<p>This is not an a totally absurd proposal if dosage and time-related issues weren't a factor, but it is rife with practical difficulties otherwise.</p>
<p>In schizophrenia patients, what you're talking about has been widely studied, under terms like <a href="https://pubmed.ncbi.nlm.nih.gov/31077727/" rel="nofollow noreferrer">&quot;antipsychotic-evoked dopamine supersensitivity&quot;</a>, &quot;supersensitivity psychosis&quot; (SP) etc. The latter is <a href="https://www.karger.com/Article/Fulltext/477313" rel="nofollow noreferrer">basically</a> &quot;a limbic equivalent of TD&quot;.</p>
<p>The problem is that TD and SP are pretty correlated, in terms of the dosage required to obtain them, and require &quot;overdosing&quot; the (schizophrenia) patient. Typically, in order to obtain the anti-psychotic effect, 65%-80% peak striatal D2 occupancy is needed. TD/SP most commonly occur at greater than 80% occupancy.</p>
<p>Using 1st gen anti-psychotics (e.g. haloperidol) for this purpose in therapeutic is probably the worst idea, because achieving the desired super-sensitivity to striatal dopamine would mean giving the patient TD (tardive dyskinesia) with pretty high probability. TD is generally considered the worst side-effect of anti-psychotics (see previous link). You could say the cure (TD) is worse than the disease you'd want to treat (ADHD). On other hand, it may a little more plausible to do this with atypical (2nd gen) antipsychotics.</p>
<blockquote>
<p>For instance, quetiapine [39] and clozapine [33,40] can induce SP without producing overt or detectable drug-induced movement disorders.</p>
</blockquote>
<p>But atypical anti-psychotics aren't totally free of the risk of TD, they just reduce it.</p>
<p>Even disregarding side-effects (which AliceD's answer covers aplenty), which would actually be exacerbated by the high dosage needed, the problem is that the SP phenomenon (which would be the basis of propose cure for ADHD) is variable in time:</p>
<blockquote>
<p>The persistence of the dopamine supersensitivity syndrome depends on the duration of the preceding blockade [132] and on the specific antipsychotics used (fluphenazine, perphenazine, clozapine, and quetiapine) [1,41].</p>
</blockquote>
<p>So it would not be a cure for ADHD except possibly in small number of patients for whom the long-term effect comes out &quot;just right&quot;. There's also the obvious risk of &quot;overshooting&quot; and inducing actual likelihood of psychosis in someone (with ADHD) who didn't have such a risk.</p>
<p>In general, giving a patient a drug and adjusting the dosage until the desired effect is observed is simpler than giving a drug hoping for permanent effect that only stabilizes some time after not taking the drug.</p>
<p>On top of these, there's the issue that the exact mechanism of ADHD isn't absolutely sure. And that basically all psychotropics act on more than one neurotransmitter, so the don't totally cancel each other out. For these reasons, there are even <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2898838/" rel="nofollow noreferrer">publications</a> discussing co-medicating some/few patients with anti-psychotics and stimulants, even though these classes of drugs  partially cancel each other out.</p>
<hr />
<p>Now very interestingly, there is <a href="https://www.hindawi.com/journals/pd/2014/684973/" rel="nofollow noreferrer">a 2014 paper</a> (alas with only 6 citations) that does propose using very <em>low</em> doses of haloperidol as an adjuvant of L-Dopa in Parkisons precisely for this purpose of causing dopamine supersensitivity (and not for the common purpose of treating co-morbid psychosis that some Parkinson patients exhibit).</p>
<p>The trick that makes very low doses feasible for this purpose is that antipsychotics cause the D2 receptors to switch to a D2High (high-affinity) state. Apparently this switching happens even a low dosage of antipsychotics.</p>
<p>Unlike in your proposal though, although the effect apparently lasts for a while after haloperidol discontinuation, it begins on it.</p>
<blockquote>
<p><a href="https://i.sstatic.net/RsPrS.png" rel="nofollow noreferrer"><img src="https://i.sstatic.net/RsPrS.png" alt="enter image description here" /></a></p>
</blockquote>
<p>The authors of this paper also emphasize a more substantial decline in &quot;freezing&quot; (a Parkinson symptom) that may coincide with the peak (and delayed) effect of D2High caused by haloperidol, but frankly the data is pretty weak in that regard and one can easily level &quot;p-hacking&quot; at this particular finding:</p>
<blockquote>
<p><a href="https://i.sstatic.net/5Kyy4.png" rel="nofollow noreferrer"><img src="https://i.sstatic.net/5Kyy4.png" alt="enter image description here" /></a></p>
</blockquote>
<p>If it needs saying, even if this &quot;trick&quot; were to work better (e.g. with other doses), since Parkinson is neurodegenerative, there's only so much tweaking at the margin of the remaining neurons' sensitivity you can hope to do, before the loss of more/enough neurons overtakes that extra sensitivity.</p>
<p>Also, there actually many ways to trigger D2High states, stimulants themselves (e.g. amphetamine) <a href="https://www.pnas.org/content/102/9/3513.full" rel="nofollow noreferrer">do that</a>.</p>

