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Dysphoria from Dextroamphetamine

RichardMooner

RichardMooner

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Jan 10, 2014
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I was browsing another site and stumbled across a thread, that has gone unanswered, about feeling dysphoric while on dextroamphetamine.

This raised an eyebrow for me because I too, get feelings of brief dysphoria while on dextroamphetamine (At higher doses). They're usually brief episodes that only last a couple of minutes, but occasionally they'll last for quite a while, depending on what I'm doing. For example, if I'm socializing with a person that I thoroughly enjoy spending time with, and then I have to leave, or stop speaking to them, I will be dysphoric for quite some time.

This person, who started the thread I mentioned in the beginning, had a theory that it may be due to low serotonin levels and inhibition of tryptophan hydroxylase's conversion to 5-HTP.

I guess my question is whether or not, this guy's theory is a possibility? And if not, what might it be?

EDIT: It's my understanding that amphetamines downregulate AADC, so if the inhibition of tryptophan conversion to 5-HTP is the cause, would it be a good idea to take St.Johns Wort on top of 5-HTP?
 
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aadc does not catalyse the rate-limiting step in the biosynthesis von serotonin or dopamine/noradrenalin. i haven't found anything saying that amphetamine inhibits tryptophan hydroxylase (in other animals than cats). only for methamphetamine.

the efficacy of 5-htp raising serotonin levels significantly in the brain is questionable anyway. the great majority of it is converted to serotonin before it even has the chance to get to the bbb. a way to counteract this would be carbidopa (in fact when 5-htp is prescribed in a medical setting it's almost always combined with a peripheral aadc inhibitor).
i'm not quite up to date concerning the pharmacology of st. john's wort, but wasn't it supposed to be a weak maoi? if so, it might be dangerous to combine with 5-htp.

but to get back to your original question, the effects you describe to me sound way to short-term and dependent on psychological factors to be due to enzyme inhibition...
 
Stimulants with no serotonergic action tend to have some dysphoric edge to me too - at least they feel stressful and wired after the first two or three days of intake. Combined with either a SSRI or when I take some substance that also affects 5-HTlike 3-MMC or Napthylphenidate it gives a much smoother feeling...

Also specific to dexamphetamine I have read somewhere that one of its metabolites does lower brain 5-HT levels (don't remember what the underlying mechanism was) and this becomes more pronounced after repeated use, which matches my experience ...
 
Thanks for the replies guys. I'll have to find the journals I was reading about Dexamp and get back to you. I think they're online in PDF documents, somewhere.
 
"Amphetamine and its derivatives are known to cause increased production of hydroxyl radical (•OH) in the brain (Huang et al., 1997; Wan et al., 2000a) resulting in acute striatal DA and serotonin depletion (Kita et al., 1999; Shankaran et al., 1999). It has also been shown to induce neurodegeneration in animals (Wan et al., 2000b; Jeng et al., 2006)."

Huang, N.K., Wan, F.J., Tseng, C.J., Tung, C.S., 1997. Amphetamine induces hydroxyl radical formation in the striatum of rats. Life Sci. 61, 2219–2229.

Wan, F.J., Lin, H.C., Lin, Y.S., Tseng, C.J., 2000a. Intrastriatal infusion of D-amphetamine induces hydroxyl radical formation: inhibition by MK-801 pretreatment. Neuropharmacology 39, 419–426.

Kita, T., Takahashi, M., Kubo, K., Wagner, G.C., Nakashima, T., 1999. Hydroxyl radical formation following methamphetamine administration to rats. Pharmacol. Toxicol. 85, 133–137.

Shankaran, M., Yamamoto, B.K., Gudelsky, G.A., 1999. Involvement of the serotonin transporter in the formation of hydroxyl radicals induced by 3,4-methylene-dioxymethamphetamine. Eur. J. Pharmacol. 385, 103–110.

Wan, F.J., Lin, H.C., Huang, K.L., Tseng, C.J., Wong, C.S., 2000b. Systemic administration of D-amphetamine induces long-lasting oxidative stress in the rat striatum. Life Sci. 66, 205–212.

Jeng, W., Ramkissoon, A., Parman, T., Wells, P.G., 2006. Prostaglandin H synthase-catalyzed bioactivation of amphetamines to free radical intermediates that cause CNS regional DNA oxidation and nerve terminal degeneration. FASEB J. 20, 638–650.

Source: 2-Phenylethylamine, a constituent of chocolate and wine, causes mitochondrial complex-I inhibition, generation of hydroxyl radicals and depletion of striatal biogenic amines leading to psycho-motor dysfunctions in Balb/c mice. T Sengupta KP. Neurochemistry International. 11/2010; 57(6):637-46. DOI: 10.1016/j.neuint.2010.07.013
Top of p. 638.


