|
Amphetamine and Benzodiazepines: clash or synergy?
SWIM has been looking around this forum about this combination and has read mixed opinions and views. Some say that this combination is dangerous or should be avoided, some say its the perfect synergy. I started to do some research and came up with my own theory of how this combination works and hopefully I can help some swimmers who request information on this combination.
We know amphetamines exert there rewarding and reinforcing effects by a reuptake inhibition and release of dopamine in the nucleus accumbens as evident by the increased DA concentrations in the nucleus accumbens in DAT-KO mice
Quote:
Behavioral and biochemical studies suggest that dopamine (DA) plays a role in the reinforcing and addictive properties of drugs of abuse. Recently, this hypothesis has been challenged on the basis of the observation that, in mice genetically lacking the plasma membrane dopamine transporter [DAT-knock out (DAT-KO)], cocaine maintained its reinforcing properties of being self-administered and inducing place preference, despite the failure to increase extracellular dopamine in the dorsal striatum. Here we report that, in DAT-KO mice, cocaine and amphetamine increase dialysate dopamine in the medial part of the nucleus accumbens. Moreover, reboxetine, a specific blocker of the noradrenaline transporter, increased DA in the nucleus accumbens of DAT-KO but not of wild-type mice; in contrast, GBR 12909, a specific blocker of the dopamine transporter, increased dialysate dopamine in the nucleus accumbens of wild-type but not of DAT-KO mice. These observations provide an explanation for the persistence of cocaine reinforcement in DAT-KO mice and support the hypothesis of a primary role of nucleus accumbens dopamine in drug reinforcement.
Carboni E, Spielewoy C, Vacca C, Nosten-Bertrand M, Giros B, Di Chiara G.
Department of Toxicology and Consiglio Nazionale
delle Ricerche Center for Neuropharmacology,
University of Cagliari, 09126 Cagliari, Italy,
and
Neurobiology and Psychiatry Faculte de Medicine de Creteil,
94000 Creteil, France
|
Benzodiazepines also exhibit a sort of euphoria that people tend to enjoy but this is not caused by the same mechanism, in fact midazolam led to a decrease of extracelluar DA in the nucleus accumbens. This may lead to a reduction in amphetamine reward and dosage might have to be adjusted accordingly.
Quote:
In vivo microdialysis was used to assess the effects of acute and repeated injections of the benzodiazepine midazolam on extracellular dopamine (DA) concentrations in the nucleus accumbens. Acute administration of midazolam (5 mg/kg, SC) elicited a 22% decrease in extracellular DA in the nucleus accumbens but failed to affect DA concentrations in the striatum. Similarly, six spaced intravenous infusions of midazolam, at a dose that has previously been found to support self-administration (0.05 mg per infusion), produced a 50% decrease in extracellular DA in the nucleus accumbens. In order to assess the effects of subchronic midazolam injections, two groups of rats were given injections of saline or midazolam (5 mg/kg, SC) for 14 days (two injections per day). A subsequent challenge injection of midazolam (5 mg/kg) decreased extracellular DA in the nucleus accumbens by 25% in both groups, indicating that neither tolerance nor sensitization occurred during the repeated drug administration. These experiments indicate (1) that midazolam differentially affects meso-accumbens and nigrostriatal DA neurons, and (2) that the midazolam-induced decrease in extracellular DA in the nucleus accumbens is not affected by repeated drug administration. The data further suggest that the rewarding effects of midazolam are not associated with increased release of DA in the nucleus accumbens.
Department of Psychiatry, University of British Columbia, Vancouver, Canada.
|
Benzodiazepines also have an interesting effect on heart rate and blood pressure.
Quote:
The actions of benzodiazepines are due to the potentiation of the neural inhibition that is mediated by gamma-aminobutyric acid (GABA). Practically all effects of the benzodiazepines result from their actions on the ionotropic GABA(A) receptors in the central nervous system. Benzodiazepines do not activate GABA(A) receptors directly but they require GABA. The main effects of benzodiazepines are sedation, hypnosis, decreased anxiety, anterograde amnesia, centrally mediated muscle relaxation and anti-convulsant activity. In addition to their action on the central nervous system, benzodiazepines have a dose-dependent ventilatory depressant effect and they also cause a modest reduction in arterial blood pressure and an increase in heart rate as a result of a decrease of systemic vascular resistance. The four benzodiazepines, widely used in clinical anaesthesia, are the agonists midazolam, diazepam and lorazepam and the antagonist flumazenil. Midazolam, diazepam and flumazenil are metabolized by cytochrome P450 (CYP) enzymes and by glucuronide conjugation whereas lorazepam directly undergoes glucuronide conjugation. CYP3A4 is important in the biotransformation of both midazolam and diazepam. CYP2C19 is important in the biotransformation of diazepam. Liver and renal dysfunction have only a minor effect on the pharmacokinetics of lorazepam but they slow down the elimination of the other benzodiazepines used in clinical anaesthesia. The duration of action of all benzodiazepines is strongly dependent on the duration of their administration. Based on clinical studies and computer simulations, midazolam has the shortest recovery profile followed by lorazepam and diazepam. Being metabolized by CYP enzymes, midazolam and diazepam have many clinically significant interactions with inhibitors and inducers of CYP3A4 and 2C19. In addition to pharmacokinetic interactions, benzodiazepines have synergistic interactions with other hypnotics and opioids. Midazolam, diazepam and lorazepam are widely used for sedation and to some extent also for induction and maintenance of anaesthesia. Flumazenil is very useful in reversing benzodiazepine-induced sedation as well as to diagnose or treat benzodiazepine overdose.
Olkkola KT, Ahonen J.
Department of Anaesthesiology
|
Benzodiazepines also have been shown to reduce turnover and release of serotonin and norepinphrine which might contribute to their depressant effects.
Quote:
The anxiety-reducing effects of minor tranquilizers in the rat conflict test were mimicked by serotonin antagonists and by p-chlorophenylalanine, an inhibitor of serotonin synthesis; the depressant effects of the minor tranquilizers were mimicked by norepinephrine antagonists. Intraventricular injections of serotonin led to a suppression of behavior, and also antagonized the anxiety-reducing action of benzodiazeprines. Intraventricular injections of norepinephrine led to a release of punished behavior from suppression, and also antagonized the depressant action of benzodiazepines. The anxiety-reducing activity, and the decrease in serotonin turnover induced by benzodiazepines, were maintained over repeated doses, whereas depressant activity, and the decrease induced in norepinephrine turnover, both rapidly underwent tolerance. Tranquilizers may exert their anxiety-reducing effects by a reduction of serotonin activity in a behaviorally suppressive punishment system, and they may exert their depressant effects by a reduction of norepinephrine activity in a behaviorally facilitatory reward system.
Wise, C. David; Berger, Barry D.; Stein, Larry
|
This can lead to a reduction in anxiety, heart rate, and locomotor activity induced by amphetamine.
In conclusion, this combination while appearing to be safe enough, one might need to account for dosage adjustments as benzodiazepines might reduce the rewarding and focusing effects of amphetamine. They also might reduce heart rate and anxiety during amphetamine exposure which might be positive for some. Hope this helps some people out there.
Happy SWIMming 
|
08-02-2009, 18:56
Linear Mode
