][42]

 

 

Concentration, time to appearance1 and duration of detection2 of cannabinoids in the blood after smoking a marijuana cigarette containing 15.8 mg or 33.8 mg of D9THC

Component

Maximum concentration

Time to appearance

of peak (hr)

Duration of detection

(hr)

D9THC

84.3 (50‑129)3

162.2 (76‑267)4

 

0.14 (0.10‑0.17)

0.14 (0.08‑0.17)

 

7.3 (3‑12)

12.5 (6‑27)

11‑OH‑D9THC

6.7 (3.3‑10.4)

7.5 (3.8‑16.0)

 

0.25 (0.15‑0.38)

0.20 (0.15‑0.25)

4.5 (0.54‑12)

11.2 (2.2‑27)

D9THC‑COOH

24.5 (15‑54)

54.0 (22‑101)

2.43 (0.8‑4.0)

1.35 (0.54‑2.21)

84.0 (48‑168)

152.0 (72‑168)

(1)(1)     average interval between start of consumption and appearance of a concentration peak

(2)(2)     average interval between start of consumption and moment when lowest concentration of component is detected (> 0.5 mg/ml)

(3)(3)     cigarette containing 13.8 mg (1.75%) of D9THC

(4)(4)     cigarette containing 33.8 mg (3.55%) of D9THC

 

Bio‑availability of D9THC is slower and weaker when the drug is ingested orally (cookies, cakes, herbal teas): approximately 4% to 12%; although slower to be felt and different in quality, its effects are longer lasting.

In all, we do not know how the effects of THC (concentration) interact with personal factors (way of smoking, health status, alcoholism or medication). However, it is likely that the same THC concentration does not have the same effect on all smokers, which moreover tend to be confirmed by the plasticity of cannabis in the hormonal stream (see below).

D9THC is highly lipophilic and is quickly distributed to all fatty tissues, including the brain. It is also characterized by an entero‑hepatic cycle and renal reabsorption which results in persistent effects. In a driving simulator study, a significant linear correlation was found up to seven hours following absorption, particularly on the trajectory control.

D9THC undergoes oxydative metabolism resulting in the production of various elements, in particular 11‑hydroxy‑tetrahydrocannabinol (11‑OH D9THC) a psychoactive metabolite which, transported by albumin, whereas D9THC attaches mainly to lipoproteins, penetrates the brain more deeply than D9THC; 8 b‑hydroxy‑D9‑tetrahydrocannabinol, potentially psychoactive but whose action would be negligible; and various other components not known for their psychoactive effects. In addition to the potentially psychoactive elements, cannabis contains approximately 200 derivatives of combustion and pyrolysis comparable to those found in tobacco, though some of which are highly carcinogenic and are more concentrated in cannabis smoke than tobacco smoke.

Cannabinoids are eliminated in various ways: through digestion, the kidneys and perspiration. Approximately 15% to 30% of D9THC in the blood is eliminated in urine, 30% to 65% through stools. Because it binds strongly to tissues, D9THC is eliminated slowly in urine: the urine of regular heavy users contains traces of D9THC‑COOH 27 days after they have last used cannabis.

Regular users metabolize D9THC up to twice as fast as individuals who have never previously used the drug. One study showed, in particular, that the intravenous administration of one 5 mg dose of D9THC resulted in higher blood levels in regular users than occasional users.[3][43]

Cannabinoids act on the body through the endogenous cannabinoid system, consisting of neurochemical substances (endogenous ligands) and specific receptors. The behavioural and central effects of cannabis are due to the agonistic action of its main ingredients (in particular D9THC, exogenous cannabinoid), on the endogenous cannabinoid receptors (anandamide, 2‑arachidonoylglycerol) present in the nervous tissues of the brain.

Although the chemical structure of D9THC was identified by Mechoulam in 1964,[4][44] it wasn't until very recently that the characteristics and location of the endogenous cannabinoid system was determined.[5][45] Two types of cannabinoid receptors have been isolated: CB1 in 1990[6][46] and CB2 in 1993.[7][47] CB1 is mainly expressed in the central and peripheral nervous system. CB2 is expressed essentially in the cells of the immune system. It follows from this distribution that CB1 is essentially involved in psychotropic effects and CB2 in immunomodulatory effects.

The main endocannabinoids are arachidonoylethanolamide (also called anandamide - a word derived from Sanskrit, literally meaning congratulated) and 2‑arachidonoylglycerol (2‑AG). These are the only two endogenous molecules known to be capable of binding to cannabinoids receptors CB1 and CB2 and replicating the pharmacological and behavioural effects of D9THC. Anandamide levels in the brain are comparable to those of other neurotransmitters such as dopamine and serotonine. The highest levels corresponding to high CB1 density areas, that is to say the hippocampus, striatum, the cerebellum and the cortex. Like anandamide, 2‑AG reproduces all the behavioural effects of D9THC or anandamide, but its action is less powerful.

