Theory on Amphetamine-Induced Delusionality

[SpunkySkunk347]

Amphetamine achieves most of its effects by blocking and reversing the reuptake of dopamine, norepinephrine, and serotonin. This causes these neurotransmitters to be released into the synapse, as well as to be "stuck in the synapse" (I believe until the neurotransmitters are metabolized by monoamine oxidase). Since amphetamine is blocking the reuptake, dopamine is unable to be re-packaged into the presynaptic neuron for future use, resulting in low dopamine levels.
Amphetamine releases dopamine in neural pathways where dopamine is primarily responsible for psychological "motivation" - psychologically, dopamine allows for the ideas of "possible actions" to be converted into real actions. Dopamine is responsible for the "desire" for a particular action be completed, and hence the observed effect is increased motivation.

The delusionality observed in particular cases of amphetamine use (especially prolonged usage or with high doses) can be theorized as the result of a psychological "overly estimated significance" of a possible action. In other words, an amphetamine user thinks that what's going on around him is more important than it actually is.
When our brain is deciding what responses to give to various stimuli, dopamine increases the likelihood of such responses occurring through increased motivation. The desire to produce a response is escalated; the neuronal signals are much stronger than what they actually would be if the individual was not on amphetamine.

Another key neurotransmitter responsible for delusionality is norepinephrine. Norepinephrine increases (both consciously and subconsciously) our awareness of the environment around us. Norepinephrine is also released in significant amounts by amphetamine.

The result is, the amphetamine user receives an excessive amount of incoming stimulation of the surrounding environment (due to norepinephrine), and the stimulus is determined to be significant enough to produce a response (due to dopamine).

Paranoia can easily result. A chain reaction can occur where norepinephrine levels continuously increase. This happens when a stimulation is accompanied by fear, and the desire to respond to a stimulation is also accompanied by a signal to release more norepinephrine (as well as epinephrine) - causing for more stimulation to be received and "over perceived" from dopamine levels, and this can in many cases cause a perpetual panic attack.

However, amphetamine also releases serotonin. The serotonin released can indirectly produce an inhibitory response to dopamine-pathways (and partially norepinephrine). This is where "mind over matter" comes in. When a person is experiencing paranoia and realizes it is merely all in their head and says to themself "Hey, everything is going to be alright, its all in my head", serotonin is the key neurotransmitter responsible. Dopamine-pathways are inhibited and serotonin can furthermore provoke the release of endorphins to cause a sense of comfort and relaxation.

This also explains why methamphetamine (which releases higher amounts of serotonin) is perceived to be more pleasurable than amphetamine, especially in users who already have pre-existing anxiety (suggesting pre-existing low serotonin levels).

From this we can conclude that dopamine does not cause pleasure, it causes desire. It is serotonin's inhibitory effects on dopamine-pathways and the indirect release of endorphins that is responsible for amphetamine's pleasurable effects.

Amphetamines During SSRI Withdrawals

Upon the discontinuation of SSRIs (zoloft, paxil, etc) serotonin levels in the brain drop to an incredibly low amount. Not only this, but the impact made from the little remaining serotonin is mitigated due to our brains desensitization of endogenous serotonin (because of the increased serotonin levels while the SSRI was still in use).

The result is, there is no longer enough serotonin to effectively inhibit dopamine-pathways. This causes the symptoms of anxiety, paranoia, delusionality, agitation, disassociation, and depression.

If amphetamine is administered during SSRI discontinuation, the results can be horrific.

I experienced this first hand while discontinuing Zoloft 200mg/day yet still taking Adderall 60mg/day. I entered a psychosis, and this was before I came to the realization that discontinuing my zoloft was the cause of my psychosis.

Pleasure in my life was completely non-existent during this time, and I can't even imagine the amount of neurological damage I have done as a result.

Among the symptoms of psychosis, I also experienced a large amount of "deja vu" (which has been attributed by neurologists to an excessive amount of dopamine). I also suffered from severe amnesia, and much of my psychosis is absent from my memory (amnesia is commonly experienced during trauma).

Amphetamine "Crash"
When dopamine levels become depleted after the use of amphetamine, norepinephrine levels are still at a high. This causes an excess of stimulation to be received (due to NE) but no motivation for a response (due to depleted DA). The effect is agitation, anxiety, restlessness, and oversensitivity to incoming stimulation.


References:
Amphetamine Depresses Excitatory Synaptic Transmission via Serotonin Receptors in the Ventral Tegmental Area
http://www.jneurosci.org/cgi/content/full/19/22/9780

Balance between Dopamine and Serotonin Release Modulates Behavioral Effects of Amphetamine-Type Drugs
http://www3.interscience.wiley.com/journal/120175749/abstract

 

[SpunkySkunk347]

You can also draw a great number of other conclusions from this, such as:

- Individuals with pre-existing anxiety are more likely to suffer from delusions and paranoia while on amphetamine.

