The Contribution of cocoa additive to cigarette smoking addiction

RIVM report 650270002 Page 183 of 207
Anandamide
Kinetic parameters
Male mice were administered 50 mg/kg 3 H-anandamide (i.v.). At 1, 5, 15 and 30 min
after administration, the animals were sacrificed and various tissues were removed,
solubilized and counted to determine the distribution of the radioactivity. Also, the
anadamide were determined in the samples from brain, adrenal gland and in
plasma.The radio activity was detectable in brain 1 min after injection. Although the
1 and 5 min metabolic profiles of brain radio activity showed that anandamide was
clearly present, most anandamide had already been transformed to arachidonic acid
and other polar metabolites, and there were almost no detectable brain levels of
anandamide at 15 and 30 min in plasma and adrenal gland. It is suggested tha
anandamide quickly reaches the brain and that the rapid metabolism of anandamide
plays a key role in the time course of the pharmacological activity of this naturally
occurring cannabinoid receptor ligand (34).
Critical assessment
The oral data indicate a low bioavailabilty of anandamide. The in vivo studies seems
to indicate that anandamide is endogenously distributed widely in the human body.
Anandamide is also extensively metabolized as indicated by the half life (t1/2 < 5
min). There are no data available on pharmacokinetics in animals and humans from
respiratory studies.
Conclusion
There are no in-vivo pharmacokinetic data available on respiratory exposure of
anandamide. The rapid elimination of anandamide indicates that pulmonary
anandamide exposure will not exert any systemic effects.
TOXICOLOGY
Acute toxicity
Human
No data available.
Animal
TDLo i.p. rat:140 µg/kg (1)
TDLo s.c. mouse: 100 mg/kg (1)
High doses of injected anandamide (10 – 100 mg/kg of body weight) cause typical in
vivo cannabimimetic inhibitory effects (decreased motor activity, rearing activity,
ring catalepsy, hypothermia, analgesia and agonistic behaviour) and inhibition of
leukocyte phagocytosis. In contrast, low doses of injected anandamide (0.01 mg/kg)
stimulated activities in open field and ring, increase aggresive behaviour and
stimulated phagocytosis (36).
The acute anandamide effects were studied in unanaesthetized freely behaving rats.
Intravenous anandamide caused dose-related decreases in locomotor behaviour, a
pronounced hyper-reflexia, and a moderate antinociceptive state. At doses between 3
and 30 mg/kg, a dose-dependent hypothermia and profound, time-dependent
cardiovascular changes were also observed.The exerted behavioural and
physiological effects were similar to those seen following natural cannabinoids (22).
Local tolerance
Human