Pharmacokinetics of THC in brain and testis, male gametotoxicity and premature apoptosis of spermatozoa.

An earlier report described the pharmacokinetics of delta-9 THC and the resulting brain function responses. In the present studies the pharmacokinetics of THC in plasma, brain and testis were related to impairment of spermatogenesis. THC- containing preparations, whatever their route of administration, were associated with the induction of gametotoxicity in all species studied including man. The pharmacokinetics and molecular binding of THC is similar in all experimental models. Concentrations of THC in plasma, fat, testis, brain and spleen were measured following administration of tracer amounts of C(14) delta-8 THC labelled at the C(11) position. Rats were administered 2 microCi of the tracer by i.m. injection, and killed at regular intervals after a single or multiple dose of the label. After a single dose, the maximal radioactivity was reached in brain after 2 and 4 h and amounted to 0.06% of the administered dose. In the testis, the concentration did not exceed 0.023% of the administered dose. In epididymal fat, the total radioactivity after 4 h was five times higher than in the brain and after 24 h it was eight times greater. After multiple injections of C(14) THC, concentrations of the drug remained low in the plasma, brain and testis not exceeding 2-7 ng/g, but the epididymal fat tracer concentration was 40-80 times higher. Plasma concentrations of C(14) THC were of the same magnitude as those measured by GCMS in the plasma of men exposed to marihuana smoke or THC, and in whom alterations of spermatogenesis were observed. In these studies, plasma THC ranged from 9.5x10(12) M to 2.4x10(14) M. These data illustrate the efficiency of the blood-brain barrier and blood-testicular barrier in limiting the storage of THC into brain and testis. During chronic exposure to THC the pharmacokinetic molecular mechanisms which limit the storage of THC in the brain and testis are not sufficient to prevent a persistent deregulation of membrane signalling and the induction of functional and morphological changes which reflect a premature apoptosis of spermatogenic cells. Long term, longitudinal epidemiological studies have reported decreased spermatogenesis in healthy, fertile adult males. But no study has been initiated to relate the oligospermia of this population to the consumption of widely used psychoactive drugs.

The pharmacokinetics of THC in fat and brain: resulting functional responses to marihuana smoking.

A pleasant sensory perception (PSP), the high of THC or of marihuana consumption, is a consistent functional response to this drug only manifested by man, and which occurs concurrently with an increased heart rate. However, it has not been possible to relate consistently magnitude and duration of these functional markers to THC plasma concentration, whatever the route of administration. A re-analysis of all the available clinical and experimental data reporting the pharmacokinetics and storage of THC in tissues in function of time, have indicated that the discrepancies between functional responses and plasma molecular THC concentration may be accounted for by the pharmacokinetics of THC. The instant uptake and unlimited storage of THC by neutral fat limits the molecular concentration of the drug present in the plasma to a level which does not exceed 6 x 10(14) molecules/ml. The physicochemical nature of the membrane lipid bilayer (of the blood-brain barrier) will restrict the access of THC into the bilayer receptors and its: reactive enzymes. The PSP and increased heart rate of marihuana is correlated with the molecular concentration of THC in the bilayer (blood-brain barrier) of the order of 10(12)-10(14) molecules/ml. This number in turn would be related to the number of functional THC receptor sites in the lipid bilayer. THC would exert its functional properties on PSP and heart rate through a molecular transmission to specific receptor site and bilipid layer physicochemical interations. Rapid uptake and slow release of THC in fat associated with a rate-limited uptake into brain may be a general philogenetic mechanism which would protect brain function from prolonged exposure to xenobiotics like THC and other fat soluble drugs. Copyright 2001 John Wiley & Sons, Ltd.

Psychoactive cannabinoids and membrane signaling.

THC-like psychoactive cannabinoids permeate the lipid bilayer of the membrane, altering its physicochemical properties and activating phospholipases. As a result, an increased production of arachidonic acid occurs with its cascade of eicosanoids, including prostaglandins. In addition, THC and its psychoactive derivatives bind within the membrane in a stereospecific fashion, to a transmembrane G protein coupled receptor (GPCR) for which THC has a much higher affinity than the natural ligands, arachidonylethanolamide (AEA) and 2-arachidonyglycerol (2-AG). These natural lipid ligands may be considered signaling molecules which are generated in the membrane lipid bilayer. THC alters the physicochemical disposition of the lipid bilayer and interacts with the integral membrane protein receptors through alteration of the boundary lipid. This effect is distinct from the mechanism resulting from its persistent binding to a G protein coupled transmembrane receptor. THC does not interact directly with neurotransmitter receptors but alters their pharmacological response in an allosteric fashion. It is proposed that the binding of AEA and 2-AG to the G protein coupled transmembrane receptor possesses a physiological function which is to regulate the signaling between boundary lipids and membrane receptors in response to extracellular signals. AEA and 2-AG are eicosanoid signaling molecules which modulate the activity of G protein coupled transmembrane receptors. AEA and 2-AG should not be identified with synthetic ligand molecules dubbed 'endogenous cannabinoids' which are 'xenobiotics' with no physiological regulating function. THC deregulates persistently a basic signaling mechanism of the membrane lipid bilayer and of its integrated receptors with resulting impairment of cellular function of brain, heart and male gonads. Copyright 2000 John Wiley & Sons, Ltd.