Synergistic Effects of Lamotrigine and Vyvanse?

[Lightning-Nl]

J Neurophysiol. 1994 Aug;72(2):1024-7.
Importance of unpredictability for reward responses in primate dopamine neurons.
Mirenowicz J, Schultz W.


J Neurophysiol. 1998 Jul;80(1):1-27.
Predictive reward signal of dopamine neurons.
Schultz W.


There's even a cool slide to back it up with.

Scientists recorded the activity of dopamine neurons in the VTA of a rat (or presumably some other unfortunate little critter) and graphed them around the stimulus-reward interval, both before they learned the stimulus gave them a reward, during the process of learning, and then afterwards.

from the Neuron review on this

So what does this mean?
Let's say you live on rice and beans for a long, but indefinite period of time. You work 9 to 5 at Burger Parthenon and don't go out much. Now your friend Steve, from out of town, comes in and invites you to party with him. Steve is loaded, a trust fund kid. Maybe you don't trust him at first because of the social standing, or you don't like his cologne or whatever. But regardless, out of boredom, you go out with him, hit the bars, scope out girls (or guys, if that's what you're into). The novelty and feeling of freedom are liberating and make you feel awesome. That night you pass out exhausted, and return to your doldrum day job again. Steve calls you a few weeks later, the same things happen, you go out on the town and feel great, maybe even better than last time.

(A dopamine response is induced via pleasurable behaviour - wine women, and song - in response to a stimulus - Steve calling you)

Since Steve works on an oil rig far away, though, his visits are spotty at best. Steve calls you a few months later, the next time it happens, and then a week after that. Work at Burger Perthnon is hard. You eventually start to anticipate when he'll call - as soon as you see Steve's name flash on your phone you know you'll be having a good time again. You start to relax and feel better knowing there's plans for the weekend - even though they haven't been made yet because you haven't answered his call!

(The dopamine neuron response migrates from the reward = party - to the stimulus - Steve)

Eventually Steve moves next door to you. Seems like a good idea - you can hit the town on a regular basis. So you do. But once it's a planned thing and the Friday call comes in ... bar-hopping with Steve stops being so exciting. The magic is lost.

(The dopamine neurons adjust their response to a continuous reward in response to the stimulus).

The same thing happens in lots of scenarios, with any reward and stimulus.

It seems to me this system is in place for 2 reasons:
1. Discourage repetitive activity that results in no improvement to encourage energy be spent elsewhere - scratching of itches, sexual activity, defecation etc are normally pleasurable, but you don't see people fixate on them, usually.
2. Encourage novel risk-taking behaviours. If you go exploring and find a specimen of your favourite fruit tree in a hidden grove, bearing a delicious juicy fruit just for you, you'd feel more satisfied than going to a fruit orchard and picking a fruit from there. Both experiences are more rewarding than going to the supermarket - as long as you don't live on a farm, that is.

The theory that chills during urination are tied to heat loss makes more sense to me than urination being intrinsically rewarding. It is indeed critical to our survival - without waste removal one would surely perish - but in general, defecating more doesn't increase your prospects at advancing the species.

For most people I have to assume it is not going to be a random result whether their bladder is going to empty or not - and even then, I know of nobody toilet-trained who gets really happy when they have to piss, because of the upcoming reward!

Just wanted to say; this is, without a doubt, one of THE best posts on Bluelight.

I was unaware that I had bought into the misconception that Dopamine is a reward hormone hook, line, and sinker.

With all the other combined knowledge I have, I was able to apply the information you provided to a possible (and very probable) explanation to the mechanism behind Obsessive-Compulsive Disorder, Pathological Addictions (Such as Compulsive Gambling and Shopping), Impulse Control Disorders and the impulsiveness due to ADHD (although, I believe that more is going on than just Dopamine reinforcing the reward aspect of emotion, in the case of ADHD)

I was also able to identify why I, personally, have compulsive buying issues, why I can't resist taking a drug if it's in front of me (even though I am not addicted to anything persay. I never crave a substance or actively seek them out. If they are in front of me, however, I can't stop myself from using the substance.), and why I actively try to seek-out CC information, and other things, when I know that doing so will cause long-term negative consequences.

So, I figured that Dopamine was playing a big role in that behavior, and I decided to try an experiment. When I felt a really intense impulse to do something, I took the antipsychotic Risperidone. Usually, when I have an impulse as intense as the one I as felt in that situation - it builds up to the point that I can't suppress the urge to act on it anymore and it gets put into action. When Risperidone was taken, the impulse was gone in around 30 minutes. The only down side to Risperidone (or any other Dopamine antagonist for that matter) I am literally so unmotivated that I can't do anything.

