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:
pubmed.ncbi.nlm.nih.gov
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.
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:
Improvement in major depression after low subcutaneous doses of MIF-1 - PubMed
In this double-blind pilot study, 20 significantly depressed patients who all met the DSM-III R criteria for major depression were given a single subcutaneous injection of either 10 mg MIF-1 (Pro-Leu-Gly-NH2) or placebo on each of 5 consecutive days. Treatments were reversed for a second week of...
pubmed.ncbi.nlm.nih.gov
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.
