MIF-1 (and other peptides) for Anhedonia/Depression

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Thought I would start a discussion about this awesome lesser known peptide, yet one of the peptides with quite a few actual human studies behind it.

So I'll start with my experience before getting to the science:

I have done a few cycles (they last 5-7 days of 8-10 mg) of it this year and found it to be helpful for anhedonia. The first cycle I did back in May, I didn't feel the effects until he 4th day when suddenly I could feel the 'vibe' of an outdoor mall again. In July, I had done it again and in 3 days I was back to enjoying my interests/hobbies. However I think I may have overdone it that time with doing 8.3 mg for 8 days and then the effects kind of reversed. That's when I realized for me it can only be done for like 5-7 days depending on the dose I use.

Recently had crashed really badly last month. Was feeling hopeless, very numb, desperately anxious and had all kinds of dark thoughts about the numbness. The next day I injected 10 mg MIF-1 subQ and within 2 hours this all vanished. The world was brighter, felt grateful, I could enjoy a walk and the sun, got a huge surge of motivation to exercise and make the most of it. It also greatly reduced anxiety too. That was completely unexpected as previous cycles it took like 2 days at least for the effects. This full effect didn't last, there is tolerance, but I made sure to use the window to exercise intensely for the 6 days I was doing it and this kind of helped me get back to a copable point. I also took Mucuna L-dopa which it potentiated, in an effort to kind of restore my dopamine system.



They say Ketamine is anti anhedonic, but having done it and not had much from it for me MIF-1 is far superior. And I have had no side effects. Unlike all the psych drugs out there with all sorts of problems, this is truly a gem. Its a shame that its not studied much or made into an approved drug because it cannot be patented. The analog Nemifitide a small company tried to make but it went bankrupt and it was never pursued by anyone else further.

I also tested my alpha-MSH levels directly before and after a MIF-1 cycle, and it only went from around 13 to 9, so wasnt a huge decrease.

Studies:

So the first study is basically the one with the 5 day subQ protocol for MDD:


This other one is an oral dosing protocol that found it more effective than Imipramine (a TCA) and it also mentions though that too much reverses things: Rapid clinical effectiveness of MIF-I in the treatment of major depressive illness

This biphasic effect is directly mentioned here: Dose-related biphasic effect of prolyl-leucyl-glycinamide (MIF-I) in depression - PubMed

Mechanism of Action:

So MIF-1 is a D2 and D4 PAM and also an opiod antagonist. I admit I do not fully understand how the opiod antagonism part improves symptoms, other than that I speculate maybe its a "super-LDN" (thats why I dont take LDN during MIF cycles, to avoid interactions). I do notice however that my LDN endorphin rebound gets potentiated for a few days after MIF-1. So it must be acting on the opiod system somehow for sure.

Brain Activation by Peptide Pro-Leu-Gly- N H (MIF-1) -- This study talks about MIF1 potentiating L-dopa (this is why Mucuna on it is beneficial) as well as more molecular bio level stuff like c-Fos (way over my head). But it can even help Parkinson's disease.

Effects of L-prolyl-L-leucyl-glycine amide (MIF-I) on dopaminergic neurons -- Another on dopamine actions and effects when combined with L-Dopa.

Modulation of Agonist Binding to Human Dopamine Receptor Subtypes by l-Prolyl-l-leucyl-glycinamide and a Peptidomimetic Analog -- MIF-1 increases the binding to the D2L receptor. Note that D2 receptors are actually either inhibitory or stimulatory, and the L form is the latter whereas the S form is inhibitory.

There is even potential (in animal models) of it helping Tardive Dyskinesia-a nightmare side effect of antipsychotics: MSH and MIF-I in animal models of tardive dyskinesia - PubMed

Antagonism of morphine analgesia in humans: Antagonism of morphine analgesia by prolyl-leucyl-glycinamide (MIF-1) in humans.

Half life: Differential metabolism of Tyr-MIF-1 and MIF-1 in rat and human plasma. MIF-1 has a long half life in human plasma of 5 days. This is why I think cycling with enough gap is needed in order to make sure it doesn't accumulate.