I was also able to identify why my ADHD meds (Vyvanse 70MG's atm) was causing me to be more impulsive - when it should have the opposite effect. I noticed that when Vyvanse was taken at the same time as Lamotrigine - It eliminated all the impulsiveness I felt due to the Vyvanse.

I based this on the fact that I believed that Lamotrigine was a Serotonin agonist. After doing immense research on the Mesolimbic Reward Pathways, I noticed that studies mentioned that the feeling of "reward" has an immense relationship with Serotonin release. So, at the time, I thought taking Lamotrigine would be a good fit with the Vyvanse as I thought Lamotrigine would cause increased neuronal firing due to 5-HT3 agonism.

I have since learned that Lamotrigine is a possible Serotonin antagonist. However, there are many conflicting things on the internet about Lamotrigine mechanism of action. All websites I looked at said that Lamotrigine binds to 5-HT3 and Sigma-1, however, each website had different info for whether or not Lamotrigine is an Agonist, Antagonist, or Inverse Agonist. I know wikipedia says it's an antagonist at 5-HT3 and Sigma-1, however, no sources are cited so I don't count that as credible (even though it might be correct)

So I'm not sure, at this point in time why Lamotrigine would cause a synergistic effect with Vyvanse. Oddly enough, taking the Lamotrigine with the Vyvanse would greatly boost the stimulating effects of Vyvanse, while at the same time, oddly decreasing my impulses to do something negative.

Can anyone input their thoughts on the matter?

Anyways, this post became about something entirely different than I originally posted it about. Just wanted to say to sekio that; your information literally led me to solving literally everything that's wrong with my behavior.

You, sir, deserve an award.

 

[sekio]

lamotrigine is a filthy dirty drug that has a wide variety of effects, I think it is generally accepted as being a sodium channel blocker though. It does have mood stabilising properties, that would explain the lack of impulsivity.
(By the way, 5ht3 is more involved with vomiting than it is with dopamine release.)

If you have impulse control problems on Vyvanase you should probably either reduce your dose or switch to e.g. a NRI.

 

[endotropic]

I based this on the fact that I believed that Lamotrigine was a Serotonin agonist. After doing immense research on the Mesolimbic Reward Pathways, I noticed that studies mentioned that the feeling of "reward" has an immense relationship with Serotonin release. So, at the time, I thought taking Lamotrigine would be a good fit with the Vyvanse as I thought Lamotrigine would cause increased neuronal firing due to 5-HT3 agonism.

I have since learned that Lamotrigine is a possible Serotonin antagonist. However, there are many conflicting things on the internet about Lamotrigine mechanism of action. All websites I looked at said that Lamotrigine binds to 5-HT3 and Sigma-1, however, each website had different info for whether or not Lamotrigine is an Agonist, Antagonist, or Inverse Agonist. I know wikipedia says it's an antagonist at 5-HT3 and Sigma-1, however, no sources are cited so I don't count that as credible (even though it might be correct)

The binding data on the wikipedia page comes from reference 23, which links here (the reference button is just above the binding data).

They mention that the effect at 5-HT3 is inhibitory, but don't specify neutral antagonist vs. inverse agonist. At sigma they don't even mention agonist vs. antagonist, and that page doesn't give a link to the primary literature unfortunately Either way the binding at these receptors is fairly weak (especially sigma), my bet is that they're not relevant to the interaction.

 

[Lightning-Nl]

lamotrigine is a filthy dirty drug that has a wide variety of effects, I think it is generally accepted as being a sodium channel blocker though. It does have mood stabilising properties, that would explain the lack of impulsivity.
(By the way, 5ht3 is more involved with vomiting than it is with dopamine release.)

If you have impulse control problems on Vyvanase you should probably either reduce your dose or switch to e.g. a NRI.

I've tried NRI's (atomoxetine and pseudoephedrine) and they have little to know effect on helping focus for me. They usually induce panic attacks and also exacerbate my insomnia.

However, due to the combination of Lamotrigine and Vyvanse, I don't have to worry about that happening anyways! In fact, now this this works so well, My doctor wants to up the dosage on the Vyvanse.

The binding data on the wikipedia page comes from reference 23, which links here (the reference button is just above the binding data).

They mention that the effect at 5-HT3 is inhibitory, but don't specify neutral antagonist vs. inverse agonist. At sigma they don't even mention agonist vs. antagonist, and that page doesn't give a link to the primary literature unfortunately Either way the binding at these receptors is fairly weak (especially sigma), my bet is that they're not relevant to the interaction.

