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
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.