I'm looking for studies explaining the mechanism for stimulant-induced anxiety. How do amphetamine and methylphenidate increase anxiety exactly?

I'm fairly certain it's not caused by a simple "drop in serotonin."

When you take one of the said stimulants it increases the production and or blocks the re uptake of a number of neurotransmitters in the brain. Two of note being Dopamine (DA) and Noradrenaline(NA). Noradrenaline is the same transmitter that is triggered in the face of danger also known as Fight or Flight response. Thus by revving your body up and constantly being more stimulated by Noradrenaline you get the same anxious impending sense of doom.

When you take one of the said stimulants it increases the production and or blocks the re uptake of a number of neurotransmitters in the brain. Two of note being Dopamine (DA) and Noradrenaline(NA). Noradrenaline is the same transmitter that is triggered in the face of danger also known as Fight or Flight response. Thus by revving your body up and constantly being more stimulated by Noradrenaline you get the same anxious impending sense of doom.

I don't think that's the mechanism. For example, Strattera, which is a NRI, causes less anxiety on average than stimulants do.

Some studies:

The purpose of this study was to examine the anxiety-related effects of acute and repeated amphetamine administration using the elevated plus maze (EPM) and light/dark box tests in mice. D-amphetamine (2 mg/kg ip, 30 min after injection) had a significant anxiogenic effect only in the EPM test, as shown by specific decreases in the percentage of time spent in the open arms as well as in the percentage of open arm entries. Tolerance to this anxiogenic action developed after 8 days of daily d-amphetamine administration (2 mg/kg, ip). An anxiolytic effect was observed after the ninth injection, i.e. there were specific increases in the percentage of time spent in the open arms and in the percentage of open arm entries. L-type voltage-dependent calcium channel antagonists: nimodipine (5, 10 and 20 mg/kg, ip), flunarizine (5, 10 and 20 mg/kg, ip), verapamil (5, 10 and 20 mg/kg, ip), and diltiazem (5, 10 and 20 mg/kg, ip) were also injected prior to an acute low dose of d-amphetamine or to each injection of subchronic d-amphetamine. Our results revealed that calcium channel blockers dose-dependently attenuated both an anxiogenic effect of d-amphetamine and the development of tolerance to this effect. Our results suggest that neural calcium-dependent mechanisms are involved in the anxiety-related responses to acute and subchronic amphetamine injection that may lead to addiction relapse in human users.The purpose of this study was to examine the influence of chronic d-amphetamine (AMPH) treatment (2 mg/kg i.p., for 9 consecutive days) on behavioral and neurochemical responses to a subsequent exposure - 4 days after the last AMPH injection--to the elevated plus-maze (EPM), as well as to determine the involvement of a dopaminergic mechanism in that influence. Results showed that chronic AMPH treatment induced an 'anxiogenic-like' response when animals were evaluated in the EPM test. Pretreatment with either haloperidol (HAL, 1 mg/kg i.p., 20 min prior to each injection) or SCH-23390 (0.1 mg/kg i.p., 10 min prior to each injection) completely abolished the chronic AMPH-induced 'anxiogenic-like' effect displayed in the EPM test. However, sulpiride pretreatment (60 mg/kg i.p., 10 min prior to each AMPH injection) did not modify such effect. In addition, rats treated with AMPH and subsequently exposed to the EPM, showed a decrease in the maximal GABA-stimulated chloride uptake in cortical microsacs. HAL pretreatment restored the maximal chloride uptake induced by chronic AMPH. Altogether, these results suggest that: (1) previous exposure to chronic AMPH treatment induces an increased emotional response following a conflict situation, (2) dopamine D(1) receptors are mainly involved in chronic AMPH-induced changes in the behavior displayed in EPM test, and (3) an interaction between GABAergic and dopaminergic mechanisms may be implicated in neurochemical and behavioral changes induced by chronic AMPH treatment.