- When our brain forms memories on our neuronal "to-do-list", amphetamine may cause us to add things to this metaphorical "to-do-list" that we would not normally add. This is due to the increased motivation caused by high dopamine-levels. After amphetamine has worn off, we develop a psychological craving for more amphetamine to complete the tasks on our brain's "to do list". This is partially because of post-amphetamine low dopamine levels, but also because we may have undertaken tasks that we are not actually interested in (although we may have been interested in them while on amphetamine).

- In order for us to experience pleasure adequately, we must have endogenous serotonin available to indirectly release endorphins to give us a feeling of "satisfaction". Serotonin is also necessary to inhibit the desire produced from dopamine pathways which would cause us to continually desire more.

- If a recreational drug does not have agonistic action (either directly or indirectly) upon the serotonergic system itself, then endogenous serotonin is required for the drug to be pleasurable.

- Pleasure is not a stimulation, but a cessation of stimulation. Desire is stimulation, but the desire can only be satisfied by ending the stimulation that caused it.

Also, if we apply all this information to our own metacognition, it offers a unique insight to the way our brain processes the human concept of "pleasure". This insight is amazingly helpful in understanding the fields of not only psychology, psychiatry, pharmacology, and neurology, but also philosophy.

 

[ebola?]

Amphetamine achieves most of its effects by blocking and reversing the reuptake of dopamine, norepinephrine, and serotonin.

Plain old, non n-methylated amphetamine really effects little 5ht efflux. The activity in your cited studies must be some complicated downstream effect. I don't see how we'd yet have a good picture of its behavioral significance in humans. . .

Another key neurotransmitter responsible for delusionality is norepinephrine.

Citations? Informal evidence, even?

However, amphetamine also releases serotonin. The serotonin released can indirectly produce an inhibitory response to dopamine-pathways (and partially norepinephrine). This is where "mind over matter" comes in. When a person is experiencing paranoia and realizes it is merely all in their head and says to themself "Hey, everything is going to be alright, its all in my head", serotonin is the key neurotransmitter responsible. Dopamine-pathways are inhibited and serotonin can furthermore provoke the release of endorphins to cause a sense of comfort and relaxation.

Then why do we not see reduced levels of psychosis in meth addicts in comparison to amp addicts? If you argue that increased duration, potency, and a higher incidence of routes allowing for rapid administration overpower any moderating effect of 5ht-efflux, your hypothesis loses a great deal of parsimony.

From this we can conclude that dopamine does not cause pleasure, it causes desire. It is serotonin's inhibitory effects on dopamine-pathways and the indirect release of endorphins that is responsible for amphetamine's pleasurable effects.

Like I said, d-amp doesn't really increase intercellular 5ht, yet it's fun.

Among the symptoms of psychosis, I also experienced a large amount of "deja vu" (which has been attributed by neurologists to an excessive amount of dopamine).

Citation?

Amphetamine "Crash"
When dopamine levels become depleted after the use of amphetamine, norepinephrine levels are still at a high. This causes an excess of stimulation to be received (due to NE) but no motivation for a response (due to depleted DA). The effect is agitation, anxiety, restlessness, and oversensitivity to incoming stimulation.

I agree with much of this.

Pleasure is not a stimulation, but a cessation of stimulation. Desire is stimulation, but the desire can only be satisfied by ending the stimulation that caused it.

Why would things be so simple? There are multiple types of pleasures, some perhaps mapping onto disparate neural pathways.

ebola

 

[SpunkySkunk347]

Plain old, non n-methylated amphetamine really effects little 5ht efflux. The activity in your cited studies must be some complicated downstream effect. I don't see how we'd yet have a good picture of its behavioral significance in humans. . .

It has only has a very minuscule ability to reverse the reuptake of 5-ht, but what I am saying still makes sense - the pleasure just results from the 5-HT our brain releases on its own. However, with this knowledge, you could manually release endogenous 5-HT with your executive cognition (although "manually releasing" sounds like a tricky proposition or just flat-out false, it is in fact possible for individuals who have a level of metacognition, and its also possible to learn how to do it manually through meditation)

Citations? Informal evidence, even?

