While 5-IAI has been suggested to generate some serotonergic neurotoxicity, it's been posited that such activity is not as significant as related compounds. However, Nichols et. al. are careful to state that the data derived from the above study cannot contribute to a simple relationship between serotonergic neurotoxicity for several reasons. First, the reserpinized synaptosome method used is incapable of distinguishing uptake inhibition from release of non-vesicular norepinephrine - and despite the fact that 5-IAI was observed to inhibit norepinephrine uptake, there is no obvious trend characterizing either neurotoxic or non-neurotoxic compounds to be more potent noradrenergic uptake inhibitors. A similar concern exists for serotonin, as all drugs
tested were potent non-vesicular serotonin releasers - including both neurotoxic and non-neurotoxic agents. Finally, in vivo
pharmacokinetic factors have not been established for 5-IAI - and evidence exists suggesting that the drugs vary widely regarding such properties; for example, 5-IAI and PIA are characterized by considerably lower potency in substituting for MDMA in drug discrimination experiments than would be anticipated from the in vitro
data presented in the tables provided by the study. Accordingly, 5-IAI cannot be definitively characterized as a non-neurotoxic substitute for MDMA, despite evidence supporting lower levels of serotonergic neurotoxicity.
The following figure demonstrates the apparently low level of serotonergic neurotoxicity. PIA caused a significant decrease in serotonergic markers a week after a single 40mg/kg dose - and 5-IAI appeared to be significantly less neurotoxic, as only a slight decrease of serotonergic markers (15% or less) was observed a week subsequent to one 40 mg/kg SC dose. The only statistically significant decreases were observed in cortical uptake sites, as well as hippocampal levels of serotonin. Importantly, 40 mg/kg SC is 20- to 40- times higher than required for behavioral activity - and comparable doses of many amphetamine analogues has been observed to approach fatal levels.
Hospitalization from 5-IAI