This post is not made to encourage the use of RU58841, instead for those who are currently using RU58841 I would like to offer some advice that MAY help (non-medical advice). I have recently done a deep dive into the literature and I will provide citations.

What is Ru58841 : RU58841 is a non-steroidal anti-androgen which binds to the androgen receptor, blocking DHT from binding to the androgen receptor and causing miniaturization. 

Understanding RU58841s pharmacokinetics and tolerance: Ru58841 was studied preclinically 18 times, most but not all of which looked at its positive effects on androgenic alopecia, with 9 looking at its ability to cause systemic side effects and all 9 reporting it didn’t show any systemic antiandrogenic side effects. There were also phase 1 and 2 human clinical trials conducted on Ru58841 which both reported no systemic antiandrogenic side effects and reported good tolerance. Here is a link to my blog article which provides evidence for all of this: https://shorturl.at/Cx45m 

Ru58841 a non-steroidal anti androgen – meaning there is no negative feedback look to the HPG (Hypothalamus-Pituitary-Gonadal) axis, particularly in the low concentrations used recreationally.

Ru58841 is a weak/silent antagonist of the androgen receptor, which means once it binds to the androgen receptor it doesn’t transcribe any effects (the upregulation of gene pathways – which is typical through the agonist made by androgens). This was shown in a paper titled “IDENTIFICATION OF A POSITIVE REGULATORY ELEMENT FOR THE HUMAN TR4 ORPHAN RECEPTOR AND IDENTIFICATION OF POTENTIAL ANDROGEN TARGET GENES FOR HAIR GROWTH AND MUSCLE DEVELOPMENT”  which noted no upregulation of genes once RU58841 bound to the androgen receptor meaning it just bound to the AR and did nothing but prevent DHT/Testosterone from binding. 

According to a study titled ‘Preliminary pharmacokinetics and metabolism of novel non-steroidal antiandrogens in the rat: relation of their systemic activity to the formation of a common metabolite’ Ru58841 had a half life of ~6 hours whereas its metabolites persisted for ~24 hours. This is why I believe researchers thought Ru58841 was such a promising treatment, it could be applied topically at night when Testosterone levels (and thus DHT) naturally peak and work during the time your asleep which is the time androgenic alopecia would be most potent due peaked DHT levels, and then by the time you’re awake and your T/DHT levels are low it has been broken down into weak antiandrogenic metabolites (which ill explain below why they dont cause antiandrogenic effects systemically).

Even when INJECTED INTO THE BODY of rats at 1mg/kg Ru58841 did not reduce prostate or seminal vesicle weight (a preclinical measure of anti androgenicity).

Remember this is after being injected straight into the body. When RU58841 is used in humans it is applied topically to maximise the amount of local activity and minimise systemic absorption, yet when injected at 1 mg/kg (much higher then amounts used recreationally) it still didn’t cause antiandrogenic systemic effects. Clearly the RU58841 molecule itself, from the existing evidence we have, is likely to not be problematic in inducing systemic antiandrogenic activity – this is why we have to consider its metabolites.

The metabolites of Ru58841 : Ru58841 is metabolised into Ru56279 and Ru59416.

In a paper titled ‘Preliminary pharmacokinetics and metabolism of novel non-steroidal antiandrogens in the rat: relation of their systemic activity to the formation of a common metabolite’ researchers stated ‘“RU 56279 is formed in a very low proportion, representing about 1% of RU 58841 administered, compared with RU 59416, which represents 93%”

So clearly Ru59416 is the primary metabolite of Ru58841. Well according to the researchers this molecule Ru59416 displays very little androgenicity. The measure of androgenicity is reduction of prostate and seminal vesicle weights in rodents. According to the researchers Ru59416 displayed little anti androgenicity likely due to the fact it had a low affinity for the androgen receptor. 

So clearly RU59416 (RU58841s primary metabolite) has a negligible chance of causing systemic antiandrogenic effects. 

Ok.. So what about RU56279?

