Agreed.
And such differences between the stated and actual dose are, in my opinion, a major reason for why people tend to assume they were being affected by "dirty" LSD - if a blotter is underdosed, the physical aspects of the LSD experience become more pronounced, whereas at higher doses the user tends to be fully engaged with the mental and visual aspects of the trip. Likewise, if there is 100 micrograms of "LSD" present, but a significant amount of those 100 micrograms is iso-LSD, it is going to have a more pronounced bodyload relative to the mental effects; not because the iso-LSD is actively causing the body load, but because there is a relative lack of the psychoactive isomer to keep you engaged with the headspace and the visuals.
The chances of finding a compound that's active at a dose in the low microgram range is already pretty small. The chances that it would be active *only* when combined with psychedelics (and not at all when not on a psychedelic) are even smaller.
If iso-LSD is supposed to be active at less than 40 micrograms when combined with LSD, shouldn't there be *some* level of activity at an insane overdosage of 4000 micrograms? If it were, for example, a 5HT2A antagonist, then one would at the very least expect it to be sedating, for example.
It's not like Hofmann and Shulgin were the only people interested in the activity of LSD's isomers and analogues - while not everyone may have seen the potential of psychedelic therapy, ergoline-based pharmaceuticals did represent a pretty massive commercial market at one point, being used in the treatment of Parkinson's disease, migraines/cluster headaches and post-childbirth vaginal bleeding, so many of these compounds were being screened for their pharmacological activity.
This is where I like to apply Occam's Razor, i.e. the principle that one should go with the hypothesis that involves the fewest/smallest assumptions.
iso-LSD being active in the low-microgram range in a way that has not yet been noticed using various in-vitro/in-vivo/human assays is already a pretty big assumption; the reason for this being that it only becomes active in conjunction with a psychedelic is an even bigger assumption.
The placebo effect being a powerful phenomenon, though? I think that's been proven pretty conclusively over and over and over again in medical research. Psychedelics increasing suggestibility, and consequently also the impact of the placebo effect? Also not exactly a major assumption.
People sometimes interpret the idea of falling victim to the placebo effect as a sort of personal insult to their intelligence, which it really isn't. If psychological/pharmacological research has taught us anything, it's that personal reports should always be taken with atleast a grain of salt, even if they're coming from oneself. Researchers have devoted *a lot* of time coming up with things like double-blind studies to minimize the impact of the placebo effect, because they are well-aware they cannot fully trust themselves or their colleagues, no matter how smart or honest they may be.
Obviously, yes. One of the main reasons he worked on what would eventually become PIHKAL was that a compound that was highly active due to a high selectivity for the desired neurological targets would be less likely to have harmful side-effects due to unwanted metabolites, byproducts or activity at undesirable target sites.
However, he would probably also have encouraged people to be skeptical of claims regarding purity that come from their drug dealer, especially if they come associated with vaguely defined marketing terms ("yeah no this is totally 99.998% pure golden needlefluff, dude!") and with bold claims regarded the drug's activity, which might influence the trip via the placebo effect.
Wait, you mean Shulgin is trying to keep the psychedelic activity of these compounds a secret? So other people will not bother synthesizing these compounds, thus not bringing them to the government's attention, and Shulgin can keep them a secret between himself and his friends? That doesn't really sound like Shulgin at all. I mean, why publish TIHKAL/PIHKAL in the first place, then?
If you're referring to DOT/Aleph-1 (although that was in PIHKAL rather than TIHKAL), he did write down in his notebook how it was "the essence of power" and to "tell no one". Except he did tell people after all, dedicating a chapter in PIHKAL to the trip report.
In the chapter detailing the compound's synthesis, he describes the aforementioned trip report as "important in that gives an interesting example of some thought processes associated with psychedelic intoxication, ego-inflation, and what might be thought of as bits of mania." Shulgin was obviously pretty hyped about working on DOT due to it being the first in a family of psychedelic compounds switching out an oxygen atom with a sulphur atom, and he when talks about the stimulation he felt during his first trial of the substance at a dose of 250 nanograms (with a normal dose later being determined to be 5-10mg, i.e. 5-10 *million* nanograms), he specifically states that any activity he might have felt at such a low dose was "certainly all placebo response".
So let that sink in for a while: Even someone as smart and well-versed in the world of psychedelics as Alexander Shulgin fully accepted that he could be rendered susceptible to ego-inflation and mania during a psychedelic experience, and that he certainly wasn't above being affected by the placebo effect.
