Journal of Human Hypertension (2007) 21, 594–597 & 2007 Nature Publishing Group All rights reserved 0950-9240/07 $30.00 www.nature.com/jhh COMMENTARY Stroke, with or with no ice? Observations on for the management of acute stroke

CV Borlongan and DC Hess Department of Neurology, Medical College of Georgia and Medical Research Service, VA Medical Center, Augusta, GA, USA

Journal of Human Hypertension (2007) 21, 594–597; doi:10.1038/sj.jhh.1002206; published online 19 April 2007

Known as the and as a robust performance among its personnel in World War II to assist them to enhancer around the world, amphetamine (- remain attentive and vigilant. Anecdotal accounts of methyl-) is a Adolf Hitler, who displayed Parkinson-like symp- that has become a mainstream prescrip- in his latter years, reveal his personal physician tion drug to treat and attention-deficit administered him daily intravenous injections of hyperactivity disorder (ADHD). Amphetamine is the as a treatment for depression and parent compound of a broad range of psychoactive fatigue. In contemporary military operations, the US derivatives, such as 3,4-methylenedioxymetham- military and even NASA have previously used phetamine (MDMA) (Ecstasy) and methampheta- to retard fatigue in their troops and mine. Originally available as racemic salt sulphate astronauts. with equal amounts of levo- and dextro-isoform, the Despite their medical use, illicit production and current predominant form of the drug is dextroam- diversion of amphetamines and phetamine sulphate (also called dexamphetamine or have led to classification of these drugs as controlled D-amphetamine) consisting entirely of the D-. substances with high potential for drug addition, Laboratory evidence indicates that D-amphetamine which is a major problem in world societies.2 and L-amphetamine act preferentially on the dopa- Nonetheless, when the drugs are used within the minergic system and norepinephrinergic, respec- recommended doses, the drug’s addictive, as well as tively, but the main reinforcing and behavioural- other physical (e.g., obsession to perform repetitive stimulant effects of amphetamine are correlated tasks, decreased appetite, increased sexual re- with enhanced activity, primarily in sponse, and fatigue and depression following the the mesolimbic dopaminergic system.1 excitement stage) and psychological (e.g., hallucina- The methylation of amphetamine renders the tions, mental states resembling schizophrenia, loss substance more soluble, thereby facilitating its of REM sleep) side effects, can be greatly reduced. transport across the blood– barrier and enhan- To this end, although such use remains experimen- cing its psychostimulatory effects. Its N-methylated tal, novel clinical indications of D-amphetamine analog methamphetamine, popularly referred to as include reduction of fatigue in cancer patients3 and crystal meth or ice, has been prescribed as the as an for HIV patients with depres- centrally active D-isomer of methamphetamine or D- sion and debilitating fatigue.4 Most recently, methamphetamine to control narcolepsy, ADHD, and D-amphetamine has been proposed as a therapeutic extreme , whereas the other isoform L- agent for stroke. methamphetamine, a potent sympathetic nervous The concept of using D-amphetamine, or amphe- system trigger (i.e., increasing heart rate and blood tamines in general, for treating stroke, although only pressure), is available as an the over-the-counter drug recently gaining considerable attention, has a long Vicks inhaler for nasal . history. In 1977, Bloom and co-workers treated Classic examples of amphetamine and metham- stroke animals with the antidepressant desmethyli- phetamine use include the distribution of metham- mipramine (commonly known as desipramine), phetamine-laced by the German military which inhibits the reuptake of , and found that the focal cortical infarction-induced hyperactivity was blocked.5 This observation chal- Correspondence: Professor CV Borlongan, Department of Neuro- lenged the prevailing concept at that time (and logy, Medical College of Georgia and Medical Research Service, VA Medical Center, Augusta, GA 30912, USA. maybe some in the field still hold this view even E-mail: [email protected] now) that while stroke presents with an apparent Published online 19 April 2007 local injury producing deficits via a point-to-point Amphetamine for the management of acute stroke CV Borlongan and DC Hess 595 brain structure-behavioural function mechanism, tent across these laboratory studies is that the assessment and subsequent treatment interven- D-amphetamine is shown to enhance recovery when tion of these stroke symptoms will benefit from the drug is paired with lesion-specific training or considering the ‘gestalt brain’ approach. That is, sensory stimulation, paving the way to introduce stroke symptoms of apathy and depression may pharmacologic enhancement of recovery after focal correspond to emotional alterations resulting from brain injury as a justified treatment regimen for pathophysiological processes in (i.e., stroke patients undergoing physical therapy. norepinephrine) that are remotely located Since the initial pilot clinical study in 1988, at away from