Try this site for copies of those articles. Buying a subscription is on my to do list.

③ Original E-Books Library - 博学网(boxuesky.com) - Academic! 博学问 知天下! All you need are in the Boxuesky!
 
red22 said:
"Amphetamine and its derivatives are known to cause increased production of hydroxyl radical (•OH) in the brain (Huang et al., 1997; Wan et al., 2000a) resulting in acute striatal DA and serotonin depletion (Kita et al., 1999; Shankaran et al., 1999). It has also been shown to induce neurodegeneration in animals (Wan et al., 2000b; Jeng et al., 2006)."

Huang, N.K., Wan, F.J., Tseng, C.J., Tung, C.S., 1997. Amphetamine induces hydroxyl radical formation in the striatum of rats. Life Sci. 61, 2219–2229.

Wan, F.J., Lin, H.C., Lin, Y.S., Tseng, C.J., 2000a. Intrastriatal infusion of D-amphetamine induces hydroxyl radical formation: inhibition by MK-801 pretreatment. Neuropharmacology 39, 419–426.

Kita, T., Takahashi, M., Kubo, K., Wagner, G.C., Nakashima, T., 1999. Hydroxyl radical formation following methamphetamine administration to rats. Pharmacol. Toxicol. 85, 133–137.

Shankaran, M., Yamamoto, B.K., Gudelsky, G.A., 1999. Involvement of the serotonin transporter in the formation of hydroxyl radicals induced by 3,4-methylene-dioxymethamphetamine. Eur. J. Pharmacol. 385, 103–110.

Wan, F.J., Lin, H.C., Huang, K.L., Tseng, C.J., Wong, C.S., 2000b. Systemic administration of D-amphetamine induces long-lasting oxidative stress in the rat striatum. Life Sci. 66, 205–212.

Jeng, W., Ramkissoon, A., Parman, T., Wells, P.G., 2006. Prostaglandin H synthase-catalyzed bioactivation of amphetamines to free radical intermediates that cause CNS regional DNA oxidation and nerve terminal degeneration. FASEB J. 20, 638–650.

Source: 2-Phenylethylamine, a constituent of chocolate and wine, causes mitochondrial complex-I inhibition, generation of hydroxyl radicals and depletion of striatal biogenic amines leading to psycho-motor dysfunctions in Balb/c mice. T Sengupta KP. Neurochemistry International. 11/2010; 57(6):637-46. DOI: 10.1016/j.neuint.2010.07.013
Top of p. 638.


Try this site for copies of those articles. Buying a subscription is on my to do list.

③ Original E-Books Library - 博学网(boxuesky.com) - Academic! 博学问 知天下! All you need are in the Boxuesky!
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I'm not sure what point this post is trying to make, but large amounts of radical species form simply from excessive cytosolic/synaptic dopamine autoxidation and MAO metabolism. Intra-NAcc/cortical injection of DA will produce literally the exact same radical species as seen in these studies for amphetamine.


@OP: Dysphoria from amph is what Rx info refers to as "mood swings". It's an age-related side effect for some users. I suspect it's more a consequence of transient DA fluctuations as opposed to those of 5-HT since amphetamine's DAergic effect is what mediates its euphoric properties.
 
I think just about everyone who uses heavy doses of Amphetamines or uses them for a prolonged period of time experiences some dysphoric effects. I have only used Dextroamphetamine in the form of Dexedrine instant release and Dexedrine Spansules and when i get into day 3 of heavy use with no sleep i can pretty much bet that i will be in a shit pit of despair. It's as if all your life's problems become magnified come to the forefront and are set on a time loop in my head. I have bipolar disorder but just about everyone else i know reports the same problems with heavy Dextroamphetamine, Methamphetamine or Adderall use.
 
RichardMooner said:
I was browsing another site and stumbled across a thread, that has gone unanswered, about feeling dysphoric while on dextroamphetamine.

This raised an eyebrow for me because I too, get feelings of brief dysphoria while on dextroamphetamine (At higher doses). They're usually brief episodes that only last a couple of minutes, but occasionally they'll last for quite a while, depending on what I'm doing. For example, if I'm socializing with a person that I thoroughly enjoy spending time with, and then I have to leave, or stop speaking to them, I will be dysphoric for quite some time.

This person, who started the thread I mentioned in the beginning, had a theory that it may be due to low serotonin levels and inhibition of tryptophan hydroxylase's conversion to 5-HTP.

