PAS and PSSD have remarkable similarities, both involve persisting sexual dysfunction along with other mental side effects such as depersonalisation, anhedonia, depression and apathy/emotional numbness. Both conditions appear to be fairly unresponsive to hormone therapy and dopamine agonists. This is unusual as both androgen therapy and dopamine agonists act directly on the dopaminergic system of the brain, which is thought to play a major role in sexual function, reward and pleasure. One possible reason for this, is a dysfunction with the dopaminergic system itself as in Schizophrenia, which is looked at in another thread. Another possibility is that there is an excessive inhibitory mechanism acting on the dopaminergic system to suppress dopaminergic activity in important regions of the brain leading to these symptoms.
For PSSD, it's thought that the sensitivity of serotonin (5HT) receptors specifically 5HT1A auto-receptors involved in modulating serotonergic activity, has been altered due to the excessive levels of serotonin produced by SSRI usage. These desensitised 5HT1A receptors lead to enhanced serotonergic activity which persistently dampens/suppresses dopaminergic activity.
Its possible that Accutane has altered serotonergic activity. One study has shown that Accutane significantly increases 5HT1A receptor expression, synthesis of serotonin and SERT protein levels in a rat cell line. This cell line specifically expressed 5HT1A receptors (1). Thus its possible Accutane causes PAS by changing the serotonin system through the 5HT1A receptor or by increasing the expression of other 5HT receptors. One such receptor is the 5HT2C receptor.
5HT2C receptors
5HT2C receptors are highly expressed throughout the mesocorticolimbic dopamine system of humans. This system is made up of dopamine releasing neurons of the ventral tegmental area (VTA) which projects to the nucleus accumbens and prefrontal cortex (PFC) (2). The mesocorticolimbic system plays a significant role in motivation, pleasure and reward seeking behaviour. There are strong reasons to suggest that most of the symptoms of PAS can be explained by a dysfunction of this brain region particularly the mesolimbic pathway.
5HT2C receptors have also been found in the striatum and appear to negatively regulate dopamine efflux and thus dopaminergic activity (3). Its been found that over-expression of 5HT2C receptors in the forebrain is associated with elevated anxiety and hypoactivity (4).
Studies in male mice also indicate that 5HT2C activation may have a suppressive influence on the control of male sexual behaviour (5).
There isn't much research concerning the effect of Accutane on 5HT receptors particularly 5HT2C receptors. However, one study showed that all-trans retinoic acid (metabolite of Accutane) significantly enhanced the expression of 5HT2C receptors in the early stages of differentiation of embryonal carcinoma cells. This has been proposed to occur as a result of epigenetic activation (6). Thus its possible Accutane could increase 5HT2C receptor expression in the adult brain.
Another interesting facet of 5HT2C receptors is that they can remain constitutively active, meaning they can have activity in the absence of a ligand/serotonin. They also undergo RNA editing, and there are several isoforms of the 5HT2C receptor meaning that some drugs which act as 5HT2C receptor antagonists don't necessarily act on all receptors. Agomelatine for example is a 5HT2C antagonist but it doesn't appear to work on the 5HT2C receptors in the mesolimbic pathway (7).
Given this, its possible that Accutane has substantially increased 5HT2C receptors in susceptible individuals resulting in greatly diminished dopaminergic activity in important brain regions such as the reward pathway. Reduced dopamine activity in the prefrontal cortex would also help to explain cognitive deficits which some users report.
Treatments and ways to investigate this
Given the constitutive activity of 5HT2C receptors, an inverse agonist would be more useful than antagonists. We would also need compounds which are capable of acting at 5HT2C receptors in the mesocorticolimbic pathway, which would exclude agomelatine. Here is a list of compounds I could find, unfortunately its difficult to find highly specific compounds which are in mass production. Thus several compounds which have a great activity profile are research chemicals and are incredibly expensive to buy. It's also best to avoid 5HT2A antagonism as it inhibits dopamine release. Here is a list in no particular order:
SB 242084 (This would be ideal) - Highly selective 5HT2C antagonist which appears to work on receptors of the mesolimbic system of rats. However it is currently a research chemical and so is very expensive.
