relvinnian
06-08-05, 02:54 PM
This is a rant on people's conception of drug mechanisms, and how they percieve it affects them personally. This is long, and below is a condensed summary.
I've read on here in several places people saying things like: "Dexedrine is more norepinephrine than dopamine, which is why it's more...(insert here)"
The fact is these medicines have some commonalities, but they are totally different.
Dexedrine/Adderall (Dextroamphetamine) are dual acting catecholaminergic medications. They increase the release and block the re-uptake of norepinephrine and dopamine, and also have a mild serotonin effect. Studies show that at doses that are considered therapeutically equivelant, dextroamphetamine is MUCH more potent than methylphenidate (ritalin) at increasing extracellular dopamine, and slightly more potent at increasing norepinephrine.
Methylphenidate on the other hand has no releasing mechanism, and works via re-uptake of norepinephrine and dopamine. Additionally, methylphenidate is a primarily noradrenergic medication at therapeutic doses, and in a healthy "normal" it requires approximately a 40mg single oral dose to block at least %70 of the dopamine re-uptake transporter. Thus, methylphenidate is a strong noradrenergic enhancer and a mild dopaminergic enhancer.
Methylphenidate has no affinity for the serotonin uptake pump, and at supra-therapeutic doses has been proven not to effect extracellular serotonin, or influence serotonergic pathways. This is in contrast to the amphetamines, which have mild effects in this respect.
But there's more: Describing extracellular concentrations of neurotransmitters affected by a given medication only tells part of how it actually does it's magic. The brain is composed of very elaborate systems of interaction and modulation. These pathways of modulation interact on the micro-levels of DNA/RNA, and on macro-levels activating and de-activating brain structures all over. There are too many little structural nuances to give particular meaning to a given neurotransmitter based mechanism, but these generalizations can be quite good at giving a broad meaning, not a specific one.
For example, the medication Strattera is considered a noradrenergic-specific drug. And yet, strattera increases dopamine in the prefrontal cortex to the same amount it does norepinephrine. So is strattera now a dopaminergic/noradrenergic medication? Yes and no. It selectively blocks the re-uptake of norepinephrine, so it's a NRI, but since the noradrenergic systems interact and extensively modulate the dopaminergic systems, it definately has dopaminergic effects. The reason strattera increases dopamine in the PFC is because the PFC does not have a dopamine transporter, and dopamine binds readily to the norepinephrine transporter (which strattera blocks, of course). However, in the rest of the dopamine-rich regions of the brain there are active dopamine transporters, and so dopamine, having a higher affinity for the dopamine transporter than the norepinphrine transporter, selectively binds to it's main cleanup molecule.
This could go on forever. Norepinephrine can bind and activate dopamine receptors, and visa versa. There are many different varieties or receptors that a particular transmitter will bind to that have seemingly opposing effects, and they set off selective and non-selective reactions throughout the brain, from whole systems, to peptides, to the level of RNA. The brain has all kinds of little quirks like this.
Finally for the most important point. As a generalization, the medications are classified based on mechanism, and mechanism determines efficacy. But keep in mind not to spend too much time dissecting mechanism and trying to extrapolate to your own experience. The main thing that determine's efficacy, and I'm going to bold this: The drug mechanism, it's ability to properly absorb and distribute to relevant areas (pharmacokinetics), in combination with YOUR unique physiology. If, because of your physiology, your brain does not release dopamine well at all, then the mild DAT blocking of ritalin is unlikely to help as much as a releaser like the amphetamines. But it may work great, for example, because the dopamine starved regions have gone back to the RNA and said "We don't have have dopamine, make more receptors so that the smallest increases in dopamine cause a prominent effect".
Condensed version:
The brain has many nuances and modulatory mechanisms that distort simple mechanistic-based reviews of efficacy. Your individual physiology is at least as important in determining efficacy, both in terms of mechanism and the absorbtion/metabolize, distribution, and site-selective availability.
Three things effect efficacy: Dose pharmacokinetics (absorbtion/metabolism, distribution, and tissue availability), drug mechanism of action, and individual physiological variability. The last can be influenced by anything environmental including, sleep, diet, concommitant drug use, stress and social interaction, etc.
You must address these aspects of treatment in order to experience the most efficacious treatment. Be patient with the medicines, and be aware of any additional factors that may effect them. Be good to your body and your mind will respond in kind.
