In the previous part, we talked about what enantiomers are in general and using the example of amphetamine. I will not stop at explaining the terms, all the necessary definitions have been given in that topic. Today we will talk about the mirror twins of methamphetamine. And here the situation is not as unambiguous as with amph.
Since there is no separate topic about methamphetamine in this section yet, we will consider its pharmacokinetics in more detail with reference to stereoisomerism. As always, there are D- and L-enantiomers. Let's dive into their similarities and differences.
It is often suggested that d-meth exerts more potent physiological and pharmacological effects than L-meth does, and that the stimulating effects exerted by l-meth on the central nervous system are 2–10 times less potent than those of D-meth.
Data on the pharmacological activity of meth enantiomers are presented in one of the classic studies of 2006 year. In this study 12 meth abusers received intravenous D-meth (0.25 and 0.5mg/kg), L-meth (0.25 and 0.5 mg/kg), racemic methamphetamine (0.5 mg/kg), or placebo with the use of a 6-session, double-blind, placebo-controlled, balanced crossover design. The perfection!
In general, d-meth and racemic meth produced significantly longer-lasting cardiovascular and subjective effects than l-meth. Although the peak effects of 0.5 mg/kg of l-meth were similar to those with the doses containing d-meth, these effects dissipated rapidly.
The 0.5-mg/kg l-methamphetamine dose produced significantly fewer subjective effects across time than the comparable dose of d-meth and racemic meth. The exception was monetary value, which remained similar to all doses containing d-meth across time. For those effects that were increased by the higher l-meth dose, the magnitude was similar to the 0.25-mg/kg d-meth dose. In contrast, the 0.25-mg/kg dose of l-meth produced few physiologic or subjective effects, often no greater than placebo. Both isomers produced a dose-response effect for the majority of subjective measures.
Methamphetamine is thought to exert its behavioral effects by increasing midbrain synaptic concentrations of dopamine and norepinephrine by a combination of enhanced release and uptake inhibition. However, dopamine release in the nucleus accumbens appears to be most involved in mediating the rewarding effects. The amphetamines interact with several components of the monoamine synapse including the neuronal transporter (uptake transporter), vesicular storage system, and monoamine oxidase. Reports indicate that these actions on the synapse are stereoselective, with the d-enantiomer being more potent than the l-enantiomer.
The stereoisomers of methamphetamine produce markedly different dopamine, norepinephrine, and serotonin responses in various brain regions in rats. D-meth (2 mg/kg) is more potent in releasing caudate dopamine than l-meth (12 and 18 mg/kg). By use of in vitro uptake and release assays, d-metha was 17 times more potent in releasing dopamine than l-meth and significantly more potent in blocking dopamine uptake (inhibition constant [Ki], 114+-11 nm versus 4840+-178 nm (sic!). These differences in dopamine release could explain the significantly greater subjective effects produced by d-meth (racemic and 0.5 mg/kg) compared with l-meth (0.5 mg/kg) on several measures. The effects of 0.5 mg/kg of l-meth were less than even a lower dose of d-meth.
Furthermore, the subjective effects for l-methe dissipated relatively quickly, reaching baseline values at 3 hours after dosing compared with approximately 6 hours for d-meth. Peak ratings for arousal, elation, positive mood, and vigor were significantly higher for doses containing d-metha than for placebo and continued to increase over time, whereas l-meth (0.5 mg/kg) produced greater ratings only on arousal, which also dissipated rapidly (trough at 1.5 hours).
Earlier it was reported that the cardiovascular system is more affected by the l-isomer of amphetamine might lead us to expect a similar or greater cardiovascular response after l-meth. In contrast, all doses containing d-meth significantly increased systolic and diastolic blood pressure, heart rate, and rate-pressure product, whereas l-meth had significantly fewer cardiovascular effects.
Also, interesting results were obtained from a 2017 study where the locomotor effects of meta enantiomers were studied in mice.
They showed that psychostimulant effects induced by l-meth are lower than those elicited by one-tenth the dose of d-metha. In addition, plasma pharmacokinetic parameters and striatal concentrations of methamphetamine following administration of l-meth at 10 mg/kg (which did not induce psychomotor activity) were approximately 11 and 16 times as high, respectively, as those following administration of 1 mg/kg d-meth. Despite the fact that there are differentiable psycho-stimulating effects between two enantiomers, no significant difference in plasma pharmacokinetic parameters was detected at 1 mg/kg.