CC BY-SA 4.0
2020-12-18T02:03:46.460Z
2020-12-18T05:20:44.380Z
2020-12-18T05:20:44.380Z
got trolled too much this week
<p><strong>Short answer</strong><br />
Taking dopamine antagonists leads to serious side effects, and stopping taking them leads to other, equally nasty side effects. None of them include happiness or feeling energized.</p>
<p><strong>Background</strong><br />
So basically, based on our discussion in the comments, I think you are after the following:</p>
<blockquote>
<p>Is it viable to use a drug originally meant to suppress dopamine
transmission to induce tolerance and thus increase dopaminergic
effects to enhance dopaminergic transmission to enhance mood and happiness after stopping the drug to reap the benefits of long-term 'withdrawal' symptoms?</p>
</blockquote>
<p>First off, drugs targeting the dopaminergic (DA) system are associated with serious negative side effects. To step into the class where you are after, the classical anti-psychotics that inhibit DA signaling are associated with the following side effects (taken from the <a href="https://www.webmd.com/drugs/2/drug-8661/haloperidol-oral/details#:%7E:text=Dizziness%2C%20lightheadedness%2C%20drowsiness%2C%20difficulty,increase%20the%20risk%20of%20falling." rel="nofollow noreferrer">page on haloperidol from WebMD</a>):</p>
<ul>
<li><p>dizziness</p>
</li>
<li><p>lightheadedness</p>
</li>
<li><p>drowsiness</p>
</li>
<li><p>difficulty urinating</p>
</li>
<li><p>sleep disturbances</p>
</li>
<li><p>headache</p>
</li>
<li><p>anxiety</p>
</li>
<li><p>in rare cases sometimes permanent tardive dyskinesia, a nasty side effect marked by stiff, jerky movements of the face and body, muscle twitches, eye blinking, tongue thrusting, uncontrollable shaking, or arm waving.</p>
</li>
<li><p>rarely neuroleptic malignant syndrome occurs including: fever, muscle stiffness or muscle pain or muscle weakness, tiredness, confusion, sweating, fast/irregular heartbeat, dark urine, and kidney problems.</p>
</li>
<li><p>And the list goes on, and on, and on (see also <a href="https://www.drugs.com/sfx/haldol-side-effects.html" rel="nofollow noreferrer">Drugs.com</a>)</p>
</li>
<li><p>Long term-use may lead to drug-induced Parkinsonism, which is actually the second most common cause of Pakinsonism in older people, after Parkinson's syndrome <a href="https://pmj.bmj.com/content/85/1004/322" rel="nofollow noreferrer">(Thanvi &amp; Treadwell, 2009</a>.</p>
</li>
</ul>
<p>Now fast forward to your withdrawal state that should make you happy, as dopamine transmission may indeed be exacerbated. The tolerance to haloperidol comes, at least in part, because D2 transmission is enhanced in the striatum in the brain <a href="https://www.nature.com/articles/npp2008116.pdf?origin=ppub" rel="nofollow noreferrer">(Ginovart <em>et al</em>., 2009)0</a>. This leads to the dreaded tardive dyskinesia.</p>
<p>Abrupt stopping haloperidol intake after chronic use results in side-effects on their own in psychotic patients (apart from re-inducing psychotic states), namely <a href="https://pubmed.ncbi.nlm.nih.gov/8464331/#:%7E:text=The%20current%20findings%20indicate%20that,and%20internal%20chaos%20(1)." rel="nofollow noreferrer">(Bronson, 1993)</a>:</p>
<ul>
<li>nausea and vomiting</li>
<li>sweating</li>
<li>as well as a relapse into psychosis characterized by anxiety, depression and internal chaos. Interestingly, the authors conclude that the so-called relapse into psychosis may actually be caused by withdrawal instead of the underlying disease state .</li>
</ul>
<p>In all, happiness doesn't seem part of the deal of acute withdrawal from a well-investigated dopamine antagonist, unfortunately. Taking them is a pain, and stopping them abruptly is also not a pleasant thing to do either. When you slowly decrease dosage the withdrawal side effects will be less severe.</p>
<p><sub><strong>References</strong><br />
<strong>-</strong> <a href="https://pubmed.ncbi.nlm.nih.gov/8464331/#:%7E:text=The%20current%20findings%20indicate%20that,and%20internal%20chaos%20(1)." rel="nofollow noreferrer">Bronson, <em>Life Sci</em> (1993); <strong>52</strong>(16): PL129-33</a><br />
<strong>-</strong> <a href="https://www.nature.com/articles/npp2008116.pdf?origin=ppub" rel="nofollow noreferrer">Ginovart <em>et al</em>., <em>Neuropsychopharmacology</em> (2009); <strong>34</strong>: 62–671</a><br />
<strong>-</strong> <a href="https://pmj.bmj.com/content/85/1004/322" rel="nofollow noreferrer">Thanvi &amp; Treadwell, <em>BMJ</em> (2009); <strong>85</strong>(1004): 322</a></sub></p>