I'm not saying you're wrong. However, this study and this study claim otherwise. That's why I'm confused as to what's really going on here...

 

[Moredopamine]

I noticed when I first started to use Adderall I'd be a fiend to my impulses to engage in rewarding behaviors.. like play video games, socialize, smoke cigarettes, watch pornography, etc. This lack of impulse control correlated highly with the euphoria adderall game me, and once that wore off, I was better able to focus on tasks at hand as the medication was intended for.

It also helped a ton to be in an environment where I can't engage my impulses, like my college library.

 

[Lightning-Nl]

I noticed when I first started to use Adderall I'd be a fiend to my impulses to engage in rewarding behaviors.. like play video games, socialize, smoke cigarettes, watch pornography, etc. This lack of impulse control correlated highly with the euphoria adderall game me, and once that wore off, I was better able to focus on tasks at hand as the medication was intended for.

It also helped a ton to be in an environment where I can't engage my impulses, like my college library.

I agree with this for sure. However, once I took Adderall for around a year, the euphoria actually started building back up again and became more prevalent again, over time. I am the only person I know that has had this happen to them. Therefore, I don't know if it's placebo or if it's actually happening. It's not anywhere near it was at the honeymoon, but it's (i'd say) about half that now and I've only had a dose bump up 3 times. 2 right when i first started taking it, then again about 6 months later.

 

[sekio]

In fact, now this this works so well, My doctor wants to up the dosage on the Vyvanse.

Don't.

The fastest way to fuck up a good amphetamine regimen is increasing the dosage. You will burn out eventually. If it works fine, leave it be.

 

[truckeeman]

This entire thread makes me happy and mad. I am happy that there are others trying to be chemists in their on-going quest for success and at the same time it angers me that so many, like me have had to resort to this level of understanding as to how things work in order to get the help they need. I am not a fucking mad scientist and I am mad that I feel like I have to be in order to figure out what the lazy fucking Drs won't bother to.

 

[endotropic]

I'm not saying you're wrong. However, this study and this study claim otherwise. That's why I'm confused as to what's really going on here...

I'm thinking we misunderstood each other somewhere. All I meant to say in my first post was that the interaction of Lamotrigine with 5-ht3 and sigma is fairly weak, and if I had to guess, the mechanism of interaction between Lamotrigine and Vyvanse involves Lamotrigine acting at some other site(s). I don't think either of the links you posted touch on that (I still could be wrong though, I often am ).

 

[Lightning-Nl]

I'm thinking we misunderstood each other somewhere. All I meant to say in my first post was that the interaction of Lamotrigine with 5-ht3 and sigma is fairly weak, and if I had to guess, the mechanism of interaction between Lamotrigine and Vyvanse involves Lamotrigine acting at some other site(s). I don't think either of the links you posted touch on that (I still could be wrong though, I often am ).

Ah, okay.

It seems to me, after doing more research about Lamotrigine, Dextroamphetamine, and the causing mechanism behind Impulse Control Disorders - that the reason why it works at decreasing impulsive behavior is due to Lasmotrigines effects as a voltage-gated Sodium Channel Blocker and Calcium Channel Blocker.

My understanding of Impulse Control Disorders is; when an impulses is thought-of, the brain debates it which creates a positive feedback loop. As the brain keeps "thinking about it" neurons have to keep firing, which keeps the impulse in mind and makes it impossible to forget. In order to keep the neurons firing - Glutamate release keeps growing and growing, which in turn, makes the neurons fire faster and more frequently. So, literally, the more you think about executing the compulsion - the more likely you are to do. And since the neurons are firing at a fast rate - it's nearly impossible to stop thinking about it. This increased neuronal firing causes anxiety to build up fast and therefore, the brain finally sends those electrical impulse down your spinal cord and into your muscles which puts the compulsion into action.

Lamotrigine (as I said above) acts as a voltage-gated sodium channel, and (to a lesser extent) calcium channel blocker. I believe it's mechanism in helping stop compulsive behavior is most likely due to this.

Neuronal firing is caused by Sodium, Calcium, Potassium, or Chloride Ions moving from the outside of the cell, to the inside of the cell. What makes the ions do this is a change in electrical charge in one side of the cell. What causes this change is the absence of positively charged ions, or an imbalance of positively charged ions. This rectifies the cell and changes the flow of these ions. To further explain how this system works.......