Overall, I'm surprised and how not well known it is. As of now theres only like 1 place to get it. I hope eventually peptide/HRT clinics start offering this gem. I mean the fact that so many other peptides are offered but not one with actual human studies behind it is strange.

One thing I noticed is there is no mention of any BDNF/neuroplastic changes with this peptide. Something I am interested in looking into potentially trying (in order to extend and maximize the effects) is whether an agent like Ketamine could be used for that BDNF aspect, followed by a course of MIF-1 and hoping it sticks. Ketamine infusion alone doesn't really directly help me that much, although there is a subtle effect a few days later from it.

This peptide is kind of the 'opposite' also to PT-141, which can induce anhedonia. In fact for me severe anhedonia years ago got induced by PT-141 akin to PSSD/PFS like symptoms just from one 200 mcg injection and I needed to do ECT. Prior to that I had never ever experienced anhedonia in my life. Not even when my hormones like T or cortisol were off, only low mood but never ever anhedonia/blunting which are entirely different and FAR more debilitating to me.

It got me out of it back then in 2018 but I think it may have planted a vulnerability as I never experienced anhedonia before. I was fine for years until last year when suddenly after a combination of covid/alcohol hangover/caffeine relapsed me into moderate anhedonia/blunting again. Things have been up/down since but MIF-1 is really helpful for me, just the time between cycles even though it improves my baseline every time is an issue. My response to MIF-1 though does perhaps make sense given the PT-141 incident years ago.
 
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This sounds like an ordinary stimulant. I doubt it "accumulates", more like your brain develops tolerance to it by downregulating neuroreceptors. Such a chase of the high is typical for stimulants and drug users. In TRT they call the testosterone high "the honeymoon".

I also don't buy the rationalizations for "neuroplastic changes". You seem to believe everything that is claimed in a medical "study" and most of them do not understand the mechanism at all. If it is such a great antidepressant, it would have taken the market so far by a storm. Ketamine according to your own account is also overhyped by similar "studies" - seems like a cash cow for "clinics".

Try a regular herbal stimulant used for thousands of years - for example guarana powder or red ginseng combined with green tea.

All these stimulants are clearly not addressing the root problem why you have anhedonia and depression but contemporary medicine can get you that far and then you have to experiment.

I personally noticed that if I don't take my digestive enzymes, I feel horrible in a few days with severe lack of energy and depression. This is just an example how the reason for your mental state can be in a completely unexpected place - the digestive tract.
 
This sounds like an ordinary stimulant. I doubt it "accumulates", more like your brain develops tolerance to it by downregulating neuroreceptors. Such a chase of the high is typical for stimulants and drug users. In TRT they call the testosterone high "the honeymoon".

I also don't buy the rationalizations for "neuroplastic changes". You seem to believe everything that is claimed in a medical "study" and most of them do not understand the mechanism at all. If it is such a great antidepressant, it would have taken the market so far by a storm. Ketamine according to your own account is also overhyped by similar "studies" - seems like a cash cow for "clinics".

Try a regular herbal stimulant used for thousands of years - for example guarana powder or red ginseng combined with green tea.

All these stimulants are clearly not addressing the root problem why you have anhedonia and depression but contemporary medicine can get you that far and then you have to experiment.

I personally noticed that if I don't take my digestive enzymes, I feel horrible in a few days with severe lack of energy and depression. This is just an example how the reason for your mental state can be in a completely unexpected place - the digestive tract.

I already take ox bile/tudca with meals for fat digestion. It helped increase my cholesterol levels which were low at 100 at one point to like 130.

But this compound isn’t a stimulant. MIF-1 is not releasing nor inhibiting reuptake of DA/NE. Actually its not really acting on NE much. Standard stimulants (like MPH) which affect NE actually worsen my issue since for me NE specifically is very emotionally blunting. Even Parnate the MAOI I tried taking twice and it was way too blunting from what felt like an amphetamine-like effect. Im not sure why my body reacts that way to NE.

