View Full Version : Chlormethiazole effects methamphetamine


theta
02-13-08, 03:08 AM
1: Eur J Pharmacol. 2004 Jun 28;494(2-3):183-9.
Links
Chlormethiazole potentiates the discriminative stimulus effects of methamphetamine in rats.
Gasior M, Witkin JM, Goldberg SR, Munzar P.

Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, MSC: 1408, Building 10, Room 5N250, Bethesda, MD 20892-1408, USA. gasiorm@ninds.nih.gov

Chlormethiazole is a positive modulator of gamma-aminobutyric acid (GABA)(A) receptors used in the treatment of alcohol withdrawal seizures. It recently has been reported to attenuate seizures engendered by acute and repeated exposure to cocaine in mice and neurotoxic effects of methamphetamine in rats. The aim of the present study was to determine whether chlormethiazole could also attenuate the discriminative stimulus effects of methamphetamine, a behavior predictive of the subjective effects of methamphetamine in humans. In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine [intraperitoneally (i.p.)] from saline under a fixed-ratio schedule of food delivery, the ability of chlormethiazole (i.p.) to (1) substitute for methamphetamine, (2) antagonize effects of methamphetamine and to (3) shift the methamphetamine dose-effect function was investigated. Chlormethiazole (18 and 30 mg/kg, i.p.) partially substituted for the discriminative stimulus effects of methamphetamine when administered alone (maximum group average, 60% responses on the methamphetamine-appropriate lever). Chlormethiazole did not attenuate effects of methamphetamine when coadministered with the training dose of methamphetamine. Instead, chlormethiazole potentiated the discriminative stimulus effects of methamphetamine as demonstrated by a significant (about 2.5-fold) leftward and upward shift in the methamphetamine dose-effect function in the presence of chlormethiazole (10 mg/kg). In conclusion, the present findings suggest that there is a behavioral interaction between methamphetamine and chlormethiazole. The profile of this interaction is qualitatively different from that of methamphetamine and classical GABAergic drugs (i.e., benzodiazepines and barbiturates), suggesting the involvement of non-GABAergic mechanisms in the effects produced by chlormethiazole.

PMID: 15212973 [PubMed - indexed for MEDLINE]

This study said chlormethethiazole was neuroprotective.
complete study:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1908047
Abstract:

1: Br J Pharmacol. 1993 Mar;108(3):590-6.
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Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine.
Baldwin HA, Colado MI, Murray TK, De Souza RJ, Green AR.

Astra Neuroscience Research Unit, London.

1. Administration to rats of methamphetamine (15 mg kg-1, i.p.) every 2 h to a total of 4 doses resulted in a neurotoxic loss of striatal dopamine of 36% and of 5-hydroxytryptamine (5-HT) in the cortex (43%) and hippocampus (47%) 3 days later. 2. Administration of chlormethiazole (50 mg kg-1, i.p.) 15 min before each dose of methamphetamine provided complete protection against the neurotoxic loss of monoamines while administration of dizocilpine (1 mg kg-1, i.p.) using the same dose schedule provided substantial protection. 3. Measurement of dopamine release in the striatum by in vivo microdialysis revealed that methamphetamine produced an approximate 7000% increase in dopamine release after the first injection. The enhanced release response was somewhat diminished after the third injection but still around 4000% above baseline. Dizocilpine (1 mg kg-1, i.p.) did not alter this response but chlormethiazole (50 mg kg-1, i.p.) attenuated the methamphetamine-induced release by approximately 40%. 4. Dizocilpine pretreatment did not influence the decrease in the dialysate concentration of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) produced by administration of methamphetamine while chlormethiazole pretreatment decreased the dialysate concentration of these metabolites still further. 5. The concentration of dopamine in the dialysate during basal conditions increased modestly during the course of the experiment. This increase did not occur in chlormethiazole-treated rats. HVA concentrations were unaltered by chlormethiazole administration. 6. Chlormethiazole (100-1000 microM) did not alter methamphetamine (100 microM) or K+ (35 mM)-evoked release of endogenous dopamine from striatal prisms in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 8467354 [PubMed - indexed for MEDLINE]

I think this says it was not neuroprotective.

1: Pharmacol Biochem Behav. 1997 Apr;56(4):737-45.
Links
Is chlormethiazole neuroprotective in experimental global cerebral ischemia? A microdialysis and behavioral study.
Thaminy S, Reymann JM, Heresbach N, Allain H, Lechat P, Bentué-Ferrer D.

Laboratoire de Pharmacologie, Faculté de Médecine, Rennes, France.

Chlormethiazole, an anticonvulsive agent, has been shown to have a possible neuroprotective effect against cerebral ischemia. In addition, chlormethiazole inhibits methamphetamine-induced release of dopamine, protecting against this neurotransmitter's neurotoxicity. The aim of this work was to ascertain whether, in experimental cerebral ischemia, chlormethiazole administration attenuated the ischemia-induced rise of the extracellular concentration of aminergic neurotransmitters and whether it reduces ischemia-induced deficits in memory and learning. Histology for assessment of ischemic damage was a so included. The four-vessel occlusion rat model was used to induce global cerebral ischemia. Aminergic neurotransmitters and their metabolites in the striatal extracellular fluid obtained by microdialysis were assayed by high-performance liquid chromatography-electrochemical detection. The drug was administered either IP (50 mg/kg-1) or directly through the dialysis probe (30 microM) 80 min before ischemia. For the behavioral test and histology, the drug was given IP (100 mg/kg-1) 1 h postischemia. The results obtained did not demonstrate any statistically significant evidence that chlormethiazole has an effect on the ischemia-induced rise in extracellular dopamine and serotonin levels. There was also no variation in metabolite levels. Behavioral measures (learning, recall) were not changed appreciably by the treatment. We observed no significant cell protection in the hippocampus (CA1, CA1), striatum, and entorhinal cortex in animals treated with chlormethiazole. We conclude that, under our experimental conditions, chlormethiazole has little or no effect on the neurochemical, neurobehavioral, and histological consequences of global cerebral ischemia.