In previous experiments beta-phenylethylamine (PEA), like the standard anxiogens caffeine, pentylenetetrazole, and yohimbine, has exhibited an anxiogenic effect in the two animal models of anxiety: the social interaction test and the conflict situation test. In the present study, PEA acts as an anxiogen in an elevated plus-maze, diminishing (compared to controls) the ratio of entries into open arms over the total number of entries and shortening the time spent in the open arms. DL-Amphetamine sulfate (AMPH) also had a similar action. These data support the previous suggestion that PEA may belong to the group of endogenous anxiety-inducing compounds. Pretreatment with ethanol prevented the effects of both PEA and AMPH.

Guanfacine is an alpha-2 adrenoceptor agonist and it doesn't increase anxiety

yea nd my psychiatrist didnt even budge when I suggested it to him (and this made me ask him if he had heard of it and he said yes)

http://en.wikipedia.org/wiki/Amphetamine all the info you need

Guanfacine is an alpha-2 adrenoceptor agonist and it doesn't increase anxiety

Is there any way you could summarize those scientific abstracts on amphetamine-induced anxiety? I just can't get through all that jargon, even if it's reduced to one paragraph.

Anxiety is a major problem for me, where stimulants are concerned--I too would like to know what the mechanism is...

Is there any way you could summarize those scientific abstracts on amphetamine-induced anxiety? I just can't get through all that jargon, even if it's reduced to one paragraph.

Anxiety is a major problem for me, where stimulants are concerned--I too would like to know what the mechanism is...

Summary:
- D-amp induces anxiety. Users usually develop tolerance to this anxiety. This tolerance to anxiety may "signal" an addiction to the substance and/or tolerance to the substance itself. L-type calcium channel blockers reduced stimulant-induced anxiety and also stopped users from developing "tolerance" to the anxiety-inducing effect. Meaning while the users are taking the blockers, anxiety decreases, but stopping the blockers would cause the anxiety to return since users don't develop tolerance to the side effect of anxiety. But since users don't develop tolerance to the anxiety, and tolerance to anxiety could be linked to addiction/tolerance, users also don't develop tolerance/addition to the substance.
- The anxiety effect of d-amp could be related to a dopamine mechanism. GABA might be being affected by this dopamine mechanism as well.
- Alcohol (Ethanol) could reduce stimulant-induced anxiety

The more NE the more anxiety you have and the more DA the less GABA. Its not complicated.

Increased glutamate in general.

Benzos were invented for a reason.

sounds good to me! :D

Guanfacine is an alpha-2 adrenoceptor agonist and it doesn't increase anxiety
<!-- / message --> <!-- controls --> Guanfacine actually has a dual action . . . it is an agonist, meaning that it increases stimulation of alpha2 receptors. Alpha 2 receptors are located both postsynaptically (on neurons which don't release noradrenaline) and presynaptically (on the neurons which do release noradrenaline). It stimulates receptors at both locations. Postsynaptically, that can cause a variety of effects which mimic noradrenaline binding to the alpha2 receptor.

Problem is, when you stimulate the receptors that are located on the noradrenaline neurons themselves, there is a negative feedback loop that is triggered. That means that stimulating these presynaptic receptors results in a decrease in noradrenergic cell firing rate, and a decrease in noradrenaline release, which means there is less noradrenaline available to stimulate other receptor subtypes (like beta and alpha 1 receptors).

That is why guanfacine can make you feel sleepy (lack of beta and alpha1 receptor stimulation , and decreased noradrenaline release), whereas the stimulants and straterra increase extracellular noradrenaline availability across the board.

The more NE the more anxiety you have and the more DA the less GABA. Its not complicated.

Less GABA = More anxiety

Then you're saying more dopamine will also cause more anxiety? So you feel both dopamine and NE increase anxiety?

Guanfacine actually has a dual action . . . it is an agonist, meaning that it increases stimulation of alpha2 receptors. Alpha 2 receptors are located both postsynaptically (on neurons which don't release noradrenaline) and presynaptically (on the neurons which do release noradrenaline). It stimulates receptors at both locations. Postsynaptically, that can cause a variety of effects which mimic noradrenaline binding to the alpha2 receptor.