Norepinephrine in Acute Exacerbations of Chronic Schizophrenia
From http://archpsyc.ama-assn.org/cgi/content/abstract/47/2/161 :
"In recent years the dopamine hypothesis has failed to explain the complexities of schizophrenia. Because both negative symptoms and noradrenergic activity appear to increase with psychotic relapse, we studied negative symptoms, psychosis, cerbrospinal fluid norepinephrine, and cerebrospinal fluid monoamine metabolites in 32 male patients with a DSM-III diagnosis of schizophrenia while both receiving and not receiving long-term haloperidol treatment. Drug-free cerebrospinal fluid norepinephrine and 3-methoxy-4-hydroxyphenylglycol levels correlated significantly with the severity of negative symptoms and psychosis ratings. When the patients were divided into those who did and did not relapse while not receiving the drug, significant positive correlations between negative symptoms and cerebrospinal fluid norepinephrine and 3-methoxy-4-hydroxyphenylglycol were observed only in the patients who relapsed. Nonsignificant but negative correlations were observed between the same variables in the nonrelapsers. Thus, increased norepinephrine activity in drug-free patients is associated with intensification of schizophrenic symptoms without necessarily causing the symptoms."




Althought noradrenaline is not a direct contributor to psychotic symptoms, its disruptive effects on the sleep cycle and the recollection of traumatic incidents from the past can provoke psychosis similar to one caused by sleep deprivation or a PTSD episode

Then why do we not see reduced levels of psychosis in meth addicts in comparison to amp addicts? If you argue that increased duration, potency, and a higher incidence of routes allowing for rapid administration overpower any moderating effect of 5ht-efflux, your hypothesis loses a great deal of parsimony.

I am sorry if it seemed like I implied that 5-HT is capable of curing psychosis. Although, 5-HT can help alleviate some of the symptoms of psychosis, it does not "strike at the roots" of the problem. Most stimulant-induced psychosis had to have a little subconscious psychological "nudge" to kick it into gear, meaning that there is usually some underlying psychological conflict in the user's life; serotonin would not solve this as much as it would temporarily alleviate it - the problem is still there and it still needs to be solved/fixed or else a person might keep relapsing into psychosis. In meth users, the efflux of serotonin would not negate the user's delusionality, but simply grant him an acceptance of it. Also, simply because serotonin is released does not necessarily mean that it will inhibit the appropriate corresponding dopamine pathways; by coincidence, it may slightly benefit the inhibition, but a complete inhibition of said dopamine pathways is not entirely possible since the 5-HT was not naturally released with our brain's intention of it targeting the inhibition of dopamine pathways. Also, with methamphetamine, the 5-HT efflux may actually deplete 5-HT during the comedown/crash (because it was already released) causing the user to not have the 5-HT needed to naturally inhibit delusional thoughts.

Dopamine does not exclusively operate motivation for only "pleasureful" stimulation, it also operates the motivation for "displeasurable" stimulation as well. Meaning that just because a certain stimulus is "scary", "depressing", or "harmful", dopamine will still produce motivation necessary to at very least contemplate the negative stimulus for a possible response.
Dopamine can not differentiate "good thoughts" from "bad thoughts" and will produce motivation for both regardless, the dopamine system is tied to memory, and if our brain receives stimulation familiar to it in our memory, then dopamine will likely be used to develop the motivation to respond to it.
However, because of the complexity of human intelligence, we are able to use our own self-awareness and metacognition to find loopholes allowing for us to realize "these thoughts are bad thoughts and I should not be thinking about them" - this in turn allows for us to have a desire to cease desire, and from here the discussion would dive into the human advent of morality.

Like I said, d-amp doesn't really increase intercellular 5ht, yet it's fun.

I can agree with this, but I still see sources from time to time claiming that d-amp does indeed cause some 5-HT Efflux, however not nearly as much as methamphetamine.
It may also depend on certain variables. If a person develops a "liking" for amphetamine, then their brain may be releasing 5-HT by its own free will in response to taking a drug that it likes.
I would argue that this "liking" occurs because our mind functions at such a high level (due to the massive release of dopamine) that we find ourselves easily capable to understand things we previously did not have the motivation to understand. For exmaple, a person who has a lot of homework might develop an immediate "liking" for amphetamine because it gives him the motivation needed to do his homework.

Citation?

Although I know this is not exactly the most reliable source, this is from wikipedia:
"It has been reported that certain drugs increase the chances of déjà vu occurring in the user. Some pharmaceutical drugs, when taken together, have also been implicated in the cause of déjà vu. Taiminen and Jääskeläinen (2001) reported the case of an otherwise healthy male who started experiencing intense and recurrent sensations of déjà vu on taking the drugs amantadine and phenylpropanolamine together to relieve flu symptoms. He found the experience so interesting that he completed the full course of his treatment and reported it to the psychologists to write-up as a case study. Due to the dopaminergic action of the drugs and previous findings from electrode stimulation of the brain (e.g. Bancaud, Brunet-Bourgin, Chauvel, & Halgren, 1994), Taiminen and Jääskeläinen speculate that déjà vu occurs as a result of hyperdopaminergic action in the mesial temporal areas of the brain. Many scientists are still working towards the actual link of deja vu with hynangogic epilepsy.
"

Why would things be so simple? There are multiple types of pleasures, some perhaps mapping onto disparate neural pathways.

