Amphetamine increases blood pressure and heart rate but has no effect on motor recovery or cerebral haemodynamics in ischaemic stroke: a randomized controlled trial (ISRCTN 36285333)

Amphetamine enhances recovery after experimental ischaemia and has shown promise in small clinical trials when combined with motor or sensory stimulation. Amphetamine, a sympathomimetic, might have haemodynamic effects in stroke patients, although limited data have been published. Subjects were recruited 3-30 days post ischaemic stroke into a phase II randomised (1:1), double blind, placebo-controlled trial. Subjects received dexamphetamine (5mg initially, then 10mg for 10 subsequent doses with 3 or 4 day separations) or placebo in addition to inpatient physiotherapy. Recovery was assessed by motor scales (Fugl-Meyer, FM), and functional scales (Barthel index, BI and modified Rankin score, mRS). Peripheral blood pressure (BP), central haemodynamics and middle cerebral artery blood flow velocity were assessed before, and 90 minutes after, the first 2 doses. 33 subjects were recruited, age 33-88 (mean 71) years, males 52%, 4-30 (median 15) days post stroke to inclusion. 16 patients were randomised to placebo and 17 amphetamine. Amphetamine did not improve motor function at 90 days; mean (standard deviation) FM 37.6 (27.6) vs. control 35.2 (27.8) (p=0.81). Functional outcome (BI, mRS) did not differ between treatment groups. Peripheral and central systolic BP, and heart rate, were 11.2 mmHg (p=0.03), 9.5 mmHg (p=0.04) and 7 beats/minute (p=0.02) higher respectively with amphetamine, compared with control. A non-significant reduction in myocardial perfusion (Buckberg Index) was seen with amphetamine. Other cardiac and cerebral haemodynamics were unaffected. Amphetamine did not improve motor impairment or function after ischaemic stroke but did significantly increase BP and heart rate without altering cerebral haemodynamics.

Speeding stroke recovery? A systematic review of amphetamine after stroke

Introduction: The use of drugs to enhance recovery (“rehabilitation pharmacology”) has been assessed. Amphetamine can improve outcome in experimental models of stroke, and several small clinical trials have assessed its use in stroke. Methods: Electronic searches were performed to identify randomised controlled trials of amphetamine in stroke (ischaemic or haemorrhagic). Outcomes included functional outcome (assessed as combined death or disability/dependency), safety (death) and haemodynamic measures. Data were analysed as dichotomous or continuous outcomes, using odds ratios (OR), weighted or standardised mean difference, (WMD or SMD) using random-effects models with 95% confidence intervals (95% CI); statistical heterogeneity was assessed. Results: Eleven completed trials (n=329) were identified. Treatment with amphetamine was associated with non-significant trends to increased death (OR 2.78 (95% CI, 0.75– 10.23), n=329, 11 trials) and improved motor scores (WMD 3.28 (95% CI −0.48–7.04) n=257, 9 trials) but had no effect on the combined outcome of death and dependency (OR 1.15 (95% CI 0.65–2.06, n=206, 5 trials). Amphetamine increased systolic blood pressure (WMD 9.3 mmHg, 95% CI 3.3–15.3, n=106, 3 trials) and heart rate (WMD 7.6 beats per minute (bpm), 95% CI 1.8–13.4, n=106, 3 trials). Despite variations in treatment regimes, outcomes and follow-up duration there was no evidence of significant heterogeneity or publication bias. Conclusion: No evidence exists at present to support the use of amphetamine after stroke. Despite a trend to improved motor function, doubts remain over

The Role of Cannabinoids in the Neurobiology of Sensory Gating: A firing rate model study

Gating of sensory (e.g. auditory) information has been demonstrated as a reduction in the auditory-evoked potential responses recorded in the brain of both normal animals and human subjects. Auditory gating is perturbed in schizophrenic patients and pharmacologically by drugs such as amphetamine, phencyclidine or ketamine, which precipitate schizophrenic-like symptoms in normal subjects. The neurobiological basis underlying this sensory gating can be investigated using local field potential recordings from single electrodes. In this paper we use such technology to investigate the role of cannabinoids in sensory gating. Cannabinoids represent a fundamentally new class of retrograde messengers which are released postsynaptically and bind to presynaptic receptors. In this way they allow fine-tuning of neuronal response, and in particular can lead to so-called depolarization-induced suppression of inhibition (DSI). Our experimental results show that application of the exogenous cannabinoid WIN55, 212-2 can abolish sensory gating as measured by the amplitude of local field responses in rat hippocampal region CA3. Importantly we develop a simple firing rate population model of CA3 and show that gating is heavily dependent upon the presence of a slow inhibitory (GABAB) pathway. Moreover, a simple phenomenological model of cannabinoid dynamics underlying DSI is shown to abolish gating in a manner consistent with our experimental findings.