LSD "trigger hypothesis"

[lux]

According to "Acid Dreams":
"Research on human subjects [?] showed that LSD lodged primarily in the liver, spleen, and kidneys. Only a tiny amount (.01%) of the original dose entered the brain, and it only remained there for twenty minutes. This was a most curious finding, as the effects of LSD were not evident until the drug had disappeared entirely from the central nervous system." (22)

and "Pharmacotheon":
The drug [LSD] is almost completely eliminated from the body before the peak effects commence, suggesting that it acts as some sort of catalyst, inducing the neurochemical changes which subsequently result in the visionary experience." (128)

Neither book provides a citation.

George Aghajanian, by contrast, found a T1/2 of 175 minutes for LSD in man, and found a tight correlation between drug plasma levels and cognitive impairment measures. He concluded, along with James Ketchum, that the "trigger hypothesis" was based on an overgeneralization of early animal research, which found a T1/2 of 20 minutes in rodents. http://www.erowid.org/references/refs_view.php?ID=2224

I'm inclined to side with Aghajanian here, but would be interested in further comments if anyone has additional information.

 

[fastandbulbous]

IN RODENTS!

PMA is as active than LSD in rodents if I recall. Vivesectionists 0 Animal Rights nutters 1

Applying pharmacokinetics from animals to the human model is, well... wrong

 

[kidamnesiac]

I've also read that the spectroscopy in the early '60s simply was not sensitive enough to detect the miniscule amounts of metabolites found after ~2 hrs. Gotta remember, 200ug distributed throughout a human body and then slowly eliminated doesn't exactly give massive concentrations in the urine or other tissue.
More sensitive equipment has since shown your last statement to be true. (sorry, dont have a link)

 

[lux]

Aghajanian improved plasma detection significantly, mentiond by James Ketchum in Chemical Warfare, and here:
http://www.erowid.org/chemicals/lsd/lsd_pharmacology1.shtml

 

[Jabberwocky]

Pardon my ignorance, but if the trigger hypothesis is wrong AND it has such a short half-life, then how do you trip with fairly consistent intensity for so long?

 

[Beenhead]

F&B , are you saying thst Pharmacological data gathered on Drugs in animals is a giant waste of time? I think it must have some relavence.

 

[lux]

Pardon my ignorance, but if the trigger hypothesis is wrong AND it has such a short half-life, then how do you trip with fairly consistent intensity for so long?

I think that the short half-life value (20 min) is incorrect, but I'm not sure - that's mostly what I'm hoping to clarify. Aghajanian found a half life of 175 minutes, and Ketchum found a half life of 160 minutes. Both claim that the 20 minute half life was based on rodent studies, so as far as I know that's correct.

I'm not surprised that Acid Dreams would get that wrong - I'm finding numerous minor errors in it. But I was a little surprised that Ott would make a mistake like this, so I want to double-check.

 

[fastandbulbous]

F&B , are you saying thst Pharmacological data gathered on Drugs in animals is a giant waste of time? I think it must have some relavence.

A lot is relevant, but pharmacokinetics differes wildly from animal to animal. may end up with the same metabolic fate, but the speed that it happens is dependant upon the species in question. Even primate pharmacokinetics isn't always true for humans

 

[Beenhead]

So is that implying that different species use different Enzymes?

 

[fastandbulbous]

^ Yep (well isoenzyme forms in some cases with different kinetics), that's why chlorinated hydrocarbons are toxic to cats, dogs can withstand a dose of etorphine that would kill a human and MPTP is only toxic to the substantia nigra of primates.

Having a pharmacologist other half who used to be a vet nurse means you get to learn all sorts of interesting stuff!

 

[lux]

One simple example of the variance of parameters between species is to compare LD50s, which are often quite out of proportion to differences in mass.

http://www.erowid.org/psychoactives/health/psychoactives_ld50s.shtml

 

[Beenhead]

^^ Good point, I always attributed LD50 to mass more than metabolic Enzymes and such.
Actually, weve been studying enzymesand inhibition in class, its definately where I want to start my work when I get done with school. UF has a guy doing a lot of work with finding Enzyme inhibitors

 

[lux]

I'm no pharmacologist, but I'd imagine that drug effects leading to death could be complex. For example, if a drug accelerates heart rate in mammals, some species will be more vulnerable to that than others. Direct toxicity wouldn't be a primary casue of death in that case.

Take MDMA for example - a big chunk of MDMA-related fatalities are due to hyperthermia exacerbated by too much Breaks.

 

[fastandbulbous]

^ well to be accurate, clotting mechanisnms dysfunction and organ failure due to hyperthermia is the cause of death coroners get. Hyperthermia is anything from heatstroke to basically being cooked alive

 

[MattPsy]

The very fact that 5-HT2A antagonists stop the effects of LSD and other HC-htr2A ligands would seem to disprove the "trigger" hypothesis.
(That and a whole lot of newer research)

 

[fastandbulbous]

And that's it in a nutshell (rather than my flapping on about rodent metabolism and other gibberish!)

 

[lux]

"The very fact that 5-HT2A antagonists stop the effects of LSD and other HC-htr2A ligands would seem to disprove the "trigger" hypothesis."

I have read findings that pre-treatment with 5-HT2A antagonists BLOCK the effects of the serotonergic hallucinogens, but I have not heard that subsequent administration brings effects to a halt. Do you have a reference?

If so, that's significant news for emergency rooms, which sometimes still use thorazine (eek!) to treat bad trips.

 

[5-HT2]

MPTP is only toxic to the substantia nigra of primates.

This is not true. It is toxic to mice as well, but not to rats. The prevailing theory is that rats use MAO-A instead of MAO-B to catabolize dopamine. MPTP can only be catabolized into MPP+, the toxic metabolite, by MAO-B.

 

[MattPsy]

Lux, no, I don't have references handy for this. I had a quick search but the only articles I found (remember, this was a QUICK search) was for pretreatment.

But personal experience has proven the efficacy of stopping psychedelic trips with 5-HT2A antagonists, namely Risperdal...
Though I think for the purposes of dealing with bad trips, benzodiazepines are a preferable treatment, but that's unrelated...

 

[lux]

Thank you for the info, MattPsy. I looked around a bit, and one animal discrimination study only observed LSD antagonism when risperidone was administered before T + 4 hours:

"Response rate reductions were only observed at doses greater than or equal to 0.16 mg/kg after 1 h and at 0.63 mg/kg after 2 h pretreatment. Four and 8 h after treatment, no rate-reducing effects were apparent at doses up to 2.50 mg/kg."


http://www.ncbi.nlm.nih.gov/entrez/...t_uids=2471220&query_hl=6&itool=pubmed_docsum

That may be compatible with a trigger after all, albeit a much longer one. I'm still inclined against it, however.