Things that more selectively help dopamine like MIF1 actually do help the symptoms. Same with Bromantane. Armodafinil also, which avoids too much NE at low dose mostly. EGCG from green tea is decent but builds a tolerance.

MIF-1 can’t be patented. That’s why it never took off. Theres an article here about that: Best Damn Anxiety & Depression Med (Part 2).
 
So I used 10 mg MIF-1 per day via subq injections for 6 days. I didn't notice anything at all during those 6 days -- nothing good, nothing bad, no discernable effect. I almost wondered if I was just injecting bacteriostatic water except that I saw the powder in the bottles before reconstituting.

Today is the 7th day and my first day not taking any MIF-1. I've been in an unusually happy and cheerful mood all day. Maybe starting to kick in now? Cross your fingers.
 
So I used 10 mg MIF-1 per day via subq injections for 6 days. I didn't notice anything at all during those 6 days -- nothing good, nothing bad, no discernable effect. I almost wondered if I was just injecting bacteriostatic water except that I saw the powder in the bottles before reconstituting.

Today is the 7th day and my first day not taking any MIF-1. I've been in an unusually happy and cheerful mood all day. Maybe starting to kick in now? Cross your fingers.

Yea there can definitely be a delayed effect. For me I noticed with doing more cycles though the effect came earlier on. Its weird.

But even Ketamine (which im trying now) seems to have a delayed subtle effect for me. Im planning on doing maybe 4 infusions (done 2 now) and then I will have waited enough time to do a MIF-1 cycle again. I find MIF-1 to be more powerful though than ket. Im just hoping Ket might prime my brain enough for MIF-1 to stick next time
 
So I used 10 mg MIF-1 per day via subq injections for 6 days. I didn't notice anything at all during those 6 days -- nothing good, nothing bad, no discernable effect. I almost wondered if I was just injecting bacteriostatic water except that I saw the powder in the bottles before reconstituting.

Today is the 7th day and my first day not taking any MIF-1. I've been in an unusually happy and cheerful mood all day. Maybe starting to kick in now? Cross your fingers.
Ehh. I don't think it's doing anything. Feeling pretty much identical to before I started.
 
Ehh. I don't think it's doing anything. Feeling pretty much identical to before I started.
How bad is your anhedonia typically?

I wonder if one reason I respond to MIF1 strongly is because years ago I had a severe PT141-induced anhedonia episode that I needed ECT for. Shit was a nightmare and basically I had the severity of severe PFS/PSSD cases (blank mind, anhedonia,blunting, restlessness/pacing) just from 1 200 mcg injection of it.

And somehow this condition got retriggered last year by alcohol hangover and a sudden NE stim sensitvity after that. So perhaps MIF1 just specifically works because of the past incident. But I know others without PT141 induced issues who also benefitted.
 
I already take ox bile/tudca with meals for fat digestion. It helped increase my cholesterol levels which were low at 100 at one point to like 130.
Btw, this is interesting about your cholesterol levels. Mine were too low for a while as well. Sex steroid levels are high but cholesterol very low. Might be related to thyroid function? Absorption difficulties might be present too. I'll try TUDCA.
 
Do you guys mind sharing your sources for MIF-1?
Theres only 1 source really I know of right now Limitless Life Nootropics. Couldn't find anything else.

I did another cycle just over a week ago and it helped raise my baseline again. This time it was more subtle and only a slight boost but well I'll take it. It did make armodafinil seem to work better after the cycle.
 
Theres only 1 source really I know of right now Limitless Life Nootropics. Couldn't find anything else.

I did another cycle just over a week ago and it helped raise my baseline again. This time it was more subtle and only a slight boost but well I'll take it. It did make armodafinil seem to work better after the cycle.
I might have gotten something out of it, but if so, it was very subtle and difficult to discern whether it was placebo effect.
 
I might have gotten something out of it, but if so, it was very subtle and difficult to discern whether it was placebo effect.

Every time I do a cycle it seems to be different. Sometimes it can be subtle and other times 'woah'.

In this cycle it was subtle but noticeable in that I noticed increased optimism, peace, and more anticipatory positive thoughts looking forward to stuff, so decreased anticipatory anhedonia.
 
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