You are right, there are indeed many types of pleasure, but the general rule is that some sort of stimulation had to have been ceased in order to cause pleasure.

I sort of took it the whole 10 yds "doing my homework" with this theory, because this time, my little brawl with amphetamine got personal

 

[SpunkySkunk347]

Isn't it reported that methamphetamine users who are in a stimulant-psychosis will take more methamphetamine to alleviate the symptoms of the psychosis? Even though the alleviation is only temporary and the psychosis will return even more pronounced once the initial euphoria has worn off? This supports the theory that 5-HT can alleviate psychotic symptoms, as MAMP produces a rapid and powerful 5-HT release during the initial euphoria. This also explains to me why taking more d-amphetamine does not alleviate a stimulant psychosis at all like MAMP does, and instead taking more d-amphetamine doesn't really do anything at all (other than make me feel like shit in my own personal experience) after a binge that lead to psychosis.

I have never done methamphetamine, but I talk with many people who are former users. They claimed that MAMP is a much more mellow, pleasureful, and "spun out" euphoria, where d-amp can vary greatly as to whether or not it will be euphoric (adding as evidence that a manual release of 5-HT is necessary in order to feel d-amp as "pleasurable")

This post right here is all merely speculation though

 

[pofacedhoe]

In other words, an amphetamine user thinks that what's going on around him is more important than it actually is.

well this is a new one on me

 

[TheTwighlight]

^^^

As a former amphetamine addict, I will say that this is pretty accurate. But I would say only certain things seem more important, or take precidence over, other things. Depends on the instance, and the amount of amp you're on, and whether you're actually high or on the comedown.

 

[Hammilton]

The idea that more dopamine means more deja vu is incredibly simplistic. Few mental activities could be reduced in this way. They're way to complex. The 'study' you cite to this effect is no more than meaningless. For all anyone knows, he may have been having some sort of epilepsy because of the drugs.

 

[pofacedhoe]

to much dopamine gives you racing thought patterns and you will tend to think your ideas are right as your brain is "rewarding"/abusing its neucleus acumbens so you get too much positive feedback for thinking (so you feel it must be important)

as for speed users thinking they and what happens to them is SO important: i've been adicted to amphetamines and people get arrogant and talk shit on them. the above comment was sarcasm and i hoped it would not be taken literally as anyone who has ever been near anyone on speed will notice the ego and sense of grandiosity first

 

[SpunkySkunk347]

to much dopamine gives you racing thought patterns and you will tend to think your ideas are right as your brain is "rewarding"/abusing its neucleus acumbens so you get too much positive feedback for thinking (so you feel it must be important)

as for speed users thinking they and what happens to them is SO important: i've been adicted to amphetamines and people get arrogant and talk shit on them. the above comment was sarcasm and i hoped it would not be taken literally as anyone who has ever been near anyone on speed will notice the ego and sense of grandiosity first

for me i become incredibly nice and empathetic to other people, i get all "oh i love you so much" and whatnot

not sure why

 

[pofacedhoe]

for me i become incredibly nice and empathetic to other people, i get all "oh i love you so much" and whatnot

not sure why

maybe cos your dose is moderate as opposed to speed bingers doing gram bombs of strong base at a time, also i find the loved up stage was later in the afternoon (i only used to dose in the morning) and my doses were to begin with low although time makes fool of us all

 

[TheTwighlight]

Wow.. I'm at a loss for words. No, taking more methamphetamine is not going to improve psychotic symptoms, it's going to do nothing but make them a hell of a lot worse. Merely speculation or not, this is common sense. And again, despite the fact that amphetamine and methamphetamine appear to have a generally negligible impact on serotonin ("MAMP produces a rapid and powerful 5-HT release during the initial euphoria" <- totally false dude), even if they did, enhancing serotonin is very likely to exacerbate the psychosis even more (again, as evidenced by the atypical antipsychotics and so forth).

I don't know, for whatever reason, when you've been up a week and you're flipping out on a hard meth comedown, the paranoia does temporarily go away if you do some more meth. The euphoria overwhelms the paranoid schizo shit for a little while, until it comes back worse than it was before. YMMV; I never did speed without downers on me. Never.