Lamotrigine interacts with this channel by literally blocking the inside of the cell from obtaining a positive charge. It does this by blocking the opening of the channel. When this happens - even though the cell "wants" to fire, the blocking of the opening of the channel stop the ions from ever being able to enter the cell. So what does this mean? The neuron doesn't fire.

Lamotrigine would, therefore, be great at stopping a compulsion as it literally stops the positive feedback loop. Even though the compulsion may, still, pop up in your thoughts - you don't keep thinking about it because the Lamotrigine is stopping the neuron from firing. This stops the positive feedback loop, which then stops the need for glutamate release in order to keep the neuron firing.

Amphetamine, because it causes Dopamine release, causes an enormous release of glutamate as well (from the studies I've read anyways.) Dopamine is both excitatory and inhibitory, so it can cause excitation in a specific neuron, and inhibition in another. However, the major excitatory response that Dopamine is responsible for, is mainly mediated by glutamate release.

The same studies suggested that lamotrigine acts presynaptically on voltage-gated sodium channels to decrease glutamate release, which would entirely explain it's ability to reduce compulsive urges.

 

[Lightning-Nl]

Just found out a much more reasonable explanation as to why Lamotrigine would synergize with Amphetamines. Lamotrigine is a substrate for Monoamine Oxidase. It doesn't inhibit MAO, but it's a substrate. It actually has more affinity for MAO-A than MAO-B which would explain why Amphetaime + Lamotrigine would give me heart palpitations. It's Ki values are 15nM for MAO-A and 18nM for MAO-B.

 

[h3lp]

From peliminary research I found evidence of synergy between lamotrigne and sodium valpoate in relation to patients dealing with seizures and in need of medication to mitigate such effects. Here is the chemical break down of sodium valproate so you cam compare between this and the second medication you mentioned as a means of further research.

Here are two quotes from the article going further into the topic.

"Three hundred and forty seven patients with epilepsy from 54 centres across Europe not fully controlled with sodium valproate (VPA, n=117), carbamazepine (CBZ, n=129), phenytoin (PHT, n=92) or phenobarbital (PB, n=9) monotherapy were recruited into a lamotrigine (LTG) substitution study. If 50% or more seizure reduction occurred (responders) on addition of LTG, an attempt was made to withdraw the original antiepileptic drug (AED)."

Here we can see that forty seven epilepsy patients were treated with a variety of drugs in addition to lamictal or lamotrigne. Lets see what the results were.

"This effect was seen for partial (VPA, 57%; CBZ, 39%; PHT, 39%; P<0.02) as well as tonic-clonic seizures (VPA, 70%; CBZ, 53%; PHT, 50%; NS). These data lend credence to the suggestion of therapeutic synergy between LTG and VPA."

Therefore we see that evidence precipitating from the study gave credence to the idea that lamotrigne had synergy between LTG and VPA.

The nature of this study gives me the impression that there may not be a large library of studies or evidence in favor of the subject of synergy with lamotrigne which lends to the concept of studying the molecule and compare with other substances and drugs to create a form of hypothesis or general impression on the topic as opposed to examine the evidence presented by current studies.

I am however interested in the topic as I am on a daily dose of lamictal. Therefore I look forward to reading various impressions and more evidence on this subject.

Source: http://www.epires-journal.com/article/S0920-1211(96)01007-8/abstract#

 

[endotropic]

Just found out a much more reasonable explanation as to why Lamotrigine would synergize with Amphetamines. Lamotrigine is a substrate for Monoamine Oxidase. It doesn't inhibit MAO, but it's a substrate. It actually has more affinity for MAO-A than MAO-B which would explain why Amphetaime + Lamotrigine would give me heart palpitations. It's Ki values are 15nM for MAO-A and 18nM for MAO-B.

How would that cause a synergistic effect? A substrate of MAO gets metabolized by MAO, why would that potentiate a monoamine releaser?

 

[dingophone]

I think it's probably as simple as blocking sodium channels. The other binding affinities seem too low to make a difference in all but massive doses (which could possibly be toxic). Inhibition of glutamate release induced by sodium channel blockade could have downstream effects on dopamine (or norepinephrine, serotonin, etc... we don't know a whole lot about downstream interactions in general) and these mechanisms could be why lamotrigine acts how it does.

I looked into the sigma binding affinities for lamotrigine (http://www.bindingdb.org/data/mols/tenK5003/MolStructure_50031299.html) and its *possible* that it could bind to the s1 receptor about as efficiently as it does to sodium channels. But I think that's probably not a good assumption to make; for one the IC50 is listed is ambiguously listed as >10000nM, and in addition I can't find any data on how it acts on the sigma receptor.