CC BY-SA 4.0
2020-12-17T13:02:32.583Z
2020-12-17T13:13:16.223Z
2020-12-17T13:13:16.223Z
AliceD
<p>So this may be a stupid question as I am not trained in neuroscience or psychology at all, but I had an idea about a somewhat counterintuitive approach to psychotropics and was wondering whether if it was at all scientifically sound and feasible.</p>
<p>To distill my theory, it's basically that in the same way prolonged cocaine abuse can make you chronically unhappy and apathetic, could we encourage some sort of controlled antipsychotic abuse to make you chronically happy and energized? My thinking is this:</p>
<p>Since the mechanism of antipsychotic drugs in an oversimplified sense is just to decrease dopamine, naturally when you withdraw your brain would respond by having an increase of dopamine. More specifically, since your brain overreacts to the antipsychotics it starts dramatically over sensitizing your brain to dopamine. So it seems to me that the reverse effect of the withdrawal is way more powerful than the direct &quot;purpose&quot; of the drug (this is in a sense how I understand the condition of tardive dyskinesia).
My thought is that this approach is particularly advantageous for the long-term use of physiatric drugs since in the long term the use of physiatric drugs has very little effect (and can sometimes even entrench mental illness further). Because of the fact that when dependence is developed the brain's structure and functioning in response to the ongoing presence of psychiatric medication is changing, it seems that developing drugs whose intended effects come from withdrawal would help resolve issues surrounding tolerance (as protracted withdrawal can sometimes last for years after the last dose of a drug was taken).
Is it viable to use a drug originally meant to suppress dopamine transmission to induce tolerance and thus increase dopaminergic effects to treat another disease where more dopamine is needed? For instance, can we use the anti-dopaminergic compound haloperidol to induce tolerance to address lower concentrations of dopamine transporters in people with ADHD, as opposed to using amphetamines?</p>

