Effects on the Immune System 389phenotypic and functional attributes that mimicked those of native immune cells,
including those of human origin. Because cannabinoids were recognized as highly
lipophilic, their effects on humans and animals originally were considered non-
specific and were attributed to perturbing effects on plasma membranes and other
lipid-containing structures of the cell (Wing et al. 1985; Friedman et al. 1991).
Light and electron microscopy studies performed by Raz and Goldman (1976)
demonstrated extensive vacuolation in murine peritoneal macrophages exposed
to either THC or CBD. It was indicated that these cytoplasmic alterations had been
observed also in alveolar macrophages of hashish smokers. Similar observations,
related to disruption and perturbation of cell membranes following exposure to
relatively high levels of THC, have been made by Meyers and Heath (1979) and
Cabral et al. (1987a). Cabral and Fischer-Stenger (1994) postulated that THC at
high concentrations (i.e., 10–5M), as a consequence of membrane perturbation,
has a generalized effect on immune cell functions. THC was shown in vitro to have
a differential inhibitory effect on murine P388D 1 macrophage-like cell inducible
protein expression in response to priming and activating signals such as interferon
(IFN)-γand bacterial lipopolysaccharide (LPS). It was postulated that interaction
of the highly lipophilic cannabinoid with cell membranes resulted in alterations in
membrane fluidity and selective permeability and the attendant increase in intra-
cellular sodium resulted in shutdown of protein synthesis. A similar process has
been proposed for virus infection of cells in which insertion of virus-specified gly-
coproteins into the cell surface membrane alters selective permeability and affects
a shutdown of cell-specified macromolecular synthesis (Carrasco and Smith 1976;
Garry et al. 1979, 1982). Nahas et al. (1977) reported that CBD and CBN exerted
greater inhibitory effects on phytohemagglutinin (PHA)-induced human lympho-
cyte transformation as measured by^3 H-thymidine incorporation when compared
to THC. These effects were exerted at drug concentrations ranging from 10–4Mto
10 –6M, which are relatively high.
With the discovery of cannabinoid receptors in the 1990s, novel insights were
obtained regarding modalities by which cannabinoids affect immune functions.
Indeed, a general picture emerged that cannabinoids exhibited a duality of action.
Effects on immune functions exerted by cannabinoids at concentrations below
the micromolar level may be through the activation of cannabinoid receptors.
However, cannabinoids also can exert non-receptor-mediated effects (Felder et al.
1992; Derocq et al. 1998). Such non-receptor-mediated effects may be exerted at
high concentrations (i.e., micromolar levels). Such levels are achievable in the lung
as a result of exposure to marijuana smoke or through therapeutic application of
purified cannabinoids.
2.2
Effects on the Immune System Using In Vivo Models
Experimental animal models, using guinea pigs and mice, have been used for
nearly a century to document effects of various toxic and infectious agents on host
resistance. These in vivo models have offered unique advantages for assessment of