Title: Alternative Sweeteners

Cyclamate 79
2. Cardiovascular Effects of Cyclohexylamine
The other major question about the safety of cyclohexylamine involves its possible
effects on blood pressure. Cyclohexylamine is an indirectly acting sympathomimetic
agent, similar to tyramine but more than 100 times less potent than
tyramine (15). Intravenous administration of cyclohexylamine to anesthetized animals
causes vasoconstriction and increases both the blood pressure and heart
rate. Despite these acute effects, a rise in blood pressure was not seen in subchronic
or chronic toxicity studies with orally administered cyclohexylamine in
rats, even at high doses (0.4–1% in the diet or approximately 200–400 mg/kg/
day) (38, 72).
The cardiovascular effects of single oral doses of cyclohexylamine in humans
have been thoroughly characterized by Eichelbaum et al. (31). They found
that a 10 mg/kg bolus oral dose of cyclohexylamine caused a 30-mm rise in the
mean arterial blood pressure of healthy human volunteers. A smaller increase
was seen after a 5 mg/kg dose, but no significant change in blood pressure occurred
with a 2.5 mg/kg dose. A reflex-mediated, slight decrease in heart rate
accompanied the vasopressor effects of the two higher doses. The cyclohexylamine
levels in the plasma of these subjects were closely correlated with the
increases in blood pressure, and it was estimated that the lowest cyclohexylamine
concentration to cause a significant hypertensive effect was about 0.7–0.8 µg/
ml. However, the blood pressure in these subjects rapidly returned toward normal
despite the presence of cyclohexylamine concentrations that were associated with
a pressor effect during the absorptive phase. These observations suggested the
rapid development of tolerance or tachyphylaxis to the hypertensive effects of
cyclohexylamine.
Despite the potential of cyclohexylamine to increase blood pressure, there
is no evidence to suggest that such effects actually occur after the administration
of cyclamate. Periodic cardiovascular monitoring in some subjects participating
in cyclamate metabolism studies revealed no changes in blood pressure or heart
rate, even in those individuals who received high doses of cyclamate and were
forming large amounts of cyclohexylamine (27, 29, 78, 79). Moreover, the cyclohexylamine
blood levels in some of these subjects approached the concentrations
associated with a rise in blood pressure after a bolus oral dose of cyclohexylamine,
yet their blood pressure was apparently not affected (29).
Two human studies conducted in Germany during the 1970s also addressed
the questions of cyclamate conversion, cyclohexylamine blood levels, and possible
cardiovascular effects. In one study the high converters among a group of
44 regular users of cyclamate were initially identified on the basis of their urinary
cyclohexylamine levels. After ingestion of 1.2–1.7 g of sodium cyclamate, the
cyclohexylamine blood levels in three of the high converters ranged from 0.03–