the site of the stroke injury. Of note, least a dozen clinical trials have been conducted to norepinephrine and amphetamine are both phe- date. Walker-Batson et al.12 studied 10 hemiplegic nethylamine, with intraventricular infusion of nor- patients with stroke onset between 16 and 30 days, epinephrine replicating the effect of amphetamine.6 and used 10 doses of 10 mg dexamphetamine at Accordingly, the desipramine action on norepi- 4-day intervals, with the doses again combined with nephrine, albeit amphetamine, seen by Bloom and physical therapy. Significant improvement in the co-workers may be considered the first laboratory rate and extent of motor recovery in the treatment investigation designed to alter the amphetamine group was recognized as early as 1 week after levels in the stroke brain as a therapeutic strategy. completion of D-amphetamine therapy, which was Eleven years, however, would pass since the maintained up to at least 12 months. In response to milestone desipramine study before D-amphetamine the concern that the drug may be toxic, Walker- would be directly tested in stroke patients. A Batson et al. conducted a follow-up study on a larger double-blind pilot study was performed on a small patient pool, within 16–42 days of stroke onset, and cohort of patients with established cerebral infarc- treated 28 patients with D-amphetamine and 16 tion.7 The study was designed to evaluate the effect patients with placebo 30 min before physiotherapy of amphetamine on recovery of motor function. Four session on an alternating cycle of every third/fourth stroke patients received amphetamine, while the day for 10 sessions.13 The data revealed that the drug other four patients were given placebo within 3–10 was well tolerated during the 12-month course of days of ischaemic stroke onset. Amphetamine or the study. A parallel study by the same group placebo was combined with a session of physical revealed that such D-amphetamine paired with therapy, and patients were evaluated in their motor physical therapy accelerates recovery of stroke performance using the Fugl–Meyer scale. Patients patients from aphasia.14 In a more recent study, D- treated with amphetamine exhibited higher motor amphetamine alone increased language learning of scores than the placebo-treated patients, suggesting artificial vocabulary in healthy subjects.15 that amphetamine improved the clinical outcome of Partly because age is a risk factor of stroke, Sonde the stroke rehabilitation therapy. The small subject et al.16 performed a clinical study similar to Walker- population and the acute treatment protocol (single Batson et al., but enrolled 39 elderly subjects within dose of amphetamine and one session of physical 5–10 days of a new stroke-related hemiparesis. In therapy) and short testing study period are some addition, doses of D,L-amphetamine were given concerns raised in this study. Moreover, the authors 60 min before physiotherapy. Unfortunately, sub- conceded that the observed effect varied among jects with intracerebral haemorrhage were included individual patients, with some patients displaying in this study. More troubling is that some patients remarkable improvement of motor ability, while were discharged to complete the trial medication at others exhibiting only modest recovery. An equally home. Not surprisingly, this study resulted in critical confounding variable in this study is that amphetamine combined with physiotherapy not post-stroke depression is common, and the stroke promoting motor recovery or functional capacity in patients’ difficulties in conforming with physical stroke patients. Sonde and Lokk17 also recently rehabilitation maybe due to their concomitant performed a randomized, double-blind, placebo- depression. Therefore, effectively treating the de- controlled clinical trial and demonstrated that D- pression in stroke patients, such as with the use of amphetamine while safe and effective did not exert D-amphetamine with known antidepressant effects, added benefit than the placebo-treated patients could have mediated the observed motor recovery. exposed to physical therapy. Surprisingly, the initial pilot study on D-amphe- In an effort to assess safety of the drug, Martinsson tamine use in stroke patients was not directly based and Wahlgren18 used a placebo-controlled dose- on established stroke animal models, but from other escalation trial of 5 consecutive days treatment with brain injury models (cortical lesion, ablation or twice-daily D-amphetamine (2.5–10 mg b.d.) given suction procedures).8,9 Relevant stroke stu- within 72 h of an ischaemic stroke. Here, the drug dies on amphetamine did not become available was not paired with physical therapy. D-Ampheta- until the early 1990s, the most cited ones being mine was shown safe and well tolerated by patients, Goldstein’s work on facilitated recovery of beam but blood pressure and heart rate increased during walking10 and Ginsberg’s research on vibrissae treatment in comparison to placebo. Although stimulation-induced elevation of glucose utilization this was a safety study, the authors reported that in stroke rats treated with amphetamine.11 Consis- D-amphetamine alone improved neurological and

