What is dopamine agonist withdrawal syndrome (DAWS) and why don't other dopaminergics improve it

DAWS is a debilitating protracted syndrome that lasts for months or years on end. Scientists don't know how it is caused as of yet, so I present my own hypothesis here and how to find symptomatic relief based on my experience with patients.

Dopamine agonists - mechanism of action

Dopamine agonists work by mimicking dopamine's binding to its receptors. The majority of these agents are selective to D2-like receptor family (D2, D3, D4), with classical ergot-based ones also having affinity to several serotonin receptors as well (Cabergoline, Bromocriptine, etc). During the adaptation phase, dopamine agonists bind to the D2/D3 presynaptic autoreceptors, reducing phasic dopamine release [1]. This triggers symptoms typical of dopamine agonist adaptation such as excessive drowsiness. After a couple of weeks, the autoreceptors become desensitized and net activation of postsynaptic receptors increases.


Since dopamine agonists are selective to D2-like and activate them in a tonic manner consistently without a stimulus, they don't have abuse potential since for an euphoric reaction phasic activation is essential - and D1-like family activation plays an important role in addiction [2][3]. Other tonic dopaminergics also lack abuse potential, such as MAO-B inhibitors (Selegiline, Rasagiline, ..) and levodopa-carbidopa.


Tonic dopaminergics are mainly used for the management of Parkinson's disease and prolactinomas. They have been used off-label for the management of restless leg syndrome (RLS) and sexual dysfunction. Phasic dopaminergics, on the other hand, potentiate stimulus-based firing of dopamine, activating limbic receptors in a transient phasic manner, and allowing for euphoria and behavioral conditioning [4]. Long-term potentiation (LTP) then drives dependency and addiction [5][6][7]. Examples of phasic dopaminergics are psychostimulants such as dopamine releasing agents (Amphetamines, Methamphetamines, Cathinones, ...) dopamine reuptake inhibitors (Methylphenidate, Modafinil, Amineptine, ...)

Dopamine agonist withdrawal syndrome (DAWS)

If dopamine agonists lack abuse potential, then it makes no sense that they can induce such a severe protracted syndrome as DAWS - but they do. Let's examine the symptoms [8]:

  • Severe, debilitating depression.

  • Suicidal ideation.

  • Severe anxiety.

  • Panic attacks.

  • Dysphoria.

  • Agitation and irritability.

  • Fatigue and drowsiness.

  • Orthostatic hypotension.

  • Nausea and vomiting.

  • Diaphoresis.

  • Generalized pain.

The severity and prognosis of DAWS is highly variable, with some patients having transient symptoms and making a full recovery, while others have a protracted withdrawal syndrome lasting for months to years to decades. Risk factors for DAWS include impulse control behavior disorders (ICD), higher dopamine agonist dosage, and history of deep brain stimulation [9].

Is DAWS purely a condition of a dopaminergic deficit?

Although DAWS is caused by dopamine agonists, the condition is not exclusively dopaminergic in nature. Evidence that supports this is the lack of efficacy of various dopaminergic agents in combating it. DAWS only responds to dopamine agonist and not to levodopa or other dopaminergic medications [10].


My hypothesis: Serotonin, norepinephrine, apoptosis & neuroinflammation

It's important to examine the downstream (indirect) action of dopamine agonists in order to understand DAWS' etiology. It is found that Pramipexole alters the firing rate of DA, NE and 5-HT neurons. Furthermore, it also desensitizes presynaptic 5HT1A autoreceptor and the alpha-2 aderenergic autoreceptor [11]. This can explain some of DAWS symptoms if there is rebound 5HT1A and alpha-2 adrenergic sensitivity upon withdrawal. It could also explain why some DAWS symptoms respond to antidepressants. Rebound sensitivity of alpha-2 adrenergic receptors could explain the orthostatic hypotension and fatigue seen in DAWS.


It's also important to take into consideration other mechanisms of action unrelated to dopamine agonism. For example, Pramipexole prevents apoptosis through inhibition of c-jun NH2-terminal kinase (JNK) and p38 MAP kinase [12] and concentration-dependent inhibition of opening of the mitochondrial transition pore [13]. These actions alter the programmed cell death (apoptosis) of neurons and affects brain mitochondrial energy status [14]. With homeostasis in mind, withdrawal from Pramipexole could have unforeseen consequences.


Another example is how Cabergoline and Bromocriptine have high affinity to 5HT1A receptor and other serotonin receptors [15][16]. Long-term intake would cause desensitization of autoreceptors and an antidepressant-like effect and increase of BDNF [17]. Withdrawal from these dopamine agonists would therefore be expected to cause a rebound sensitivity of autoreceptors, decreasing serotonin firing and inducing depressive symptoms.

Conclusion:

DAWS may not be solely dopaminergic in nature and it's important to take the downstream effects into consideration when dealing with it.


Finally, patients suffering from DAWS who I've talked to report partial symptomatic relief on antidepressants, Cyproheptadine, and Metformin. Complete relief is not possible without reinstatement the offending dopamine agonist as of yet, however.


Metformin has been found to have an antidepressant effect recently by regulating the AMPK/Tet2/BDNF pathway [18][19] and by increasing serotonin's availability in the brain [20].


Pancreatic beta cells express D2 and D3 dopamine receptors which control insulin secretion [21], perhaps that is another mechanism behind some symptoms of DAWS and why Metformin helps. Something to think about.

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