I think the worry is always that centrally active compounds may have a long term effect in potentially wearing down the psyche, what they don't understand is thats exactly what some people are going for.
This is a possible eventuality after long term use of high amounts of drugs that target the same receptors. What people don't understand is that the receptors are being constantly agonized, and antagonized, by naturally occurring chemicals both ingested and made internally. A person can use heroin everyday, if in controlled and specific doses, and never suffer physiological malady if they don't suffer malnutrition or sleep deprivation. It is very likely that most phens and trypts are fairly harmless.
Their are always nuances to this suggestion, like PMA and its derivatives. Though the Di-methoxy groups seems to impede metabolism; this is why DOM is probably so potent, and harmless, and PMA is a potential 'neurotoxin by association'.
What I see the problem being is the receptors
other 'inner terminals' getting cobwebs.
That di-Rx-Amine group seems to be extremely important, but the phenol is no doubt indispensable.