Well as mentioned before it is only metabolised to about 1% of the RU58841 administered so the amount present in your body is negligible. However, yes it does cause reduction in prostate/seminal vesicle weights (indicating it had antiandrogenic activity), BUT it was also stated in this paper to have a low affinity to the androgen receptor. 

WHY we need to consider RU56279 in order to limit any potential antiandrogenic activity:

Scalp hair follicles are not nearly as dense with androgen receptors compared to other systems such as organs, the prostate, and brain. So after the large majority of the RU58841 molecules bind to the hair follicles, even if by the unlikely chance they were absorbed systemically before they could be metabolized (and thus removed from your body), the amount would be too small to affect the totality of androgen receptors in these systems. 

Clearly, if someone was to experience systemic antiandrogenic side effects it would be due to RU56279 molecule as this was the only molecule shown to have antiandrogenic activity (although this was tested at 1 mg/kg injected into rats rather than at the 1% metabolism rate from Ru58841 at a lower dose topical administration). 

It’s entirely possible that the rate of metabolism to RU56279 from RU58841 might be higher in humans than in rats (although all the evidence suggests that not to be the case). So that begs the question: How do we limit the % metabolised into RU56279?

Well it’s important we know how RU56279 is metabolised into RU58841. Well according to the researchers this is due to a process called N-dealkylation.

N-dealkylation is a metabolic process in the human body where an alkyl group is removed from a nitrogen atom. According to a few papers “Metabolic N-Dealkylation and N-Oxidation as Elucidators of the Role of Alkylamino Moieties in Drugs Acting at Various Receptors” and “N-Dealkylation of Amines” the principle pathway but which N-dealkylation occurs is through the Cytochrome P450 (CYP) enzyme family.

Therefore limiting N-dealkylation via inhibition of the Cytochrome P450 (CYP) enzyme family would lead to more conversion of RU58841 to its less antiandrogenic metabolite RU59416 rather than its more potent antiandrogenic metabolite RU56279. So how can we inhibit the Cytochrome P450 enzyme family?

Using Grapefruit Juice.

Yes that’s right, Grapefruit Juice.

It’s been long known grapefruit juice can increase the presence of certain drugs within the human body, and we discovered that it’s through this inhibition of these enzymes. 

So yes, according to my novel theory, backed up with a ton of research, drinking grapefruit juice every night (or maybe even less often) before applying your RU58841 could limit the chances/symptoms of systemic antiandrogenic effects. 

Ok that was very long winded, what are some other methods of harm reduction?

Taking days off: Without giving an arbitrary recommendation, taking one day of each fortnight could help limit the accumulation of RU58841 and its metabolites in the body. Remember, the amounts that are being applied recreationally are incomparable to the total number of androgen receptors in your body so the real risk of systemic side effects is from accumulation. Fortunately

RU58841 has such a short half life and its metabolites have a half life of 24 hours meaning day-to-day accumulation is unlikely however it’s possible. Take one day off each fortnight. If side effects persist, take one day off each week.  

Stop microneedling: Microneedling obviously enhances a topical solution’s ability to be absorbed. The skin acts as a natural barrier for topical solutions, and by limiting the amount going through it prevents excess build up in the scalp. This limits the amount of Ru58841 in the scalp, and thus the potential to go systemic. The sweet spot, based on preclinical and human trials seems to be 5% absorbed topically each day WITHOUT microneedling. Microneedling enhances minoxidil potency but it may potentiate RU58841 systemic absorption. This may be a reason why systemic side effects have been reported anecdotally despite not being present in human clinical trials (aside from the obvious NOCEBO effect).

Lowering the concentration: This requires little explanation. The fewer RU58841 molecules, the less absorbed systemically. If you’re using a 8% solution of RU58841 and you have side effects you are convinced are actually from RU58841 then switch to the 5% solution. If that continues, consider making your own 2% solution by mixing RU58841 powder with a carrier (2% was actually used in a preclinical trial and showed some efficacy).