CC BY-SA 4.0
2020-12-17T11:53:31.503Z
You say *it seems that developing drugs whose intended effects come from withdrawal would help resolve issues surrounding tolerance*. So what is it you are after? Curing psychosis or withdrawal? Or counteracting the side effects of the two? It may be just me, but I am still at a loss. Try to wrap up your hypothesis at the end with a specific question...
AliceD
CC BY-SA 4.0
2020-12-17T11:53:48.587Z
....like *'Is it viable to use a drug originally meant to suppress dopamine transmission to induce tolerance and thus increase dopaminergic effects to treat another disease where more dopamine is needed? For instance, can we use the anti-dopaminergic compound haloperidol to induce tolerance to treat Parkinson's where a shortage of dopamine is the cause?*. I'm not saying that this is your question (it's just what I can make from it), but it would lead to a working hypothesis, instead of a thought experiment that can be interpreted in multiple ways.
AliceD
CC BY-SA 4.0
2020-12-17T12:13:29.700Z
Yes, this is exactly my question! Except I was thinking about it in the context of amphetamines, but this is also a good example. Edited my question to include this. Sorry for being so unclear.
pctree
CC BY-SA 4.0
2020-12-21T18:58:42.303Z
Psychiatrist Scott Alexander discusses this idea briefly here: https://slatestarcodex.com/2016/08/15/tolerance-troubles/
Arnon Weinberg
<neuroscience><psychopharmacology><drugs><medication>
How to take advantage of the withdrawal symptoms of antidopaminergics?
pctree
# How to take advantage of the withdrawal symptoms of antidopaminergics?

(Asked by: username_0 on 2020-12-17)

So this may be a stupid question as I am not trained in neuroscience or psychology at all, but I had an idea about a somewhat counterintuitive approach to psychotropics and was wondering whether if it was at all scientifically sound and feasible.

To distill my theory, it's basically that in the same way prolonged cocaine abuse can make you chronically unhappy and apathetic, could we encourage some sort of controlled antipsychotic abuse to make you chronically happy and energized? My thinking is this:

Since the mechanism of antipsychotic drugs in an oversimplified sense is just to decrease dopamine, naturally when you withdraw your brain would respond by having an increase of dopamine. More specifically, since your brain overreacts to the antipsychotics it starts dramatically over sensitizing your brain to dopamine. So it seems to me that the reverse effect of the withdrawal is way more powerful than the direct "purpose" of the drug (this is in a sense how I understand the condition of tardive dyskinesia).
My thought is that this approach is particularly advantageous for the long-term use of physiatric drugs since in the long term the use of physiatric drugs has very little effect (and can sometimes even entrench mental illness further). Because of the fact that when dependence is developed the brain's structure and functioning in response to the ongoing presence of psychiatric medication is changing, it seems that developing drugs whose intended effects come from withdrawal would help resolve issues surrounding tolerance (as protracted withdrawal can sometimes last for years after the last dose of a drug was taken).
Is it viable to use a drug originally meant to suppress dopamine transmission to induce tolerance and thus increase dopaminergic effects to treat another disease where more dopamine is needed? For instance, can we use the anti-dopaminergic compound haloperidol to induce tolerance to address lower concentrations of dopamine transporters in people with ADHD, as opposed to using amphetamines?

**Tags:** neuroscience, psychopharmacology, drugs, medication

> **Comments:**
> **username_1**: You say *it seems that developing drugs whose intended effects come from withdrawal would help resolve issues surrounding tolerance*. So what is it you are after? Curing psychosis or withdrawal? Or counteracting the side effects of the two? It may be just me, but I am still at a loss. Try to wrap up your hypothesis at the end with a specific question...  
> **username_1**: ....like *'Is it viable to use a drug originally meant to suppress dopamine transmission to induce tolerance and thus increase dopaminergic effects to treat another disease where more dopamine is needed? For instance, can we use the anti-dopaminergic compound haloperidol to induce tolerance to treat Parkinson's where a shortage of dopamine is the cause?*. I'm not saying that this is your question (it's just what I can make from it), but it would lead to a working hypothesis, instead of a thought experiment that can be interpreted in multiple ways.  
> **username_0**: Yes, this is exactly my question! Except I was thinking about it in the context of amphetamines, but this is also a good example. Edited my question to include this. Sorry for being so unclear.  
> **username_2**: Psychiatrist Scott Alexander discusses this idea briefly here: https://slatestarcodex.com/2016/08/15/tolerance-troubles/  

---

## 2 answers

### Answer by username_3 on 2020-12-18. Score: 2

This is not an a totally absurd proposal if dosage and time-related issues weren't a factor, but it is rife with practical difficulties otherwise.

