Thursday, April 13, 2017

Minimum effective brain level (MEBL) demonstrates high potency of tryptamine

Vogel and colleagues assigned a value called the minimum effective brain level (MEBL) to several hallucinogenic drugs. These researchers wanted to know the true potency of drugs, without the confounding effects of drug uptake, elimination, distribution, and biotransformation.

MEBL is defined as the brain level of a drug expressed as moles/g of brain. After receiving a drug, when a rat begins to show a significant deviation from its normal behavior, the rat is sacrificed and the drug in its brain is quantified at that point. In this case, the rat learned a conditioned avoidance response, and at a certain time after receiving LSD, it was unable to execute the learned response, e.g. to escape from a box.

The Table below lists the effective dose (left) and MEBL (right) of several different drugs. The MEBL data provides a behavioral index of drug potency, and correlates with Domelsmith's ionization potentials, thus facilitating the analysis of structure-activity relationships.


Based on MEBL criteria, diethyltryptamine, DMT, and 5-methoxy-DMT were relatively weak, and phenethanolamines were very weak. LSD and 5-methoxytryptamine were the most potent compounds tested, with MEBL 0.5 ng/g. Tryptamine plus MAO inhibition was close to 5-methoxytryptamine in potency (MEBL = 1 ng/g), thus revealing the true potency of tryptamine when its inactivating enzyme is blocked.

Vogel wrote:
"It is of interest to note that the two compounds with the highest potency, tryptamine and 5-methoxytryptamine, are naturally occurring in the mammalian brain." (Vogel,W.H. 1977)
Note that for the Table in this review paper, data was compiled across the literature, and only after many synthetic chemistry efforts and sacrificed rats later was it possible to look at the trends across different drugs. The researchers wanted to know the amount of drug in the brain and the results were very interesting in terms of what could be inferred about tryptamine and monoamine oxidase inhibitors, however as I wrote about previously, the brain is not really the target organ of LSD. Most of the LSD that enters the bloodstream ends up in the small intestine which is the place in the body with the highest amount of 5-HT receptors. Nonetheless, MEBL is an interesting way to think about dosage levels.


Reference

Vogel W. H. and B. D. Evans (1977). Structure-activity-relationships of certain hallucinogenic substances based on brain levels. Life Sciences 20, 1629-1635. doi:10.1016/0024-3205(77)90335-6