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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 11 of 11. This is the beginning of the thread.
Posted by psychobot5000 on August 16, 2007, at 12:51:42
> I was wondering if anyone noticed that coffee was a particular antidote to benzo induced cognative problems?
>
> Coffee apparently contains beta carboline compounds which are antagonists at the benzodiazapine receptors.
>
> LinkadgeSo I started a new thread, because the original question (which I find interesting) is no longer the subject of the original, and I didn't want to intrude.
My first thought, was that any positive effect might not be an immediate one, as cognitive problems from benzos often come out only after a period of weeks or longer. Perhaps coffee, on the contrary, is good in the longer term--such as its purported help in reducing the likelihood of developing alzheimer's (if I remember that right).
My second thought is that, after drinking alcohol on one occasion (which is also an agonist at benzodiazepine receptors, as I understand, and so reduces anxiety), I was surprised to find that a cup of coffee seemed to completely neutralize the booze's anxiolytic effect, in a way that does not happen if I take a cup of tea. I did also feel as though the cognitive slowing, induced by having had alcohol, was reduced significantly--rather to my surprise. Again, this was in contrast to the experience I've had with tea. Of course it's hard to know whether this 'feel' I had was actually the case. And naturally there are other chemicals in coffee as well (larger amounts of caffeine than tea), an other effects from alcohol, to muddy the picture. But reduced anxiolytic relief and (somewhat) reduced cognitive difficulty were my impression.
I would think, though, that the beta-carboline GABA-a antagonist effect is real and clinically significant, based on the anxiety coffee gives me, even in small amounts. It would seem that there ought to be a way to make it theraputically useful. I haven't tried it with benzos.
Posted by Quintal on August 16, 2007, at 13:28:52
In reply to Beta-carbolines and benzos, posted by psychobot5000 on August 16, 2007, at 12:51:42
I think coffee is pretty widely accepted as an alcohol 'antidote' of sorts, tea less so, so there might be something in what you've observed. I took coffee with benzos and noticed an improvement in wakefulness and cognitive functioning etc, and also an increase in anxiety. It's hard to distinguish between the effect of caffeine and beta-carbolines of course, but like you I never noticed this effect with tea particularly, though that could be due to lower levels of caffeine.
I was curious, because if beta-carbolines are benzodiazepine receptor antagonists, then they would likely cause withdrawal symptoms in people dependent on benzodiazepines but I didn't notice any as such, apart from increased anxiety. I was curious if beta-carbolines are antagonists at sub-sets of benzodiazepine receptors and made several requests to see the original study to no avail. A quick search on Wiki reveals that beta-carbolines frequently act as MAOIs, so from that I conclude they must be present in fairly small amounts or heavy coffee drinkers would be suffering hypertensive crises and serotonin syndrome (in heavy coffee drinkers taking SSRIs for example) fairly oft. I've heard of studies showing higher than average MAO inhibition among regular coffee drinkers though. I think some beta-carbolines are RIMAs so that might explain the a lower incidence of adverse interactions, in fact there are no reports of hypertensive crisis or serotonin syndrome resulting from coffee drinking as far as I know, so I assume the beta-carbolines present in coffee are either not MAOIs or are present in such small quantities that they have no clinical effect. It would be interesting to see the original studies.
Q
Posted by linkadge on August 16, 2007, at 14:03:11
In reply to Re: Beta-carbolines and benzos, posted by Quintal on August 16, 2007, at 13:28:52
>It's hard to distinguish between the effect of >caffeine and beta-carbolines of course, but like >you I never noticed this effect with tea >particularly, though that could be due to lower >levels of caffeine.
One could perhaps compare a cup of coffee with a caffenated drink with equivilant caffiene content. I do get anxiety from coffee, but not from caffiene tablets (which often contain more caffiene than a cup of coffee)
>I was curious if beta-carbolines are antagonists >at sub-sets of benzodiazepine receptors and made >several requests to see the original study to no >avail.I had read something from a book called "Drugs and the Brain" by solomon H snyder. He was describing the limited clinical experience with beta carbolines. It was describing the intense anxiety that beta carbolines could produce (not sure about dose) and how the benzo's could act as a direct antidote.