Take care,
-Brian
I've read on here in several places people saying things like: "Dexedrine is more norepinephrine than dopamine, which is why it's more...(insert here)"
The fact is these medicines have some commonalities, but they are totally different.
Dexedrine/Adderall (Dextroamphetamine) are dual acting catecholaminergic medications. They increase the release and block the re-uptake of norepinephrine and dopamine, and also have a mild serotonin effect. Studies show that at doses that are considered therapeutically equivelant, dextroamphetamine is MUCH more potent than methylphenidate (ritalin) at increasing extracellular dopamine, and slightly more potent at increasing norepinephrine.
Methylphenidate on the other hand has no releasing mechanism, and works via re-uptake of norepinephrine and dopamine. Additionally, methylphenidate is a primarily noradrenergic medication at therapeutic doses, and in a healthy "normal" it requires approximately a 40mg single oral dose to block at least %70 of the dopamine re-uptake transporter. Thus, methylphenidate is a strong noradrenergic enhancer and a mild dopaminergic enhancer.
Methylphenidate has no affinity for the serotonin uptake pump, and at supra-therapeutic doses has been proven not to effect extracellular serotonin, or influence serotonergic pathways. This is in contrast to the amphetamines, which have mild effects in this respect.
But there's more: Describing extracellular concentrations of neurotransmitters affected by a given medication only tells part of how it actually does it's magic. The brain is composed of very elaborate systems of interaction and modulation. These pathways of modulation interact on the micro-levels of DNA/RNA, and on macro-levels activating and de-activating brain structures all over. There are too many little structural nuances to give particular meaning to a given neurotransmitter based mechanism, but these generalizations can be quite good at giving a broad meaning, not a specific one.
For example, the medication Strattera is considered a noradrenergic-specific drug. And yet, strattera increases dopamine in the prefrontal cortex to the same amount it does norepinephrine. So is strattera now a dopaminergic/noradrenergic medication? Yes and no. It selectively blocks the re-uptake of norepinephrine, so it's a NRI, but since the noradrenergic systems interact and extensively modulate the dopaminergic systems, it definately has dopaminergic effects. The reason strattera increases dopamine in the PFC is because the PFC does not have a dopamine transporter, and dopamine binds readily to the norepinephrine transporter (which strattera blocks, of course). However, in the rest of the dopamine-rich regions of the brain there are active dopamine transporters, and so dopamine, having a higher affinity for the dopamine transporter than the norepinphrine transporter, selectively binds to it's main cleanup molecule.
This could go on forever. Norepinephrine can bind and activate dopamine receptors, and visa versa. There are many different varieties or receptors that a particular transmitter will bind to that have seemingly opposing effects, and they set off selective and non-selective reactions throughout the brain, from whole systems, to peptides, to the level of RNA. The brain has all kinds of little quirks like this.
Finally for the most important point. As a generalization, the medications are classified based on mechanism, and mechanism determines efficacy. But keep in mind not to spend too much time dissecting mechanism and trying to extrapolate to your own experience. The main thing that determine's efficacy, and I'm going to bold this: The drug mechanism, it's ability to properly absorb and distribute to relevant areas (pharmacokinetics), in combination with YOUR unique physiology. If, because of your physiology, your brain does not release dopamine well at all, then the mild DAT blocking of ritalin is unlikely to help as much as a releaser like the amphetamines. But it may work great, for example, because the dopamine starved regions have gone back to the RNA and said "We don't have have dopamine, make more receptors so that the smallest increases in dopamine cause a prominent effect".
Condensed version:
The brain has many nuances and modulatory mechanisms that distort simple mechanistic-based reviews of efficacy. Your individual physiology is at least as important in determining efficacy, both in terms of mechanism and the absorbtion/metabolize, distribution, and site-selective availability.
Three things effect efficacy: Dose pharmacokinetics (absorbtion/metabolism, distribution, and tissue availability), drug mechanism of action, and individual physiological variability. The last can be influenced by anything environmental including, sleep, diet, concommitant drug use, stress and social interaction, etc.
You must address these aspects of treatment in order to experience the most efficacious treatment. Be patient with the medicines, and be aware of any additional factors that may effect them. Be good to your body and your mind will respond in kind.
Take care,
-Brian