386 G.A. Cabral and A. Staab
of direct exposure to high concentrations of cannabinoids, such as the lung, mem-
brane perturbation may be involved. In addition, endogenous cannabinoids or
endocannabinoids have been identified and have been proposed as native modula-
tors of immune functions through cannabinoid receptors. Exogenously introduced
cannabinoids may disturb this homoeostatic immune balance. A mode by which
cannabinoids may affect immune responses and host resistance may be by perturb-
ing the balance of T helper (Th) 1 pro-inflammatory versus Th 2 anti-inflammatory
cytokines. While marijuana and various cannabinoids have been documented to
alter immune functions in vitro and in experimental animals, no controlled longi-
tudinal epidemiological studies have yet definitively correlated immunosuppres-
sive effects with increased incidence of infections or immune disorders in humans.
However, cannabinoids by virtue of their immunomodulatory properties have the
potentialtoserveastherapeuticagentsforablationofuntowardimmuneresponses.
KeywordsB lymphocytes · Cannabinoid receptors · Cannabinoids · Cytokines ·
Endocannabinoids · Human immunodeficiency virus · Immunity · Infections ·
Macrophages · Mast cells · Microglia · Natural killer cells · THC · Therapeutics ·
Tlymphocytes
1
Introduction
Marijuana, orCannabis sativa, has been valued for its medicinal as well as its psy-
chotropic properties dating back to ancient times. However, reports from as early
as the 1960s have indicated that marijuana and select components also could com-
promise human health, including the ability to resist infections. Included among
these components is a class of compounds collectively known as cannabinoids. At
least 60 have been identified. These include cannabidiol (CBD), cannabinol (CBN),
cannabigerol (CBG), and∆^9 -tetrahydrocannabinol (THC), the major psychoactive
ingredient in marijuana that has been implicated as the major immunomodulatory
substance.
Early studies on the effects of marijuana on the immune system attributed
these to the ability of THC to perturb cellular membranes since it was highly
lipophilic. However, it was soon recognized that THC also exhibited specificity of
action at the physiological and pharmacological levels as well as in distribution in
organs and cells. Studies performed on various rodents demonstrated that THC
produced a characteristic tetrad of behavioral effects that consists of catalepsy,
antinociception, hypothermia, and hypomobility (see Wiley and Martin 2003).
These centrally mediated effects could be elicited following intravenous, intrathe-
cal, and intraperitoneal administration. Furthermore, use of radiolabeled THC
in hybridization studies revealed a distribution of binding in rodent brain slices
that was consistent with that attributed to areas in the brain that correlated with
specified behavioral activities.
A series of experiments that drove the field of cannabinoid pharmacology for-
ward as it relates to the recognition of the existence of a functionally relevant