>A quick search on Wiki reveals that beta->carbolines frequently act as MAOIs, so from that >I conclude they must be present in fairly small >amounts or heavy coffee drinkers would be >suffering hypertensive crises and serotonin >syndrome (in heavy coffee drinkers taking SSRIs >for example) fairly oft.
I read a study saying that regular coffee drinkers had something like %50 reduction in MAO-A and B. The propensity of a MAOI to produce hypertensive crisis depends on many factors, but you are right that you might expect serotonin syndrome.
The beta carbolines remind me of isatin. Have you read about isatin? Its some natural chemical that the body releases in responce to stress. It is a MAOI as well as a benzo antagonist.
>I've heard of studies showing higher than >average MAO inhibition among regular coffee >drinkers though. I think some beta-carbolines >are RIMAs so that might explain the a lower >incidence of adverse interactions, in fact there >are no reports of hypertensive crisis or >serotonin syndrome resulting from coffee >drinking as far as I know, so I assume the beta->carbolines present in coffee are either not >MAOIs or are present in such small quantities that they have no clinical effect.The beta carbolines are REMAs with a short half life. I think there are some studies to suggest that regular coffee intake does produce measurable modulation of MAO. I will see if I can find any.
Its interesting because there is some evidence to suggest that combining certain agonists with antagonists can prevent or reduce tollerance.
Some people can tollerate anxiety better at different times in the day. I don't mind anxiety in the morning, but find it very disruptive in the evening. I wonder if one could modulate the bdz system by taking a benzo at night and a good swig of coffee in the morning? There is some evidence too, that coffee can reduce the cognative problems associated with heavy alcohol intake, maybe the same extends to coffee with benzos?
Linkadge
Posted by psychobot5000 on August 16, 2007, at 15:20:37
In reply to Re: Beta-carbolines and benzos, posted by linkadge on August 16, 2007, at 14:03:11
>
> One could perhaps compare a cup of coffee with a caffenated drink with equivilant caffiene content. I do get anxiety from coffee, but not from caffiene tablets (which often contain more caffiene than a cup of coffee)
>
I think that's a more useful comparison, because tea also contains chemicals that directly reduce anxiety (theanine, for example), and thus is not a neutral caffeine source.>
> I read a study saying that regular coffee drinkers had something like %50 reduction in MAO-A and B. The propensity of a MAOI to produce hypertensive crisis depends on many factors, but you are right that you might expect serotonin syndrome.
I believe I've read that the beta-carbolines in tobacco smoke inhibited MAO (transiently) at around 40% for MAO-A, and 30% for MAO-B--I don't know what dose it was, but I think the central nervous system was where they were measuring. Those numbers suggst to me that the hypertensive or serotonin-syndrome risks when added to MAOis might be lower simply because the inhibition isn't very powerful. Docs tend to recommend a moderate intake of coffee anyway, cuz of the caffeine and such.Also, re: coffee as an antidote for alcohol--people have been using it that way for a long time, certainly, but I think the beta-carboline research is interesting because health teachers and drug warriors and the like have been insisting, for decades, that coffee doesn't help you sober up in any way.
I wonder if, by drinking coffee with alcohol, you might get the mood improvement alcohol can offer, without some of the slowness of mind and judgement. That might be useful, if not done too often or heavily, to some depressives. You'd still probably have to be careful about driving, but it could still help.
Psychbot5000
Posted by cactus on August 16, 2007, at 20:14:09
In reply to Re: Beta-carbolines and benzos, posted by psychobot5000 on August 16, 2007, at 15:20:37
Basically, if I'm feeling a little lethargic from my rivotril(clonazepam) I'll have a coffee or 2 and it goes away, with no anxiety involved
Posted by Quintal on August 17, 2007, at 21:28:34
In reply to Re: Beta-carbolines and benzos, posted by linkadge on August 16, 2007, at 14:03:11
>I had read something from a book called "Drugs and the Brain" by solomon H snyder. He was describing the limited clinical experience with beta carbolines. It was describing the intense anxiety that beta carbolines could produce (not sure about dose) and how the benzo's could act as a direct antidote.
Did he say that beta-carbolines are benzodiazepine receptor antagonists, or that benzos would be useful for treating beta-carboline induced anxiety?