The CB1 receptors are among the most abundant neuronal receptors in the central nervous system, and their distribution correlates remarkably with the behavioural effects of cannabinoids on memory, sensory perception and control of movements, as shown in the table below.

 

 

Location of CB1 receptors in the CNS and correlated pharmacological effects [8][48]

Structures

Marking

Physiological consequences

References

Forebrain

Amygdala

Olfactory systems

Cerebral cortex

Basal nuclei

Hippocampus

 

 

Thalamus/hypothalamus

 

Midbrain

Grey nucleus

Colliculi

Optic nuclei

Black substances/ventral tegmental area

 

Hindbrain

Grey periaqueductal area

Locus ceruelleus

Raphe

Bridged nucleus

Brainstem

Cerebellum

 

+

+

++

++

++

 

 

+

 

 

 

 

 

+

++

 

 

 

Cognitive effects

Locomotive effects

Cognitive effects (short-term memory inhibition) and antiepileptic action

Endocrine and antinociceptive effects

 

 

 

 

 

 

 

 

Antinociceptive effects

 

 

 

No lethal dose, no acute mortality

Motor effects (balance)

Herkenham et al., 1990

Herkenham, 1992

Tsou et al., 1998, 1999

Katona et al., 1999

Rinaldi‑Carmona et al., 1996

Matsuda et al., 1990, 1993

Hohmann, 1999

Marsiaco and Lutz, 1999

Westlake et al., 1994

++: abundant marking; +: intermediate marking; ‑: little or no marking.

 

 

This concentration of CB1 receptors largely explains the effects of D9THC. Intense expression of CB1 receptors in the basal nucleus and molecular layer of the cerebellum is thus consistent with the inhibiting effects of cannabinoids on psychomotor performance and motor coordination. Their expression in the cortex and hippocampus is consistent with the modulation of elementary forms of learning, explaining in particular the reversible deleterious effects on short-term memory and cognitive function. Their lack of marking in the brainstem explains the absence of acute toxicity or lethal doses of cannabis derivatives. The CB1 receptors in the thalamocortical system participate in the sensory disturbances and analgesic properties of cannabis. Similarly, the presence of receptors in the periaqueductal area and the dorsal horn of the spinal cord contribute to its antinociceptive power.

We also note that the CB1 receptors do not merely inhibit brain function. As a result of circuit effects, cannabinoids can stimulate certain neuron populations, in particular dopaminergic cells in the mesolimbic pathway. Together with the observation that prolonged treatment with cannabis (at doses corresponding to the equivalent of 575 cannabis cigarettes a day!) appears to induce lasting adaptive changes to the central nervous system and to the positive relationship between cannabinoids and stress hormones (corticotrophine), this explains the difficulties (irritability, sleep disorders and so on) observed in regular users when they have stopped using cannabis. We return to this issue in the Chapter 7 in the discussion on cannabis tolerance and dependence.

Lastly, recent works suggest there are significant interindividual variations in the effects of cannabinoids depending on sex steroid hormones in men and women: it appears that the effects of exogenous and endogenous cannabinoids can be modulated by the hormonal state of each individual and that, in exchange, the CB1 receptors and endocannabinoids are able to regulate hormonal activity.

As was observed in the WHO report in 1997, various research questions remain unanswered, in particular how and to what extent cannabis use alters the endogenous cannabinoid and what the relationship is between blood plasma cannabinoid levels and induced behavioural effects.

 



[1][41]  This section is based to a large extent on the INSERM 2001 report as well as the European scientific report 2002 and the survey work done by Wheelock 2002 for the Committee.

[2][42]  INSERM (2001) Cannabis. Quels effets sur le comportement et la santé? Paris: author, page 340.

[3][43]  Cited in INSERM (2001) op. cit., page 148.

[4][44]  Guoli and Mechoulam (1964) op. cit.

[5][45]  Devane, W.A. et al. (1992) "Isolation and structure of a brain constituent that binds to the cannabinoid receptor", Science, 258 (5090): 1946‑1949.

[6][46]  Matsuda, L.A. et al. (1990) "Structure of a cannabinoid receptor and functional expression of the cloned DNA", Nature, 346(6284) 5561‑564.

[7][47]  Munro, S. et al. (1993) "Molecular characterization of a peripheral receptor for cannabinoids", Nature, 365: 61‑65. Note that a recent scientific conference of the National Institute on Drug Abuse in the United States reported on the work of researchers on the hypothesis that there are additional receptors and other ligands. To our knowledge, the latter have not yet been formally identified in the research setting.

[8][48]  Table reproduced from INSERM (2001), op. cit., page 298.

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