Histamine & Possible Role In PSSD
Updated: Mar 31, 2021
I was requested to look a bit deeper into the histamine role in PSSD. Some patients report getting a window of relief after taking l-histidine, or even when they have fallen ill with the flu. So here are some of my findings. (This is a follow up and replacement to my previous article on histamine)
Histamine is an excitatory and mood-brightening neurotransmitter. There is a statistically significant correlation between major depressive disorder and low neuronal histamine level.
Antidepressants' effect on DAO and HNMT expression:
In mammals, histamine is mainly metabolized by diamine oxidase (DAO) and histamine-N-methyltransferase (HNMT). Tricyclic antidepressants (TCAs) induce enzyme mRNA synthesis and increase enzyme activity, and consequently lower tissue histamine concentration. Sertraline increases DAO activity, but had no effect on HNMT activity. 
Furthermore, antidepressants require the histamine system and it is crucial for exerting their effects , so it makes sense that PSSD is closely linked to the histaminergic system. SSRIs, or at least Citalopram, induces genome-wide DNA methylation alteration, which reduces oxytocin and dopamine functioning, but also sex hormones and histamine. 
I believe that PSSD symptoms reflect low histamine level in most cases. This, and increased epigenetic methylation, are closely implicated in PSSD pathophysiology by mechanisms sometimes unrelated to their serotonin reuptake inhibition. But before we go on about altering it, we must arm ourselves with the fundamental knowledge first.
L-histidine is converted into histamine by the histidine decarboxylase enzyme (HDC).
This HDC enzyme is the rate-limiting step in histamine synthesis. What that means is that the amount you have of this enzyme determines how much histamine you might end up with before HDC gets depleted.
In the brain, The tuberomammillary nucleus (TMN) function as the neuronal nucleus or central hub of histaminergic neurons.   
Histaminergic loci send projections to the prefrontal cortex, anterior insula and orbitofrontal cortices. This is of extreme importance, as these are appetitive, sexual and generally responsible for motivation-driven activities (feeding, sex, etc). However, high histamine state would blunt these on a chronic basis due to compensatory downregulation as a function of neuronal plasticity. 
There are two main pathways histamine can be degraded through. The first pathway is extracellular (outside of the cell), utilizing the diamine oxidase enzyme (DAO) (15 to 30%). The second pathway is intracellular (inside of the cell), utilizing the histamine N-methyltransferase enzyme (HNMT) (50 to 80%). 
Histamine, unlike other neurotransmitters, doesn't have a typical transporter protein. Two other things of note here:
1- DAO enzyme is an amine oxidase that needs copper. This means that zinc-to-copper balance and copper-related diseases can affect histamine breakdown. 
2- HNMT enzyme requires a methyl donor group from SAM-e. The state of one's methylation cycle and certain brain diseases can impact histamine breakdown through this pathway. 
There are many contradictory studies when it comes to histamine's interaction with dopamine. Perhaps to best understand how these receptors work, one must take into account duration and type of activation (acute vs. chronic / phasic vs. tonic) as well as how the receptors react adaptively to said modes of stimulation.
Histamine administration within the mesolimbic system stimulates dopamine firing in the nucleus accumbens, an effect which is reversible with an H1 antagonist . Yet, in other studies H1 antagonist administration facilitated dopamine firing in the nucleus accumbens and the striatum  .
Perhaps this discrepancy can be solved by reading another study  that shows that H1 antagonism initially (acutely) enhances dopamine release, but dopamine receptor downregulation occurs soon after (i.e. after chronic H1 antagonism). It means that H1 antagonists, as well as low histamine states, might facilitate dopamine release initially but end up blunting limbic dopamine signaling later on through downregulation, which makes sense from an adaptive point of view. 
Perhaps, then, we can deduct that H1 agonism might possibly increase dopamine firing by initially inhibiting it, leading to upregulation of dopaminergic firing. That, or both agonism and antagonism might facilitate dopamine release equally. Personally, I'm more convinced of the former.
"Mice lacking H1R (Inoue et al., 1996) show reduced exploratory behavior (ambulation and rearings) in a novel environment. Furthermore, mice lacking H1Rs show reduced emotional responses to a novel environment and do not generate a place preference conditioned by the novel object; however, they do explore (consummatory behavior?) new objects in a familiar setting (Zlomuzica et al., 2008)"
Remember: this is a phasic response; it depends on external stimuli.