>The beta carbolines remind me of isatin. Have you read about isatin?
No, I hadn't heard of it, but your post back in January came up when I Googled it. Do beta-carbolines actually reduce GABA? I'll look and see what I can find.
>Its interesting because there is some evidence to suggest that combining certain agonists with antagonists can prevent or reduce tollerance.
Here I found a study which says beta-carbolines are benzodiazepine inverse agonists:
__________________________________________________1: ScientificWorldJournal. 2007 Feb 19;7:204-23.Click here to read Links
From the behavioral pharmacology of beta-carbolines to seizures, anxiety, and memory.
Venault P, Chapouthier G.Vulnérabilité, Adaptation et Psychopathologie, CNRS UMR 7593, Hôpital Pitié-Salpêtrière, 91 Bd de l'Hôpital, 75634 Paris cedex 13, France. venault@ext.jussieu.fr
A number of beta-carbolines are inverse agonists of the GABA-A receptor complex, acting on the benzodiazepine site. They show convulsive properties when administered at high doses, anxiogenic properties at moderate doses, and learning-enhancing effects at low doses. These data suggest a possible physiological relationship, through the GABA-A receptor channel, between memory processes, anxiety, and ultimately, in pathological states, epileptic seizures. This relationship seems to be confirmed partially by experiments on mouse strains selected for their resistance (BR) and sensitivity (BS) to a single convulsive dose of a beta-carboline. These two strains also show differences in anxiety and learning abilities. However, some opposite results found while observing the behavior of the two strains suggest that in addition to pharmacologically induced anxiety, there is spontaneous anxiety, no doubt involving other brain mechanisms.
PMID: 17334612 [PubMed - indexed for MEDLINE]
__________________________________________________So they're not a direct antidote as such, rather beta-carbolines would compete with benzodiazepines at the benzodiazepine receptors. But still, they seem a useful way to temporarily reverse benzo-induced cognitive impairment and memory problems. It would be interesting to see what effects they might have on tolerance by modulating the sensitivity of the benzodiazepine receptors. I'm wondering if beta-carbolines might be helpful or harmful in that situation where the benzodiazepine receptors are locked in the inverse agonist configuration?
__________________________________________________Although the underlying mechanisms of benzodiazepine dependence are still not entirely understood, research in animals points to the clinical potential for the benzodiazepine antagonist flumazenil (Ro 15-1788) to reverse benzodiazepine dependence and tolerance and prevent withdrawal (Whitwam, 1988). Administration of flumazenil reverses tolerance and dependence to benzodiazepines (Gonsalves and Gallager, 1985) but precipitates recognizable withdrawal symptoms . However, if given during chronic treatment flumazenil can, by similarly reversing tolerance, prevent subsequent withdrawal syndromes in primates (Gallager, Heninger and Heninger, 1986) and in rats (Baldwin, Hitchcott and File, 1990). One explanation for this is the antagonism and depletion of an endogenous benzodiazepine receptor ligand with inverse agonist and thus anxiogenic activity by the antagonist flumazenil (Baldwin, Hitchcott and File, 1990). However, levels of the proposed 'anxiety peptide' ligand associated with diazepam binding inhibitor (DBI) were not found to be increased by the administration of diazepam in rats (Ball et al., 1987). An alternative explanation is that chronic agonist use causes a persistent conformational change and thus a shift in benzodiazepine receptor efficacy in the direction of inverse agonist function (Little, Nutt and Taylor, 1987) and that flumazenil resets the receptor's sensitivity (Nutt and Costello, 1988). In binding to the benzodiazepine receptor flumazenil may alter the coupling of the elements of the GABA/benzodiazepine macromolecular complex modified by benzodiazepine binding, thus restoring the GABA recognition site to its pre-drug affinity (Gonsalves and Gallager, 1985).
http://www.bcnc.org.uk/flumazenil.html
__________________________________________________Maybe a steady flow of exogenous benzodiazepine inverse agonist might help suppress endogenous overproduction and maintain balance? The problem with this though, is that a constant supply of inverse agonist would cause a constant state of anxiety, rendering the benzodiazepine ineffective. I mean, if you need to take an inverse agonist all day to counteract the cognitive impairment, would it not make more sense to take a short-acting benzo in the evening or at night?
