I've found sulbutiamine to be an interesting compound because it is often reported to simply "increase B1 in the brain" or something like that, and yet its effects are not at all subtle in my experience. Also, it seems to increase D1 receptor density in the PFC, and yet there are many accounts of withdrawal accessible by a quick google search.
So I looked into it. I'll provide some basic conclusions from reviewing the literature on Pubmed and what I've concluded. It would be great if you could chime in since this drug is quite confusing (but also interesting, of course).
An abstract from probably the most interesting paper of sulbutiamine pharmacology, "Evidence for a modulatory effect of sulbutiamine on glutamatergic and dopaminergic cortical transmissions in the rat brain":
Chronic treatment of rats by sulbutiamine induced no change in density of N-methyl-d-aspartate (NMDA) and (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA] receptors in the cingular cortex, but a significant decrease of the kainate binding sites, as measured by quantitative autoradiography. In the same treated animals, an increase of D1 dopaminergic (DA) binding sites was measured both in the prefrontal and the cingular cortex, while no modification of the D2 binding sites was detected. Furthermore, an acute sulbutiamine administration induced a decrease of kainate binding sites but no change of the density of D1 and D2 DA receptors. Acute sulbutiamine injection led to a decrease of the DA levels in the prefrontal cortex and 3,4-dihydroxyphenylacetic acid levels in both the cingular and the prefrontal cortex. These observations are discussed in terms of a modulatory effect of sulbutiamine on both dopaminergic and glutamatergic cortical transmissions. (from
http://www.sciencedirect.com/science/article/pii/S0304394000014208 )
More from the same paper:
The decreased levels of DOPAC suggest a reduced release of DA in the prefrontal cortex. The increased density of D1 DA receptors 2 h following a chronic treatment (Fig. 2), may result from this chronic modification and its induced compensatory mechanisms. These mechanisms disappear with the interruption of the sulbutiamine treatment, no more modification of D1 binding sites being observed five days later (Fig. 2). A single injection of sulbutiamine should not be sufficient to change the D1 receptor density (Fig. 3). These observations suggest that changes of receptor sensitivity take place following a chronic change in the cortical dopaminergic transmission induced by sulbutiamine. Thus, the changes in density of kainate receptor in the cortex lead to suggest that sulbutiamine and/or its metabolites may modulate the cortical glutamatergic transmission. In fact, the rapid decrease observed immediately following a single injection suggests a direct effect on the cortical glutamatergic transmission, for instance a modulation of the intra-synaptic glutamate concentration. Cellular mechanisms responsible for the effects of sulbutiamine are unknown. Thiamine triphosphate, a derivative significantly enhanced in rat brain following an injection of sulbutiamine, could have modulatory effect on neuronal membrane permeability [2] and [3]. Such a modulation induces ionic changes, and further modulate the binding on kainate receptors. Changes on glutamatergic transmission could be at the origin of the modulation of dopaminergic cortical transmission. Indeed, numerous behavioural, anatomical and electrophysiological studies report the modulation of dopaminergic cortical transmission by glutamate, notably through kainate receptors [4], [8], [10] and [12]. On the contrary, chronic blockade of dopaminergic transmission by antipsychotic drugs does not change the density of cortical kainate binding sites, even though the expression of their mRNA is affected [6] and [13]. In the nucleus accumbens kainate receptors are down regulated without any significant change in dopaminergic transmission. The interactions between dopaminergic and glutamatergic transmissions within the prefrontal cortex could play a pivotal role in the therapeutic action of sulbutiamine. Those results strongly support recent findings that demonstrate improvement in behavioural, cognitive, attentional and functional disorders in schizophrenic, alcoholic and depressed patients [5], [7] and [11]. Other experiments, including release and/or uptake studies, have to be conducted in order to further investigate the respective role of the cortical glutamatergic and dopaminergic cortical transmissions in the effect of sulbutiamine.
So from this first paper we have -
Modulation / "direct effect" on glutmate -?-> Decrease in DA --> Increase in D1 receptors
I can't tell whether the glutamatergic modulation is causing the drop in DA or if it's independent. But it seems since the effects on DA are more based on chronic usage and the kainate changes are virtually immediate that the glutamatergic effect may be causing the dopaminergic effects. And then there's the fact that AMPA and NMDA are not downregulated.
It seems to me from this mechanism that excitotoxicity is a concern.
Another abstract:
Thiamine deficiency in both man and animals is known to produce memory dysfunction and cognitive disorders which have been related to an impairment of cholinergic activity. The present experiment was aimed at testing whether, inversely, chronic administration of large doses of sulbutiamine would have a facilitative effect on memory and would induce changes in central cholinergic activity. Accordingly mice received 300 mg/kg of sulbutiamine daily for 10 days. They were then submitted to an appetitive operant level press conditioning test. When compared to control subjects, sulbutiamine treated mice learned the task at the same rate in a single session but showed greatly improved performance when tested 24 hr after partial acquisition of the same task. Parallel neurochemical investigations showed that the treatment induced a slight (+ 10%) but significant increase in hippocampal sodium-dependent high affinity choline uptake. The present findings and previous results suggest that sulbutiamine improves memory formation and that this behavioral effect could be mediated by an increase in hippocampal cholinergic activity.
So sulbutiamine also increases choline uptake (ie increases ACh).
And one last abstract:
Cortical electroencephalographic (EEG) activities and nycthemeral states of vigilance organization were studied in 6 adult rhesus monkeys during subchronic administration (10 days) of Sulbutiamin, a synthesized derivative of thiamine (300 mg/kg/day). Sulbutiamin induced the following modifications: (1) In the EEG activities: increase in occurrence of fast rhythms (over 28 c/sec) during waking and also during slow sleep (SS) in which their amplitude doubled. SS spindles increased in number and amplitude. (2) In vigilance organization: waking was enhanced all along the 24 h recording and SS was reorganized (particularly at night), mostly light sleep: large decrease in stage 2 duration, increase in stage 1. REM sleep duration remained stable. These changes, occurring at around day 5 of the treatment, were more pronounced on day 10 and disappeared 2-5 days after withdrawal. This study demonstrated the clear action of Sulbutiamin upon the mechanisms regulating waking and light sleep.