H1 receptors are stimulatory to tyrosine hydroxylase, LTP and NMDAR as well as nitric oxide and these effects are important for sexual functioning.  . H1 receptors, therefore, might play a significant role in PSSD 
H1 receptors are very important for sexual arousal at least in females, this is mediated by estrogen via upregulation of hypothalamic (VMN) H1 receptor expression. H1 receptors in that area promotes sexual arousal. 
H2 activation acutely increases limbic dopamine release and enhance penile erection in a phasic manner.   They also enhance endothelial nitric oxide release.  Tonic stimulation wouldn't be ideal though since H2 receptors increase gastric acid.
H2 receptors modulate Leydig cell steroidogenesis, being stimulatory in nature to sex hormone synthesis and release .
This receptor subtype is an autoreceptor for histamine and also inhibits release of several neurotransmitters (histamine, acetylcholine, dopamine, norepinephrine, serotonin, glutamate and GABA). 
However, it's much more complex than that. H3 receptors form heterodimers with both D1 and D2 receptors in the dorsal and ventral striatum, where the vast majority of H3 receptors are located postsynaptically. This mediates enhancement of dopamine activation through cross-activation.  H3 also form a heteroreceptor complexes with NMDA receptors, mediating NMDA potentiation and enhancing LTP also through cross-activation. 
However, due to disinhibition of several neurotransmitters, including glutamate, antagonism of H3 receptors have memory and mood promoting as well as nootropic effects. 
H3 receptors are expressed in substantia nigra compacta where it facilitate GABAergic neurotransmission, this leads to blocking of DA neurons there.  The substantia nigra compacta is important for music pleasure and hyperlocomotion. The substantia nigra pars compacta projects to the dorsal striatum; it is an area responsible for feeling the effects of infatuation & love. 
This subtype is relatively newly discovered, as such there isn't much research on its function aside from peripherally on mast cells. However, I did find that H4 histamine receptors inhibit steroidogenesis and proliferation in Leydig cells. . That being said, it's been found to be present in the mammalian neurons, so it must have a CNS effect as well that's still largely unexplored. 
4- Histamine modulation in PSSD:
OK, so we don't want to increase peripheral histamine levels — just central one. Although histamine is known to increase the blood-brain barrier (BBB)'s permeability, it hardly passes the BBB itself.  
Targeting the synthesis:
The histidine decarboxylase enzyme (HDC) is the rate-limiting step in histamine synthesis. This means one can raise histamine level by taking L-histidine but it won't be a significant elevation as there's a ceiling/limit what you can achieve.
Targeting the degradation enzymes:
Diamine oxidase enzyme (DAO) is responsible for 15 to 30% of histamine's break down while histamine-N-methyltransferase enzyme (HNMT) is responsible for 50 to 80% as mentioned earlier. Since we are talking CNS here, HNMT is the one we should focus on.
As you can see, the list is short and full of either chemotherapeutic drugs used for tumors or others that have pretty nasty side-effect profile. Definitely not suitable for trialing.
Targeting methylation and copper/zinc:
Since DAO is a copper-based enzyme, copper-to-zinc balance can affect its activity to a mild degree. Avoiding methyl- donors like SAM-e can also probably raise histamine a little bit. Each option has low potential and probably not very useful, to be honest.
Targeting H3 autoreceptors:
Finally, this mechanism is the most promising and perhaps even the most potent. Remember how this autoreceptor controls so many excitatory neurotransmitters?
It blocks histamine, acetylcholine, dopamine, norepinephrine, serotonin, glutamate and GABA release. I'd imagine that blocking H3 autoreceptor would feel like a powerful psychostimulant.
It makes sense that low histamine levels are extremely depressive, at least if H3 autoreceptors are to blame for it since it doesn't only involve histamine alone.
Betahistine is H3 antagonist but its effects are too weak with therapeutically approved doses. It seems to work mostly on the inner ear. Higher doses have noticeable CNS effect albeit mild.
Pitolisant is H3 inverse agonist that has more promise. It's prescribed for excessive daytime sleepiness in narcolepsy.
Targeting histamine release indirectly:
D2 brain receptor activation enhances the TMN neuronal firing frequency, histamine release, and wakefulness. This is the case with dopaminergic psychostimulants such as amphetamine salts. 
Modafinil can lead to histamine activation indirectly via attenuation of GABAergic input.  It also indirectly increases histamine release in the anterior hypothalamus resulting in wakefulness and, perhaps, indirect facilitation of libido. 
Low histamine release could be one of the pathological mechanisms PSSD triggers a plethora of depressive symptoms. Histamine directly control several neurotransmitters through H3 autoreceptors it can certainly explain many of PSSD symptoms although this requires studies and research to directly confirm or deny. Without these, it remains to be speculation.