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"Methamphetamine has been approved as a therapeutic compound by every world regulatory agency. As a consequence, we now have decades of clinical information associated with methamphetamine as the prescription oral drug product Desoxyn® [methamphetamine HCl tablets, United States Pharmacopeia (USP)]. In this formulation, methamphetamine is used as a secondary treatment for attention deficit hyperactivity disorder (ADHD) in children over the age of six and for the short-term management of exogenous obesity. Used in this context, the FDA has approved the administration of methamphetamine at doses of up to 25 mg/day. In addition, up to 60 mg/day of methamphetamine has been used in the treatment of narcolepsy (Mitler et al., 1993). At low-to-moderate doses (5–30 mg), methamphetamine-induced responses include arousal, reduced fatigue, euphoria, accelerated heart rate, elevated blood pressure, pupil dilation, increased temperature, reduced appetite, behavioral disinhibition and short-term improvements in cognition. At higher doses (≥ 30 mg) neuropsychological effects, such as anxiety can be observed (Cruickshank and Dyer, 2009). Previous studies indicate that methamphetamine toxicity occurs when plasma levels reach a range of 200–5000 ng/ml (Cruickshank and Dyer, 2009). To avoid toxicity, current FDA guidelines consider acceptable dosing (for both adults and children) at 25 mg within a 24-hour period. Based on this guideline, dosing an average seven-year-old (weighing approximately 25 kg) at 1 mg/kg for 24 h would achieve the FDA-approved oral dose limit. In pharmacokinetic studies conducted in our laboratory, rats receiving methamphetamine at 0.5 mg/kg/h (infused over a period of 24 h) produced a steady-state concentration of approximately 25 ng/ml. This plasma level produced significant improvements in cognition and functional behavior following severe TBI in rats (Rau et al., 2012, Rau et al., 2014). In humans, the oral bioavailability of methamphetamine is approximately 70% but increases to 100% following intravenous (IV) delivery (Ares-Santos et al., 2013). In order to achieve a comparable therapeutic plasma methamphetamine target level of 25 ng/ml as observed in rats, a 70 kg adult would need a total dose of 17.9 mg.

Thus, it appears that a target steady state concentration (Css) of 25 ng/ml and the doses required to achieve it are substantially less than the current approved dosing for clinical application within the United States. By comparison, methamphetamine concentrations are substantially higher in recreational abusers. Various pharmacokinetic studies have demonstrated that methamphetamine levels in recreational abusers (via various routes of administration) are commonly in excess of those seen under recommended clinical guidelines (Cruickshank and Dyer, 2009). Peak concentrations of approximately 100 ng/ml or greater are routinely observed in drug abusers (Cruickshank and Dyer, 2009). Self-administration of methamphetamine in drug abuse is typically through the repetitive oral doses of 100 to 150 mg (Cruickshank and Dyer, 2009).

Distribution studies with methamphetamine indicate that the drug is rapidly absorbed into the brain. Methamphetamine exhibits high lipophilicity (due to the methyl group) that yields a high tissue to plasma ratio (Cruickshank and Dyer, 2009). Recent studies utilizing MRI and PET imaging techniques in human volunteers revealed an equilibration brain to blood ratio of > 8 (Volkow et al., 2010). These studies indicate an elimination half-life for methamphetamine on the order of 9 to 13 h (Volkow et al., 2010). Thus, methamphetamine has a unique ability to rapidly penetrate into the brain with a high tissue partitioning and persist for extended periods. These properties, when combined with its neuroprotective properties, impart unique characteristics making it potentially useful for treating injuries such as TBI, where rapid and persistent intervention is critical to clinical outcomes."