5HT2C inverse agonists in order of strength - SB 206553 = Clozapine -> Mianserin -> Mesulergine = Ketanserin (8).
Sertindole - Antipsychotic - 5HT2C inverse agonist with high affinity to D2 and 5HT2A.
Pizotifen - Migraine pill with 5HT2C and 5HT2A antagonism.
Cyproheptadine - Strong antagonist of 5HT2A, 5HT2C and 5HT2B. However is also a strong antihistamine (sedative effect).
Metergoline - 5HT1B, 5HT2B, 5HT2C and dopamine agonist.
Buspirone - Reduces serotonin signalling by acting as an agonist at 5HT1A auto receptor. Also a weak 5HT2C antagonist. Well tolerated drug. Definitely worth trying, especially if you suffer from anxiety.
Other possible options worth trying
Bupropion - Inhibits dopamine re-uptake particularly in the prefrontal cortex, leads to enhanced dopaminergic neurotransmission in nucleus accumbens and prefrontal cortex.
Pramipexole - Activates D2/D3 receptors in prefrontal cortex, striatum, amygdala and thalamus. Helped some users on All Things Male forum but efficacy wore off eventually. Also some users have reported no benefit.
Berberine - Activates 5HT1A auto-receptors and inhibits post synaptic 5HT1A and 5HT receptors - Showed some efficacy in people with PSSD.
St Johns Wort - It has shown some effectiveness in people with PSSD.
Vraylar - weak 5HT2C inverse agonist (low affinity), 5HT2B antagonist, activity at dopamine receptors - Shown benefit for anhedonia.
Histidine - Helps regulate excess serotonin signalling.
(1) - https://www.ncbi.nlm.nih.gov/pubmed/17895527
(2) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422522/
(3) - https://www.ncbi.nlm.nih.gov/pubmed/15668911
(4) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777260/
(5) - https://www.ncbi.nlm.nih.gov/pubmed/12097814
(6) - https://www.ncbi.nlm.nih.gov/pubmed/15242780
(7) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128060/
(8) - http://molpharm.aspetjournals.org/content/55/5/863
- flynn
For PSSD, it's thought that the sensitivity of serotonin (5HT) receptors specifically 5HT1A auto-receptors involved in modulating serotonergic activity, has been altered due to the excessive levels of serotonin produced by SSRI usage. These desensitised 5HT1A receptors lead to enhanced serotonergic activity which persistently dampens/suppresses dopaminergic activity.
Its possible that Accutane has altered serotonergic activity. One study has shown that Accutane significantly increases 5HT1A receptor expression, synthesis of serotonin and SERT protein levels in a rat cell line. This cell line specifically expressed 5HT1A receptors (1). Thus its possible Accutane causes PAS by changing the serotonin system through the 5HT1A receptor or by increasing the expression of other 5HT receptors. One such receptor is the 5HT2C receptor.
5HT2C receptors
5HT2C receptors are highly expressed throughout the mesocorticolimbic dopamine system of humans. This system is made up of dopamine releasing neurons of the ventral tegmental area (VTA) which projects to the nucleus accumbens and prefrontal cortex (PFC) (2). The mesocorticolimbic system plays a significant role in motivation, pleasure and reward seeking behaviour. There are strong reasons to suggest that most of the symptoms of PAS can be explained by a dysfunction of this brain region particularly the mesolimbic pathway.
5HT2C receptors have also been found in the striatum and appear to negatively regulate dopamine efflux and thus dopaminergic activity (3). Its been found that over-expression of 5HT2C receptors in the forebrain is associated with elevated anxiety and hypoactivity (4).
Studies in male mice also indicate that 5HT2C activation may have a suppressive influence on the control of male sexual behaviour (5).
