Further pharmacological comparison of d-methamphetamine and l-methamphetamine in rats: abuse-related behavioral and physiological indices

Abstract

Previous preclinical research suggests that l-methamphetamine (l -MA) has potential therapeutic utility to treat psychostimulant abuse. This study examined potential abuse-related and adverse physiological effects of d -MA and l -MA alone and in combination in rats, as these effects had not been previously characterized. Potential abuse-related effects were examined in locomotor sensitization and conditioned place preference paradigms. Body temperature was monitored to assess the physiological effects of these drugs or drug combinations. In the locomotor study, d-MA induced locomotor sensitization to both d-MA and l -MA. l -MA induced locomotor sensitization only to d-MA. Responses to a combination of l-MA and d -MA were not differentially affected by l-MA or d-MA conditioning. In the conditioned place preference study, d-MA and l -MA each induced significant place preference. l -MA did not attenuate d-MA-induced place preference. In the body temperature study, d-MA induced hyperthermia and l -MA induced hypothermia. In combination, l -MA did not affect d-MA-induced hyperthermia. These data suggest that l -MA alone produces less abuse-related and adverse physiological effects than d-MA, but modulates and is modulated by concurrent and subsequent d-MA exposure, which may enhance the abuse liability of both drugs. These findings should be considered when l -MA is proposed for replacement therapy.

Distinct Effects of Methamphetamine Isomers on Limbic Norepinephrine and Dopamine Transmission in the Rat Brain

“…Solely high doses of l-METH (≥5.0 mg/kg) produced both significant increases in locomotion and stereotypy (Figure A,B), consistent with a previous study . It is plausible that l-METH’s preferential enhancement of NE over DA transmission shown here (Figures –) and previously may be responsible for the disparities in locomotion and stereotypy between isomers.…”

“…Clinically, d-METH is sold under the trade name Desoxyn and is prescribed, albeit rarely, to treat narcolepsy, ADHD, and obesity. 6−8 In contrast, l-METH is thought to have reduced abuse potential which is reflected in both clinical and preclinical studies 9 and can be purchased over the counter as the active ingredient (levmetamfetamine) in Vicks VapoInhaler nasal decongestant. 10,11 The primary targets of amphetamine-type stimulants, including METH, are the catecholamine (dopamine (DA) and norepinephrine (NE)) systems.…”

“…The latter production method is preferred by abusers as d-METH is generally associated with producing feelings of euphoria and has a heightened addictive potential. Clinically, d-METH is sold under the trade name Desoxyn and is prescribed, albeit rarely, to treat narcolepsy, ADHD, and obesity. − In contrast, l-METH is thought to have reduced abuse potential which is reflected in both clinical and preclinical studies and can be purchased over the counter as the active ingredient (levmetamfetamine) in Vicks VapoInhaler nasal decongestant. , …”

Reinforcing and Stimulant-Like Effects of Methamphetamine Isomers in Rhesus Macaques

“…The present study compared the abuse-related effects of l-MA with stimulant drugs of abuse -cocaine, d-MA, and MCAT -and assessed the effects of chronic l-MA treatment. L-MA has been shown to produce sustained decreases in cocaine and d-MA self-administration (Kohut, Bergman, & Blough, 2016;Bardo et al, 2019) and shares several behavioral and pharmacological effects with other monoamine releasers that have been proposed as candidate medications for cocaine and other stimulant use disorders (Herin et al, 2010;Czoty et al, 2016;Simien et al, 2017;Xue et al, 2019). However, unlike previous candidates, l-MA is considered to have less prominent dopaminergic and stimulant-like behavioral effects which may make it a more suitable agonist medication.…”

“…Both d-MA and l-MA produce cocaine-like discriminative stimulus effects , and l-MA substitutes for d-MA in drug discrimination studies (Yasar and Bergman, 1994;Bondareva et al, 2002;Desai & Bergman, 2010). Further, l-MA treatment has been shown to induce cross-sensitization to d-MA in rats (Xue et al, 2019). However, unlike d-MA, l-MA does not stimulate locomotor activity, nor does it induce locomotor sensitization with repeated dosing in rats (Nishimura et al, 2017;Siemian et al, 2017), suggesting that l-MA has lesser stimulant-like effects compared to d-MA.…”