For instance, the effects of D-meth on the release and uptake of dopamine in rat caudate synaptosomes are reportedly approximately 17- and 42-fold greater, respectively, than those of l-meth demonstrated that the peak dopamine concentration in rat caudate following s.c. administration of 2 mg/kg D-meth is approximately 2.3 times as high as that after administration of 12 mg/kg L-meth.
Taken together, results indicated that the psychostimulant effects elicited by d-meth are at least 10 times stronger than those induced by L-meth based on their doses for inducing psychomotor activities. Furthermore, the distinct psychoactive efficacies of the enantiomers are not due to differences in plasma pharmacokinetics or brain concentrations of methamphetamine/amphetamine following administration of the respective enantiomers.
How it works?
The pharmacodynamic differences between isomers could be explained by the metabolite of d-methamphetamine, d-amphetamine. Although the the variation of a drug concentration in blood plasma for the metabolite amphetamine was considerably smaller than that for the parent, methamphetamine, amphetamine by itself is a potent central nervous system stimulant. The distribution of d-amphetamine in the striatum is rapid after d-methamphetamine administration.34 Therefore the enantiomer-specific difference in amphetamine disposition may increase brain levels of d-amphetamine, producing significant central nervous system effects.
D-Meth may also activate alpha-adrenergic receptors by releasing norepinephrine from peripheral sympathetic terminals via monoamine transport mechanisms. In vitro, d-meth’s potency for norepinephrine release is twice that of l-meth, which may account for the greater cardiovascular effects that we observed in response to d-meth. Previous reports in humans found that after d-meth administration, systolic blood pressure and diastolic blood pressure increase significantly. But now clear, that heart rate increases but only slightly and that rate-pressure product increases markedly as a result of the increased systolic blood pressure.
What about racemate?
Of interest, racemic methamphetamine had effects similar to those of the highest dose of d-meth. It is logical to assume that, that because of the greater cardiovascular and subjective effects of the d-isomer, the racemic mixture to be less rewarding as a psychostimulant, but findings do not support this. There is no simple explanation of why racemic meth is often as potent as an equal quantity of d-meth. The variation of a drug concentration in blood plasma of d-meth or l-meth given as 0.25 mg/kg alone and the variation of the same isomer when administered as 0.25 mg/kg in the racemic mixture were equivalent, suggesting similar pharmacologic effects between doses. However, racemic methamphetamine has more than an additive effect compared with the equivalent doses of D/L-meth in the racemic mixture. One possible explanation is that differences may be a result of the metabolite d-amphetamine. Both subjective and cardiac effects of racemic methamphetamine were often similar to those of the dose containing more d-meth.
In contrast, lower dose of d-meth (0.25 mg/kg) was often similar to the high dose of l-meth (0.5 mg/kg). This suggests that behavioral and cardiac activation by l-meth may be a result of differences in receptor dynamics or may be acting through different pathways or mechanisms than d-meth.
Half-life
After the 0.5-mg/kg dose of d- and l-meth, the half-lives were 10.3+-2.6 and 13.3+-3.5 hours, respectively.
The mean half-life of l-meth was slightly longer after racemic administration.
Some conclusions
D-meth, alone or as a racemate, produces more subjective and cardiovascular effects than equivalent doses of l-meth. Although a
relatively large dose of l-meth produced similar peak subjective and cardiovascular effects, they dissipated more rapidly. The enantiomer-specific difference in d-amphetamine disposition and the greater dopamine and serotonin responses in animals with d-meth suggest pharmacologic mechanisms for the differences in response observed with the isomers.
Racemic methamphetamine have an abuse potential similar to that for d-meth. It is likely that the degree of behavioral or cardiovascular toxicity with abuse of racemic mixtures is low. L-meth does not appear to increase the toxic effects of d-meth. However, toxic effects may increase, especially under repeated-dosing conditions, because the stereoselective differences in the pharmacokinetics of d-meth, l-meth, and racemic meth may lead to an accumulation of l-meth.
And if d-meth and racemate are not forgotten, then the fate of the isolated l- is similar to l-amphetamine. But a little bit better. At least l-meth is being used now a sympathomimetic vasoconstrictor that is the active ingredient in some over-the-counter nasal decongestant inhalers in some countries. But as a recreational substance, its chances are small.
Thanks for your time.
As always, if you have thoughts or experience related to the topic, I invite you to a dialogue.
I would also be interested to know if its worth continuing to talk about the stereoisomerism of stimulants and recreational substances.
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