Journal of Human Hypertension Amphetamine for the management of acute stroke CV Borlongan and DC Hess 596 functional outcome during the drug treatment, but structures but also in their functional effects. The such benefit was not maintained at 3 months follow- varying extent in slow release and duration of up. Knecht et al.19 also reported non-detectable bioavailability in the brain among these drugs may benefits of D-amphetamine alone on somatosensory contribute to the discrepancies in the use of training in healthy subjects. A subsequent study by ‘amphetamines’ in the laboratory and in the clinic. Martinsson et al.20 designed to test efficacy of drug– The D-amphetamine dose used in the study by Bath physiotherapy pairing in 30 stroke patients with et al. is within the recommended clinical therapeu- severe motor impairments revealed absence of D- tic range of 5–30 mg for other indications (e.g., amphetamine benefits even when the intensity of suppression, increased arousal, elevation of mood, physiotherapy was increased during the first week increased self-confidence and improved concentra- after stroke onset. Hesse et al. also conducted a tion). Whether this dose is optimal for stroke needs randomized, placebo-controlled study involving 24 further investigation. Similarly, while the timing of patients within 6 weeks of stroke onset, with amphetamine injections in these clinical studies severely to moderately activities of daily living varies between 3 and 45 days post-stroke, there is no Barthel Index scores, and subjected them to direct study examining optimal drug initiation. D-amphetamine or placebo treatment using Walker- Finally, cursory descriptions of the physical therapy Batson’s protocol. Results revealed that D-ampheta- not only withholds direct comparisons across mine did not increase motor function or activities of studies, but also limits evaluating the rehabilitation daily living (ADL) compared with the control appropriate for pairing with the pharmacotherapy. group.21 Failure of these last two clinical trials Such discrepant clinical reports parallel the suggests that stroke severity of the patients enrolled preclinical status of D-amphetamine in that while in these studies adversely impacted on the clinical solid laboratory data indicate therapeutic effects outcome. Along this line, the recent clinical trial of amphetamine in stroke,25 equally compelling conducted by the Subacute Therapy with Ampheta- evidence suggests that amphetamine may not be mine and Rehabilitation for Stroke Study Investiga- indicated for stroke treatment.26 As these drugs pose tors also using Walker-Batson’s protocol showed that high risk and deleterious side effects, well-designed stroke patients with a severe motor deficit treated laboratory and clinical studies, with emphasis on with D-amphetamine did not display enhanced the Stroke Therapy Academic Industry Roundtable improvement of motor or functional recovery com- (STAIR) criteria, are warranted to fully evaluate the pared with physiotherapy alone. In contrast, pa- safety and efficacy of D-amphetamine as an adjunc- tients with moderate severity hemiparesis exhibited tive therapy to rehabilitation after stroke. significant limb motor recovery, but limited to the The current status of stroke therapy warrants an upper extremity.22 While these observations suggest urgent need to examine novel drugs that have that stroke patients with mild motor deficits are potential to exert efficacy at several hours or a few more responsive to D-amphetamine effects, another days after the stroke onset. The exact mechanism clinical study proved this hypothesis wrong, in that underlying the therapeutic benefits of D-ampheta- the trial was halted when the interim efficacy mine remains elusive, and likely involves an array analysis of 26 stroke patients with mild arm paresis of complex mechanisms. Emerging laboratory work revealed lack of motor facilitation or motor recovery implicates neuritogenesis and synaptogenesis as with D-amphetamine over placebo at immediate major components of D-amphetamine treatment.27 post-training or long-term periods.23 Combination therapies, involving pharmacological In this issue of the Journal of Human Hyperten- agents, cell transplantation and rehabilitation, sion, the new study Bath et al.24 corroborates recent may be able to augment the outcome of this delay reports that amphetamine has limited therapeutic in post-stroke treatment. effects for improving stroke outcome. Here, the authors report that amphetamine does not improve motor function, but increases blood pressure and References heart rate. Similar to the previous clinical trials, the 1 Bonci A, Bernardi G, Grillner P, Mercuri NB. The major limiting factor in this study is the small -containing : maestro or simple mu- sample size (n ¼ 33) that clearly diminishes con- sician in the orchestra of ? Trends Pharmacol fidence in the data interpretation. Moreover, the Sci 2003; 24: 172–177. conclusions put forward by the authors echo similar 2 Teter CJ, McCabe SE, LaGrange K, Cranford JA, reservations in recent clinical studies about the use Boyd CJ. Illicit use of specific prescription of amphetamines for stroke. among college students: prevalence, motives, and Although the inconclusive data from these clin- routes of administration. Pharmacotherapy. 2006; 26: ical trials can be easily ascribed to the small sample 1501–1510. 3 Homsi J, Walsh D, Nelson KA. Psychostimulants in patient population, additional shortcomings across supportive care. Support Care Cancer 2000; 8: 385–397. the studies are obvious including the drug type, 4 Wagner GJ, Rabkin R. Effects of on dose, timing and physical training content and depression and fatigue in men with HIV: a double- intensity. Amphetamine, D-amphetamine and blind, placebo-controlled trial. J Clin Psychiatry. 2000; methamphetamine differ not only in their chemical 61: 436–440.

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