There isn't much research concerning the effect of Accutane on 5HT receptors particularly 5HT2C receptors. However, one study showed that all-trans retinoic acid (metabolite of Accutane) significantly enhanced the expression of 5HT2C receptors in the early stages of differentiation of embryonal carcinoma cells. This has been proposed to occur as a result of epigenetic activation (6). Thus its possible Accutane could increase 5HT2C receptor expression in the adult brain.
Another interesting facet of 5HT2C receptors is that they can remain constitutively active, meaning they can have activity in the absence of a ligand/serotonin. They also undergo RNA editing, and there are several isoforms of the 5HT2C receptor meaning that some drugs which act as 5HT2C receptor antagonists don't necessarily act on all receptors. Agomelatine for example is a 5HT2C antagonist but it doesn't appear to work on the 5HT2C receptors in the mesolimbic pathway (7).
Given this, its possible that Accutane has substantially increased 5HT2C receptors in susceptible individuals resulting in greatly diminished dopaminergic activity in important brain regions such as the reward pathway. Reduced dopamine activity in the prefrontal cortex would also help to explain cognitive deficits which some users report.
Treatments and ways to investigate this
Given the constitutive activity of 5HT2C receptors, an inverse agonist would be more useful than antagonists. We would also need compounds which are capable of acting at 5HT2C receptors in the mesocorticolimbic pathway, which would exclude agomelatine. Here is a list of compounds I could find, unfortunately its difficult to find highly specific compounds which are in mass production. Thus several compounds which have a great activity profile are research chemicals and are incredibly expensive to buy. It's also best to avoid 5HT2A antagonism as it inhibits dopamine release. Here is a list in no particular order:
SB 242084 (This would be ideal) - Highly selective 5HT2C antagonist which appears to work on receptors of the mesolimbic system of rats. However it is currently a research chemical and so is very expensive.
5HT2C inverse agonists in order of strength - SB 206553 = Clozapine -> Mianserin -> Mesulergine = Ketanserin (8).
Sertindole - Antipsychotic - 5HT2C inverse agonist with high affinity to D2 and 5HT2A.
Pizotifen - Migraine pill with 5HT2C and 5HT2A antagonism.
Cyproheptadine - Strong antagonist of 5HT2A, 5HT2C and 5HT2B. However is also a strong antihistamine (sedative effect).
Metergoline - 5HT1B, 5HT2B, 5HT2C and dopamine agonist.
Buspirone - Reduces serotonin signalling by acting as an agonist at 5HT1A auto receptor. Also a weak 5HT2C antagonist. Well tolerated drug. Definitely worth trying, especially if you suffer from anxiety.
Other possible options worth trying
Bupropion - Inhibits dopamine re-uptake particularly in the prefrontal cortex, leads to enhanced dopaminergic neurotransmission in nucleus accumbens and prefrontal cortex.
Pramipexole - Activates D2/D3 receptors in prefrontal cortex, striatum, amygdala and thalamus. Helped some users on All Things Male forum but efficacy wore off eventually. Also some users have reported no benefit.
Berberine - Activates 5HT1A auto-receptors and inhibits post synaptic 5HT1A and 5HT receptors - Showed some efficacy in people with PSSD.
St Johns Wort - It has shown some effectiveness in people with PSSD.
Vraylar - weak 5HT2C inverse agonist (low affinity), 5HT2B antagonist, activity at dopamine receptors - Shown benefit for anhedonia.
Histidine - Helps regulate excess serotonin signalling.
(1) - https://www.ncbi.nlm.nih.gov/pubmed/17895527
(2) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422522/
(3) - https://www.ncbi.nlm.nih.gov/pubmed/15668911
(4) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777260/
(5) - https://www.ncbi.nlm.nih.gov/pubmed/12097814
(6) - https://www.ncbi.nlm.nih.gov/pubmed/15242780
(7) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128060/
(8) - http://molpharm.aspetjournals.org/content/55/5/863
- flynn
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