In schizophrenia patients, what you're talking about has been widely studied, under terms like ["antipsychotic-evoked dopamine supersensitivity"](https://pubmed.ncbi.nlm.nih.gov/31077727/), "supersensitivity psychosis" (SP) etc. The latter is [basically](https://www.karger.com/Article/Fulltext/477313) "a limbic equivalent of TD".

The problem is that TD and SP are pretty correlated, in terms of the dosage required to obtain them, and require "overdosing" the (schizophrenia) patient. Typically, in order to obtain the anti-psychotic effect, 65%-80% peak striatal D2 occupancy is needed. TD/SP most commonly occur at greater than 80% occupancy.

Using 1st gen anti-psychotics (e.g. haloperidol) for this purpose in therapeutic is probably the worst idea, because achieving the desired super-sensitivity to striatal dopamine would mean giving the patient TD (tardive dyskinesia) with pretty high probability. TD is generally considered the worst side-effect of anti-psychotics (see previous link). You could say the cure (TD) is worse than the disease you'd want to treat (ADHD). On other hand, it may a little more plausible to do this with atypical (2nd gen) antipsychotics.

> For instance, quetiapine [39] and clozapine [33,40] can induce SP without producing overt or detectable drug-induced movement disorders.

But atypical anti-psychotics aren't totally free of the risk of TD, they just reduce it.

Even disregarding side-effects (which username_1's answer covers aplenty), which would actually be exacerbated by the high dosage needed, the problem is that the SP phenomenon (which would be the basis of propose cure for ADHD) is variable in time:

> The persistence of the dopamine supersensitivity syndrome depends on the duration of the preceding blockade [132] and on the specific antipsychotics used (fluphenazine, perphenazine, clozapine, and quetiapine) [1,41].

So it would not be a cure for ADHD except possibly in small number of patients for whom the long-term effect comes out "just right". There's also the obvious risk of "overshooting" and inducing actual likelihood of psychosis in someone (with ADHD) who didn't have such a risk.

In general, giving a patient a drug and adjusting the dosage until the desired effect is observed is simpler than giving a drug hoping for permanent effect that only stabilizes some time after not taking the drug.

On top of these, there's the issue that the exact mechanism of ADHD isn't absolutely sure. And that basically all psychotropics act on more than one neurotransmitter, so the don't totally cancel each other out. For these reasons, there are even [publications](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2898838/) discussing co-medicating some/few patients with anti-psychotics and stimulants, even though these classes of drugs partially cancel each other out.

---

Now very interestingly, there is [a 2014 paper](https://www.hindawi.com/journals/pd/2014/684973/) (alas with only 6 citations) that does propose using very *low* doses of haloperidol as an adjuvant of L-Dopa in Parkisons precisely for this purpose of causing dopamine supersensitivity (and not for the common purpose of treating co-morbid psychosis that some Parkinson patients exhibit).

The trick that makes very low doses feasible for this purpose is that antipsychotics cause the D2 receptors to switch to a D2High (high-affinity) state. Apparently this switching happens even a low dosage of antipsychotics.

Unlike in your proposal though, although the effect apparently lasts for a while after haloperidol discontinuation, it begins on it.

> [![enter image description here](https://i.sstatic.net/RsPrS.png)](https://i.sstatic.net/RsPrS.png)

The authors of this paper also emphasize a more substantial decline in "freezing" (a Parkinson symptom) that may coincide with the peak (and delayed) effect of D2High caused by haloperidol, but frankly the data is pretty weak in that regard and one can easily level "p-hacking" at this particular finding:

> [![enter image description here](https://i.sstatic.net/5Kyy4.png)](https://i.sstatic.net/5Kyy4.png)

If it needs saying, even if this "trick" were to work better (e.g. with other doses), since Parkinson is neurodegenerative, there's only so much tweaking at the margin of the remaining neurons' sensitivity you can hope to do, before the loss of more/enough neurons overtakes that extra sensitivity.