Q
Posted by Quintal on August 17, 2007, at 21:34:08
In reply to Re: Beta-carbolines and benzos, posted by psychobot5000 on August 16, 2007, at 15:20:37
>Also, re: coffee as an antidote for alcohol--people have been using it that way for a long time, certainly, but I think the beta-carboline research is interesting because health teachers and drug warriors and the like have been insisting, for decades, that coffee doesn't help you sober up in any way.
Well the next time you talk to one of them you can just show them this study :-)
____________________________________________________1: Life Sci. 1988;42(18):1765-72.Links
The benzodiazepine receptor inverse agonists beta-CCM and RO 15-3505 both reverse the anxiolytic effects of ethanol in mice.
Belzung C, Misslin R, Vogel E.Laboratoire de Psychophysiologie, Strasbourg.
The antagonistic effects of the benzodiazepine receptor inverse agonist beta-CCM (1 mg/kg) and of the partial inverse agonist RO 15-3505 (3 mg/kg) on the anxiolytic properties of ethanol (1 g/kg) in mice confronted with a light/dark choice procedure and with the staircase test were investigated. Both drugs reversed the effects of ethanol on some of the behavioral parameters, but beta-CCM alone elicited anxiogenic intrinsic effects. RO 15-3505 induced seizures in mice treated with a subconvulsant dose of pentylenetetrazole, the most efficient doses being 3 and 6 mg/kg. These data indicate that beta-CCM and RO 15-3505 can reverse some of the anxiolytic effects of ethanol, acting probably to oppose GABA function via the benzodiazepine receptor.
PMID: 2896286 [PubMed - indexed for MEDLINE]
__________________________________________________Q
Posted by linkadge on August 17, 2007, at 22:32:24
In reply to Re: Beta-carbolines and benzos » linkadge, posted by Quintal on August 17, 2007, at 21:28:34
Yeah, I have seen that too, that the beta carbolines act as inverse agonists. I have seen reports of them acting as both antagonists in some paradigms and invere agonists.
Although, I will admit I am not entirely sure how an inverse agonist behaves, I believe it can functionally antagonize the receptor at certain concentrations?
Linkadge
Posted by Quintal on August 17, 2007, at 22:54:37
In reply to Re: Beta-carbolines and benzos, posted by linkadge on August 17, 2007, at 22:32:24
Well benzodiazepine antagonists apparently have no clinical effects on healthy persons, whereas inverse agonists have the opposite effect of an agonist i.e. GABA-A agonist will mimic the effect of GABA, whereas a GABA-A inverse agonist will not simply oppose the effect of GABA, but produce the opposite effects such as anxiety, convulsions etc. Antagonists neutralize the effects of both agonists and antagonists. So, for example, flumazenil has no effect on people not dependent on, or who have no tolerance to benzodiazepines. So tolerance is more complicated than simple receptor downregulation because the brain may also upregulate the production of endogenous GABA-A inverse agonists to counteract the effect.
Wiki explains it better:
__________________________________________________Receptor agonists, antagonists and inverse agonists bind to the same receptor types. The pharmacological effect of an inverse agonist is measured as the negative value of the agonist primarily due to the historical findings of the already known agonist. Therefore, if the agonist has a positive value and the inverse agonist has a negative value, the antagonist for the receptor takes both the agonist and inverse agonist back to a neutral state.
http://en.wikipedia.org/wiki/Inverse_agonist
__________________________________________________Q
Posted by linkadge on August 17, 2007, at 23:02:25
In reply to Re: Beta-carbolines and benzos » linkadge, posted by Quintal on August 17, 2007, at 22:54:37
So an inverse agonist would still effectivly work to reverse the effect of an agonist (?)
Linkadge
Posted by Quintal on August 17, 2007, at 23:14:38
In reply to Re: Beta-carbolines and benzos, posted by linkadge on August 17, 2007, at 23:02:25
I think it would compete with the agonist at the benzodiazepine receptors, so yes an inverse agonist would, functionally at least, counteract some of the effects of a GABA-A agonist depending on the relative concentrations.
Q
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