I agree with endotropic, that explanation doesn't make a lot of sense. Many things can be substrates of enzymes without inhibiting them (eg most monoamines and MAO or GABA and GAT).

 

[Lightning-Nl]

You guys are missing the point. By occupying MAO for any amount of time, Lamotrigine, therefore, causes trace-amines to not be metabolised as quickly this leading to some build of of trace-amines.

Especially when coupled with Amphetamine (which also acts as a Monoamine substrate) you end up with decreased trace-amine metabolism and build up of neurotransmitter. Especially since Amphetamine releases trace-amines as well.

 

[ebola?]

A substrate of MAO gets metabolized by MAO, why would that potentiate a monoamine releaser?

Well, as might be obvious, all enzymatic substrates are also competitive inhibitors, so if said substrate 'ties up' the enzyme for long enough before it breaks down or dissociates, you would expect sufficient inhibition of that enzyme's effects on other ligands (assuming high sum-occupancy of the total quantity of enzyme).

Especially when coupled with Amphetamine (which also acts as a Monoamine [oxidase] substrate) you end up with decreased trace-amine metabolism and build up of neurotransmitter.

Amphetamine is a key example of a substrate that does not exert significant inhibition, as its affinity is rather weak (at least compared to enzyme inhibitors in medical use).

ebola

 

[Lightning-Nl]

Well, as might be obvious, all enzymatic substrates are also competitive inhibitors, so if said substrate 'ties up' the enzyme for long enough before it breaks down or dissociates, you would expect sufficient inhibition of that enzyme's effects on other ligands (assuming high sum-occupancy of the total quantity of enzyme).



Amphetamine is a key example of a substrate that does not exert significant inhibition, as its affinity is rather weak (at least compared to enzyme inhibitors in medical use).

ebola

Amphetamine releases large amounts of Dopamine and Norepinephrine. Both of which have significant metabolic interactions mediated by MAO. In addition to releasing DA and NE, Amphetamine also releases significant quantities of Serotonin, Tyramine, Tyrosine, Tryptamine, Tryptophan, Histamine, Acetylcholine, Glutamate, Octopamine, Phenethylamine, and N-Methylphenethylamine (via it's interaction with VMAT2 and TAAR - Glutamate release seems to be caused by a downstream mechanism related to Dopamine agonism)

All of those chemicals have metabolism significantly mediated by MAO. With Amphetamine occupying a small number of MAO and then Lamotrigine occupying MAO on top if that - it makes total sense that would be the reason why they synergize.

 

[sekio]

Many native substrates have higher affinity for MAO than either lamotrigine or amphetamine and I don't think at typical dose levels it's entirely saturated. Binding of amphetamine and lamotrigine is reversible, remember...

My vote goes with sodium channel fuckery. Cocaine is a known sodium channel ligand and that's supposedly responsible for some of the stimulant/seizure-inducing effects.

 

[Lightning-Nl]

Many native substrates have higher affinity for MAO than either lamotrigine or amphetamine and I don't think at typical dose levels it's entirely saturated. Binding of amphetamine and lamotrigine is reversible, remember...

My vote goes with sodium channel fuckery. Cocaine is a known sodium channel ligand and that's supposedly responsible for some of the stimulant/seizure-inducing effects.

True. However, sodium channel blockers are used to treat epilepsy for a reason (and selective sodium channel blockers like Lidocaine, can even stop your heart). So I'm not sure whether or not that's the case. Could be. Could not be.

Another reason why my vote goes to MAO substrate activity is due to the fact that Lamotrigine's bioavailability is 100% in all conditions (acidic/alkaline, food in stomach, food not in stomach). Especially since Lamotrigine doses are usually 200 milligrams or more - that's a lot of fucking Lamotrigine. That's, more than likely, going to slow down the metabolism of anything that binds to MAO.

MAO activity would also explain why Lamotrigine is more effective than typical antidepressants (SSRI's) for treatment-resistant depression.

 

[Meremoth]

Contrary to what I initially thought, it seems like lamotrigine can release/increase/stimulate dopamine and serotonin.

Links:

http://statperson.com/journal/scienceandtechnology/Article/Volume8Issue2/8_2_22.pdf

http://www.e-jmd.org/journal/view.php?number=55

Or perhaps I'm misinterpreting the data. Please feel free to correct/enlighten me, as I'm now pretty interested in this seemingly novel drug, lamotrigine.

Edit: Could someone elaborate on the dose needed/required of lamotrigine to be synergistic with amphetamine, and the dose required to increase dopamine and serotonin. Much thanks and appreciation for any help.