Also, there actually many ways to trigger D2High states, stimulants themselves (e.g. amphetamine) [do that](https://www.pnas.org/content/102/9/3513.full).


---

### Answer by username_1 on 2020-12-17. Score: 1

**Short answer**  
Taking dopamine antagonists leads to serious side effects, and stopping taking them leads to other, equally nasty side effects. None of them include happiness or feeling energized.

**Background**  
So basically, based on our discussion in the comments, I think you are after the following:

> Is it viable to use a drug originally meant to suppress dopamine
> transmission to induce tolerance and thus increase dopaminergic
> effects to enhance dopaminergic transmission to enhance mood and happiness after stopping the drug to reap the benefits of long-term 'withdrawal' symptoms?

First off, drugs targeting the dopaminergic (DA) system are associated with serious negative side effects. To step into the class where you are after, the classical anti-psychotics that inhibit DA signaling are associated with the following side effects (taken from the [page on haloperidol from WebMD](https://www.webmd.com/drugs/2/drug-8661/haloperidol-oral/details#:%7E:text=Dizziness%2C%20lightheadedness%2C%20drowsiness%2C%20difficulty,increase%20the%20risk%20of%20falling.)):

* dizziness
* lightheadedness
* drowsiness
* difficulty urinating
* sleep disturbances
* headache
* anxiety
* in rare cases sometimes permanent tardive dyskinesia, a nasty side effect marked by stiff, jerky movements of the face and body, muscle twitches, eye blinking, tongue thrusting, uncontrollable shaking, or arm waving.
* rarely neuroleptic malignant syndrome occurs including: fever, muscle stiffness or muscle pain or muscle weakness, tiredness, confusion, sweating, fast/irregular heartbeat, dark urine, and kidney problems.
* And the list goes on, and on, and on (see also [Drugs.com](https://www.drugs.com/sfx/haldol-side-effects.html))
* Long term-use may lead to drug-induced Parkinsonism, which is actually the second most common cause of Pakinsonism in older people, after Parkinson's syndrome [(Thanvi & Treadwell, 2009](https://pmj.bmj.com/content/85/1004/322).

Now fast forward to your withdrawal state that should make you happy, as dopamine transmission may indeed be exacerbated. The tolerance to haloperidol comes, at least in part, because D2 transmission is enhanced in the striatum in the brain [(Ginovart *et al*., 2009)0](https://www.nature.com/articles/npp2008116.pdf?origin=ppub). This leads to the dreaded tardive dyskinesia.

Abrupt stopping haloperidol intake after chronic use results in side-effects on their own in psychotic patients (apart from re-inducing psychotic states), namely [(Bronson, 1993)](https://pubmed.ncbi.nlm.nih.gov/8464331/#:%7E:text=The%20current%20findings%20indicate%20that,and%20internal%20chaos%20(1).):

* nausea and vomiting
* sweating
* as well as a relapse into psychosis characterized by anxiety, depression and internal chaos. Interestingly, the authors conclude that the so-called relapse into psychosis may actually be caused by withdrawal instead of the underlying disease state .

In all, happiness doesn't seem part of the deal of acute withdrawal from a well-investigated dopamine antagonist, unfortunately. Taking them is a pain, and stopping them abruptly is also not a pleasant thing to do either. When you slowly decrease dosage the withdrawal side effects will be less severe.

**References**  
**-** [Bronson, *Life Sci* (1993); **52**(16): PL129-33](https://pubmed.ncbi.nlm.nih.gov/8464331/#:%7E:text=The%20current%20findings%20indicate%20that,and%20internal%20chaos%20(1).)  
**-** [Ginovart *et al*., *Neuropsychopharmacology* (2009); **34**: 62–671](https://www.nature.com/articles/npp2008116.pdf?origin=ppub)  
**-** [Thanvi & Treadwell, *BMJ* (2009); **85**(1004): 322](https://pmj.bmj.com/content/85/1004/322)


---