 

[SpunkySkunk347]

just got out of a 3 day binge, and lol i was so psychotic the second night - I thought that I had disproved the existence of God and if I told anyone what I found out, God would separate me from the true reality and put me into a dream-world contained in my own head. Made a shitload of sense at the time, but then I thought "Hey, mike, you've been up for 2 nights on amphetamine, couldn't SOME of this just be in your head?". I agreed that sleep would be a good thing for me, and just meditated to let all those psychotic obsessive thoughts slowly diffuse out of me.

Now today, I woke up in a state of fear. It's hard to shake off that psychosis feeling.... Just a little bit a go when signs of normalcy began to return, a desire came back for more amphetamine.. ugh..

 

[Tsukasa]

I'm not going to read through all that, but was there any mention of the D2 receptor? amphetamine affects D1 mostly, and to a smaller degree. D1 increases acetylcholine and glutamate release, while D2 does the opposite and has a debilitating effect. At higher doses it acts more like an anti-cholinergic and induces delirium and psychosis with delusions.

 

[Lupus]

The glutamitic properties of amphetamine is often overlooked. NMDA receptors are affected by changes in glutamate transmission which could lead to all sorts of fucked up behavior in some individuals.

 

[permastoned]

Spunky, although your theory had some factual inconsistencies and incorrect statements, I enjoyed reading it. The theories involved are very interesting.

RocknRoll, I agree with most of your corrections, except for the taking more meth to decrease the psychosis very temporarily, I have read/heard of this before, it is in fact true. I do agree very much with dopamine being the principal neurotransmitter involved in pleasure, but I think that serotonin can add a unique aspect to that pleasure, which, in ways, can make it more pleasurable (and it is not just the indirect release of more dopamine, because it is a unique feeling). One thing to mention, many people on the bluelight most euphoric drug thread cite MDMA. This is likely due to the far lower number of methyl users though. I have never tried d-methylamphetamine but i have done d-amp hundreds of times. When I first used amphetamine, the pleasure I got from the high was extremely intense. Now, even if I take a very long break, the pleasure is nowhere near as high as it first was. This could be due to some neurotoxicity, who knows.

One thing I should mention, I find MDMA to be more pleasurable than d-amp anyday. It's something about that strong serotonergic feeling that really gets me going. Perhaps the anxiolysis, but no.. I think it is because it really is a uniquely pleasurable feeling. But then I guess it comes down to your definition of pleasure.

Many a day I have taken some d-amp during the day to go to work, and then tried taking a bit more later to go out but it has completely lost its ability to produce any pleasure anymore, even at the higher doses. Now figure this out: If I then take (200 mg or so of) MDMA, I get extremely intense pleasure as I normally would (as long as I don't do it too often.)

 

[Lupus]

Many a day I have taken some d-amp during the day to go to work, and then tried taking a bit more later to go out but it has completely lost its ability to produce any pleasure anymore, even at the higher doses. Now figure this out: If I then take (200 mg or so of) MDMA, I get extremely intense pleasure as I normally would (as long as I don't do it too often.)

Dosing with d-amp and redosing is a tricky thing. If you're just chasing the euphoria than its not worth your time because that ends in nothing but binging and a crash. Once you've taken a large dose and blown your DA load than you're not going to get that feeling back.

Treating the drug like a tool is much more useful than as a party substance.

 

[permastoned]

^ I know this now, when I said many a day, what I really meant was a few times a long while ago, until I learnt.

What I don't get then however, is how some people get addicted to d-amp. There is no use in taking it daily for me, the effect is completely gone by the third day and really not even worth it on the 2nd.

 

[MultiFaceted]

Need Sleep

Ok so we can get all scientific and blah blah blah but the psychosis and delusions are almost always just a simple result of not getting any sleep. As a LONG time tweaker I can speak with absolute certainty of this. You get delusional because your body needs sleep. I was never delusional on the first or second day of a high but come 3, 4 even 5 days of being constantly high, not eating, and not sleeping, I would get TOTALLY paranoid and start seeing things that werent there (the shadow people) and thinking delusional thoughts. Any of you out there that have gone on a three day run or longer know EXACTLY what i mean when i say the "shadow people". If you are experiencing any severe delusions or seeing imaginary, exaggerated things/people prior to going 48 hours without sleep than you probably have a pre-existing condition that has nothing to do with the crystal meth you are ingesting.

 

[New]

^Ha.

Truly understanding something can be the key to understanding events far beyond the scope of the original event. Why delusional patterns occur inside of the mind is a question whose answer could blow the doors of cognition wide open.