As noted above, the cannabinoid receptors in the brain account for most but not all of the effects of cannabinoids. Cannabinoids are lipophilic; they lodge in fatty tissues in the body, which are extensive. While this is not, as once believed, responsible for marijuana's characteristic effects on the Central Nervous System, the question remains as to what effect this has on other systems in the body.

The research literature indicates six areas of known or possible side effects from cannabinoid use that require explanation: pulmonary effects, immunosuppression, reproductive dysfunction, endocrine modulation, decreases in intraocular pressure, and effects on the digestive system.

Lynn and Herkenham utilized autoradiographic assay techniques to investigate non-Central Nervous System cannabinoid binding in a rat. (49) Because of the difficulty in getting fat cells to adhere to a slide, they were not able to investigate lipid binding of cannabinoids. However this study makes important strides in three areas.

First of all, Lynn and Herkenham have determined and localized additional sites of specific and non-specific binding, that is, sites not in the brain.

Second, the locations of specific binding sites in areas that regulate the immune system help clarify prior research.

Third, the location of non-specific (unrelated to specific receptors) binding questions the basis for the "fat accumulation" concerns about cannabinoids.

It was not unexpected by the researchers to discover cannabinoid receptors in the immune system (the spleen, Peyer's Patches, lymph nodes, blood, and bone marrow), as there are close similarities between neural and immune cells. While some research has suggested cannabinoid suppression of T-cells, the receptors are actually located in B-lymphocyte cells. It is uncertain if macrophages (the killer cells of the immune system) are affected by cannabinoids.

"Macrophages cannot be discounted and may contribute to binding; however, in other structures of the reticuloendothelial system besides the spleen, specifically the liver and lung, which have large numbers of macrophages, there is no specific receptor binding."(50)

Immune system suppression is a matter of great concern. Researchers have expressed concern about marijuana's use as an illicit therapeutic drug to induce appetite by AIDS patients. (51) The possible effect of marijuana on the immune system has been a special concern of Dr. Nahas for a long time. (52) And indeed, a 1974 article by Dr. Nahas is cited along with many other papers in Lynn and Herkenham's consideration of cannabinoid effects on the immune system. (53)

Leo Hollister reviewed evidence of cannabinoid immunosuppression in 1988 for the Journal of Psychoactive Drugs.

"Despite the fairly large literature that developed during the past 15 years or so, the effect of cannabinoids on the immune system is still unsettled. The evidence has been contradictory and is more supportive of some degree of immunosuppression only when one considers in vitro studies. These have been seriously flawed by the very high concentrations of drug used to produce immunosuppression and by the lack of comparisons with other membrane active drugs. The closer that experimental studies have been to actual clinical situations, the less compelling has been the evidence.

"Although the topic was of great interest during the 1970's, as indicated by the preponderance of the references from that period, interest has waned during the present decade. This waning of interest suggests that perhaps most investigators feel that this line of inquiry will not be rewarding. The AIDS epidemic has also diverted attention of immunologists to the far more serious problem of the truly devastating effects a retrovirus can have on a portion of the immune system. . .Persons infected with the virus but not diagnosed as AIDS have been told to avoid the use of marijuana and/or alcohol. This advice may be reasonable as a general health measure, but direct evidence that heeding this warning will prevent the ultimate damage to the immune system is totally lacking."(54)

The significance of the location of cannabinoid receptors in the immune system concerns possible therapeutic drugs, not danger to human users of cannabis. The authors are quite specific about the significance of this discovery:

"If cannabinoids do modulate B cell migration, proliferation, plasma cell morphogenesis, and immunoglobin production, such effects may have profound implications for the humoral immune response. Whereas suppression of B cell-mediated function could be detrimental (although there is little evidence that it is in vivo), cannabinoid suppression could play a positive therapeutic role in autoimmune disorders. [Research has shown] that Delta 9 THC is an effective prophylactic treatment for autoimmune encepalomyelitis (an animal model for multiple sclerosis) in Lewis rats and strain-13 guinea pigs, and they proposed a mechanism whereby lymphocyte migration and sequestration in the CNS are inhibited by the drug. Only subtle immune suppression has been noted in humans, which suggests a species difference in peripheral cannabinoid receptor distributions and densities."(55)

As if quite aware of the extrascientific debate over marijuana policy, Lynn and Herkenham place the external validity of their experimental animal findings in perspective.

"Whereas this finding [of cannabinoid receptors in the immune system of a rat] has implications for human immunomodulation, it should be noted that rodents are more susceptible than humans to immunomodulation by cannabinoids, perhaps reflecting the substantially higher levels of receptor in their immune cells. In humans, immune suppression is subtle and in many cases insignificant. There is little evidence for cannabinoid immunosuppression as a causative agent in disease."(56)

Finally, Lynn and Herkenham have clarified some of the issues involving marijuana's effects on the rest of the body.

As expected, non-specific binding is found in some structures with high lipid content. However high concentrations of non-specific binding were located in many structures without high fat contents. For example, the heart has high in non-specific binding, and without consequence, because the cardiovascular effects have previously been shown to be CNS-mediated. There is also noticeable non-specific binding in the pancreas.

"Other factors besides lipophilia of cannabinoids must dictate the sites of nonspecific in vitro binding."(57)

Non-specific binding of cannabinoids may account for cannabinoid effects on the reproductive systems. The lack of non-specific binding in the testes suggests that the effect of cannabinoids on sperm is due to action at some other site, perhaps the hypothalamus. Also:

"Cannabinoids have not been shown to affect fertility adversely or to be teratogens, except in extremely high chronic doses. Such effects in part may be mediated at the level of the pituitary or brain, given the evidence about prolactin suppression in frequent female users of marijuana."(58)

According to Lynn and Herkenham, the effects of cannabinoids on the endocrine system, the digestive tract, and the cardiopulmonary system are all believed to mediated in part, by the CNS.