I guess my question is whether or not, this guy's theory is a possibility? And if not, what might it be?

EDIT: It's my understanding that amphetamines downregulate AADC, so if the inhibition of tryptophan conversion to 5-HTP is the cause, would it be a good idea to take St.Johns Wort on top of 5-HTP?
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I just want to say before anything else that it is a terrible idea to take St. John's Wort with amphetamine; I made this mistake once, and the result was a week long psychosis.

Here's an idea of its pharamacological profile (from wikipedia 8) ):
St. John's wort (SJW), similarly to other herbal products, contains a whole host of different chemical constituents that may be pertinent to its therapeutic effects.[40] Hyperforin and adhyperforin, two phloroglucinol constituents of SJW, are TRPC6 receptor agonist and, consequently, they induce noncompetitive reuptake inhibition of monoamines (specifically, dopamine, norepinephrine, and serotonin), GABA, and glutamate when they activate this receptor.[5][45][46] It inhibits reuptake of these neurotransmitters by increasing intracellular sodium ion concentrations.[5] Moreover, SJW is known to downregulate the β1 adrenoceptor and upregulate postsynaptic 5-HT1A and 5-HT2A receptors, both of which are a type of serotonin receptor.[5] Other compounds may also play a role in SJW's antidepressant effects such compounds include: oligomeric procyanidines, flavonoids (quercetin), hypericin, and pseudohypericin.[5][47][48][49]

In humans, the active ingredient hyperforin is a monoamine reuptake inhibitor which also acts as an inhibitor of PTGS1, Arachidonate 5-lipoxygenase, SLCO1B1 and an inducer of cMOAT.[45][46][50] Arachidonate 5-lipoxygenase inhibitors are typically used to treat asthma, since the enzyme's product, leukotrienes, mediate some of the effects of asthma. Hyperforin is also a powerful anti-inflammatory compound with anti-angiogenic, antibiotic, and neurotrophic properties.[45][46][50] Hyperforin also has an antagonistic effect on NMDA receptors, a type of glutamate receptor.[46] According to one study, hyperforin content correlates with therapeutic effect in mild to moderate depression.[51] Moreover, a hyperforin-free extract of St John's wort (Remotiv) may still have significant antidepressive effects.[52][53] The limited existing literature on adhyperforin suggests that, like hyperforin, it is a reuptake inhibitor of monoamines, GABA, and glutamate.[54]
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In my experience, it felt like a Tricyclic Antidepressant with some other bizarre effects tossed in there; and it stays in your system a long time (days).
Mixing it with amphetamine sent me into a very unpleasant psychosis, with pronounced dysphoria, paranoid delusions, and an inability to sleep for days (even though I stopped taking amphetamine).
 
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After years of abuse I have been relegated to a debilitating apathy and anhedonia which is pronounced enough to discourage use. When dosing dextro now I get put into a horrible unmotivated and bleak state which has a prominent regret to it. Even lying down is miserable, in fact there is nothing enjoyable that I can do that on that substance anymore that warrants taking it again.
 
paranoid android said:
I think just about everyone who uses heavy doses of Amphetamines or uses them for a prolonged period of time experiences some dysphoric effects. I have only used Dextroamphetamine in the form of Dexedrine instant release and Dexedrine Spansules and when i get into day 3 of heavy use with no sleep i can pretty much bet that i will be in a shit pit of despair. It's as if all your life's problems become magnified come to the forefront and are set on a time loop in my head. I have bipolar disorder but just about everyone else i know reports the same problems with heavy Dextroamphetamine, Methamphetamine or Adderall use.
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. can concur dysphoria develops more rapidly with any amphetamine or amp analog in comparison to cocaine, MUCH more rapidly, but thats a given taking into account that amps FORCE dopamine to release and are a partial reuptake inhibitor.
 
Sometimes stimulants produce anxiety or feelings of OCD that make socializing very unpleasant. I don't like talking to anyone when I'm crashed out, and sometimes during the up it can be very uncomfortable. This especially happens if I'm taking it for the third or fourth day in the row.

Drugs are very stable composition-wise--especially pharmaceuticals, but that doesn't mean they'll always hit us the same way. Depends on our mood, physical chemistry at the time, and etc. But stimulants aren't always a good time. I recommend being in a good mood before you take them or at least a neutral one. In the past I've taken them to counteract minor depressive episodes since I was desperate for a temporary way out. Probably ended up doing more harm than good. Any substance on earth to be honest cannot be viewed as a stable anti-depressant. Even heroin has resulted in dysphoria for some users. It's safe to say as paranoid android (good name btw) that stimulants can make you crazy in higher doses. We've all been there.
 
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