PMID: 9130301 [PubMed - indexed for MEDLINE]

http://en.wikipedia.org/wiki/Clomethiazole

Wikipedia says Clomethiazole is available in 192mg capsules. The dose used in the first study was 10-30 mg/kg I.P.. Which assuming 100% oral bioavailability would put it around 3 mg/kg for most people.

http://www.behavenet.com/capsules/treatments/drugs/chlormethiazole.htm

Thats say a 300mg capsules available .

Hypothesis:
Assuming a person has anxiety, insomnia and ADHD a lower dose of
methamphetamine(perhaps other stimulants) to and Clomethiazole at
night might be useful.

TygerSan
02-15-08, 12:34 PM
Perhaps, if the chlormethiazole is taken at night to counteract the effects of the stimulants. Chlormethiazole decreases the methamphetamine-induced increases in dopamine release in the striatum, indicating that it acts a bit like an antagonist for the methamphetamine, so you'd have to be careful with the timing of doses.

FYI, modafinil (aka Alertec or Provigil) has been shown to be neuroprotective as well, and is a 2nd line treatment for ADHD.

Modafinil prevents glutamate cytotoxicity in cultured cortical neurons.

Antonelli T (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Antonelli%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstractPlusDrugs1), Ferraro L (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ferraro%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstractPlusDrugs1), Hillion J (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hillion%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstractPlusDrugs1), Tomasini MC (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tomasini%20MC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstractPlusDrugs1), Rambert FA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Rambert%20FA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstractPlusDrugs1), Fuxe K (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fuxe%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstractPlusDrugs1).
Department of Experimental and Clinical Medicine, University of Ferrara, Italy.
The ability of modafinil (Modiodal) to protect cortical neurons from glutamate-induced degeneration was evaluated by measuring electrically evoked [3H]GABA release and [3H]GABA uptake in primary cerebral cortical cultures. In normal cells, electrical stimulation (10 Hz, 2 min) increased [3H]GABA release (FR-NER St1 = 0.77+/-0.14; St2/St1 ratio = 0.94+/-0.02). The exposure of sister cells to glutamate, reduced electrically evoked [3H]GABA release (FR-NER St1 = 0.40+/-0.05; St2/St1 ratio = 0.60+/-0.08). Modafinil (0.3-1 microM) prevented the glutamate-induced reduction of the St2/St1 ratio (0.85+/-0.11; 0.88+/-0.05, respectively). A similar protective effect was observed for [3H]GABA uptake. These findings suggest that modafinil may be neuroprotective in that it attenuates glutamate-induced excitotoxicity in corticalAntiparkinsonian and neuroprotective effects of modafinil in the mptp-treated common marmoset.

Jenner P (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jenner%20P%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstractPlusDrugs1), Zeng BY (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Zeng%20BY%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstractPlusDrugs1), Smith LA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Smith%20LA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstractPlusDrugs1), Pearce RK (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Pearce%20RK%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstractPlusDrugs1), Tel B (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tel%20B%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstractPlusDrugs1), Chancharme L (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Chancharme%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstractPlusDrugs1), Moachon G (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Moachon%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstractPlusDrugs1).
Neurodegenerative Disease Research Centre, Division of Pharmacology and Therapeutics, Guy's, King's and St Thomas' School of Biomedical Sciences, King's College, London, UK. div.pharm@kcl.ac.uk
The psychostimulant drug, modafinil, protects rodents against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, striatal ischemia and partial transection of the nigro-striatal pathway. We now report on the ability of modafinil to reverse motor disability in MPTP-treated common marmosets and to prevent MPTP-induced nigral cell death in this species. In the initial experiments, adult common marmosets were treated with MPTP to produce stable motor deficits. The subsequent administration of modafinil (10, 30 or 100 mg/kg/day, p.o.) produced a dose-dependent reversal of motor disability. In a subsequent experiment, normal common marmosets were concurrently treated with 10, 30 or 100 mg/kg of modafinil once daily by gavage during acute MPTP administration (daily for 5 days), continuing for 2 weeks after the last dose of MPTP. Modafinil dose-dependently prevented the decline in motor activity normally produced by MPTP treatment. MPTP treatment caused a 76% loss of nigral tyrosine-hydroxylase-immunoreactive cells in placebo-treated animals, and this was dose-dependently prevented by modafinil. At the highest dose (100 mg/kg/day) of modafinil, there was no significant loss of tyrosine-hydroxylase-immunoreactive cells in the substantia nigra compared with normal animals. MPTP treatment also reduced striatal dopamine uptake sites by 95%, as measured by specific [3H]-mazindol binding, compared with normal controls. Modafinil treatment dose-dependently reduced the loss of specific [3H]-mazindol binding. Behavioural and morphological evidence in the present study indicate a potential antiparkinsonian and neuroprotective role for modafinil, which may form a new pharmacological approach to the treatment of Parkinson's disease.

theta
02-17-08, 04:53 AM
Perhaps, if the chlormethiazole is taken at night to counteract the effects of the stimulants. Chlormethiazole decreases the methamphetamine-induced increases in dopamine release in the striatum, indicating that it acts a bit like an antagonist for the methamphetamine, so you'd have to be careful with the timing of doses.



Hmm my interpretation was chlormethiazole has some synergistic effect with
methamphetamine increasing the perceived stimulation from methamphetamine.
Meaning while chlormethiazole may reduce dopamine release (by 40% mentioned in one abstract) it still has some unknown mechanism(s) to boost
stimulation.