Problem is, when you stimulate the receptors that are located on the noradrenaline neurons themselves, there is a negative feedback loop that is triggered. That means that stimulating these presynaptic receptors results in a decrease in noradrenergic cell firing rate, and a decrease in noradrenaline release, which means there is less noradrenaline available to stimulate other receptor subtypes (like beta and alpha 1 receptors).

That is why guanfacine can make you feel sleepy (lack of beta and alpha1 receptor stimulation , and decreased noradrenaline release), whereas the stimulants and straterra increase extracellular noradrenaline availability across the board.

thanks for the info

What do you think about the mechanism of stimulant-induced anxiety?

Less GABA = More anxiety

Then you're saying more dopamine will also cause more anxiety? So you feel both dopamine and NE increase anxiety?

Im quite sure both play a role in anxiety. But dopamine can also give such a euphoric response that the lower levels of gaba doesnt matter.

Im quite sure both play a role in anxiety. But dopamine can also give such a euphoric response that the lower levels of gaba doesnt matter.

The euphoric effects fade away quickly at common ADHD doses

What do you suggest as a solution to stimulant-induced anxiety? Besides Benzos of course.

The more NE the more anxiety you have and the more DA the less GABA. Its not complicated.


If it runs that the more NE you have, the more anxiety, why is it that NRIs like Strattera are not known for causing anxiety?

Because it depends which brain structures they are raising the neurotransmitters in.

NE, DA, glutamate and GABA all play a role in anxiety. In the case of d-amphetamine, NE is the main offender, but keep in mind that these neurotransmitters do not act independently...

Also, while Strattera releases no monoamines, I am quite sure it can cause anxiety. And even though it is only blocking the reuptake of NE, it is indirectly modulating levels of glutamate...

If it runs that the more NE you have, the more anxiety, why is it that NRIs like Strattera are not known for causing anxiety?

Both wellbutrin and strattera caused wicked anxiety/irritability in me at high doses. I imagine the fact that they're titrated slowly also plays a role in them causing less anxiety than conventional stimulants.

As for a solution to the anxiety i really cant say. I use benzos if its bad which is probably not a good solution but its the only one i can think of aside from breathing exercises.

I mean there are plenty of sedating alternatives to benzos such as Atypicals (seroquel?), an SSRI such as lexapro, straight antihistamines, beta blockers. But all are going to impact the performance of the stimulant. I choose benzos because of their side effect profile and the fact that im given large amounts of them. Valium isnt very powerful in the sense that it will put you to sleep but rather seems to be mild and has a very long h alf life.

I mean there are plenty of sedating alternatives to benzos such as Atypicals (seroquel?), an SSRI such as lexapro, straight antihistamines, beta blockers. But all are going to impact the performance of the stimulant. I choose benzos because of their side effect profile and the fact that im given large amounts of them. Valium isnt very powerful in the sense that it will put you to sleep but rather seems to be mild and has a very long h alf life.

Beta blockers seem to have the least amount of effects on the performance of stimulants out of all of those.

You're correct, i take 100mg of atenolol daily.

Although there is a theory about beta blockers possibly causing a hypertensive crisis in stimulant users. Although i've never seen proof of it outside of hypotheticals.

the less serotonin and more dopamine i get, the less anxious i seem to be... and NE seems to make me less anxious... case in point... the first time i took Adderall IR... I took about 15mg... and I noticed my anxiety and working memory were greatly enhanced compared to the dexedrine i had been taking up to that point. Only took it a few times and liked it more (could have been the different amphetamine salts and my lack of tolerance for them though... could have been a euphoric effect not anti-anxiety.) Also Wellbutrin seemed to reduce my anxiety from the first couple days I took it, it improved my working memory also... dexedrine seems to be the best anti-depressant but it makes my working memory ****.

Anxiety is an important element of mental performance, too much of too little will throw you off. One thing that is found with stimulants is that with increasing dose, their selectivity decreases along with therapeutic effectiveness. Dex is a good example, same applies to MAOIs at least in terms of selectivity.