MIF-1: The Game-Changing Peptide For Treatment-Resistant Depression

Jay Campbell

By Jay Campbell

November 10th, 2022

 

Despite depression being a problem that dates all the way back to ancient civilizations, humanity has utterly failed to find a definitive medical cure (let alone a consistently effective treatment).

In fact, you could argue we are worse off in the modern era than we were thousands of years ago.

Not only do many of our pharmaceutical solutions fail to treat depression, but many people eventually develop resistance to said solutions:

  • 8.9 million Americans annually are estimated to be on a 12-month course of medication for treating major depressive disorder (MDD)
  • 31% of those Americans (2.9 million) suffer from treatment-resistant depression (TRD)*
  • In America alone, TRD takes up $25.8 billion (5.6%) of the total healthcare burden.  

* Treatment-resistant depression is defined as “patients who have not been helped by two or more antidepressant treatment trials of adequate dose and duration” (Source)

The solution may not lie in developing drugs, but rather in uncovering what’s already proven to work yet been shoved aside.

But thanks to the good word of Limitless Life Nootropics CEO Christopher Mercer, we may have our answer in the form of a therapeutic peptide called MIF-1.

He’s had phenomenal success with this peptide and begged me to look further into it… so I did.

Here’s everything you need to know MIF-1 and how we’re rediscovering its untapped potential as an absolute gamechanger for treating depression.

 

What is MIF-1?

The MIF-1 peptide has multiple alternative names and aliases, some of which can be found below:

  • Melanocyte-inhibiting factor
  • Melanocyte-stimulating hormone (MSH) release-inhibiting hormone
  • Melanostatin
  • PLG

(NOTE: We are NOT talking about “macrophage migration inhibitory factor”, which has the same acronym and is taking up a sizeable majority of the results on medical literature databases)

It is an extremely small peptide mostly found in the hypothalamus that consists of just three amino acids: Proline, Leucine, and Glycine (Pro-Leu-Gly-NH2).

MIF-1 (Pro-Leu-Gly-NH2) | Dopamine Receptor Modulator | MedChemExpress

(Source)

More specifically, it is naturally created when the enzyme IRAP (insulin-regulated aminopeptidase) cleaves this sequence of amino acids from the N-terminal end of the hormone peptide oxytocin (aka “the love hormone”).

 

Fig. 2.

(Source)

The history of this peptide dates all the way back to the early 1970s, when neuroendocrinologist Abba J. Kastin aggressively pursued MIF-1 as a potential treatment for depression:

“Abbott Laboratories in the late 1960s and early 1970s had a “use patent” for MIF-1 in depression and other CNS conditions. Abbott had performed the extensive toxicology studies and activity of MIF-1 in animal models of depression. They had funded our first two studies. However before they had received the data from the second study (which was very positive), Abbott decided not to proceed with any further studies. As best we could fathom, this was a ‘corporate business decision to get out of peptides alltogether’.

Unfortunately, this effort proved to be futile as this peptide was no longer pursued despite best efforts:

“Wallace Laboratories funded two inpatient studies. One enrolled seriously depressed inpatients in a state hospital. MIF-1 showed significant positive effect in reducing depression. The other study was conducted in a Veterans Administration hospital. The patients in that study were described by the authors as giving absurd and perseveratory responses on self-rating forms which precluded their use. Nonetheless the authors concluded that MIF-1 was ineffective as an antidepressant. An additional outpatient study by Wallace was equivocal. Thus, Wallace stopped funding research with MIF-1.”

Could this be one of the earliest examples of deliberate suppression of therapeutic peptides by Big Pharma?

Perhaps intentional sabotage in order to focus on ineffective “cash cow” treatments such as selective serotonin reuptake inhibitors (SSRIs)?

My bet would be an unequivocal yes, but ultimately we will never know.

But the effort wasn’t entirely in vain as two important discoveries were made:

  • Significant improvements in depression that lasted as long as six months after a 2-3 day treatment course without the side effects of traditional antidepressants
  • Blocking and reversing the opiate actions of morphine in humans, making it an endogenous treatment for opioid overdose and a possible preventative for recreational opioid use

So how exactly is MIF-1 able to achieve all of this?

MIF-1’s Mechanism of Action

Even with all of the research done on MIF-1, the peptide’s mechanism of action in the body is not 100% clear.

But we do have a few points of reference which can help us put some pieces of the puzzle together.

First, we know administering MIF-1 does something to the central nervous system:

“MIF-1 treatment induces region-specific activation of the immediate early gene c-Fos, the highest activation being in the cingulate cortex, infralimbic cortex, nucleus accumbens, paraventricular hypothalamic nucleus, medial basal amygdaloid nucleus, fiber tract in the piriform cortex, paraventricular thalamic nucleus, and some other thalamic nuclei. These are regions involved in the regulation of mood, anxiety, depression, and memory”

Adding on to the first point, MIF-1 also impacts the production of neurotransmitters such as norepinephrine and dopamine:

“Dopamine levels also were elevated in striatum, pons-medulla and cerebral cortex in rats receiving 5 mg/kg dose of MIF-1. In olfactory tubercles, dopamine levels were however, reduced to 71% of control values taken as 100%.

The concentration of norepinephrine tended to increase in several brain areas examined but, the change was statistically significant only in olfactory tubercles and cerebral cortex

…MIF-1 treatment seemed to produce no consistent change in brain serotonin turnover”

Second, MIF-1 is known to inhibit the release of melanocyte-stimulating hormone (MSH), although the precise way through which this happens has not been fully elucidated. 

Third, MIF-1 is known as a “positive allosteric modulator of the D2 and D4 dopamine receptor subtypes” (Source).

As an allosteric modulator, MIF-1 binds to a separate site on the D2 and D4 receptors and changes how the receptor responds when it is bound to a substrate (in this case, dopamine)

And with regard to “positive”, this simply means MIF-1 increases the probability dopamine will bind to the D2 and D4 receptors.

While the D2 receptors are implicated in Parkinson’s and schizophrenia, the D4 receptors are implicated in ADHD and developmental disorders like autism.

The Evidence Proving MIF-1 Can Treat Depression

I want to go over the evidence for MIF-1’s role in treating depression as it is simply too much to ignore.

Unlike many other therapeutic peptides that only have a basis in animal studies, MIF-1 has been extensively used and tested in humans.

Not only do we have several clinical trials vouching for its efficacy, we also have positive testimonials from people who used MIF-1 with great success when everything else failed for them.

Let’s take a look at what’s been hidden from plain sight for the past 60 years!

Personal Anecdotes From Biohackers

Fortunately for myself and the people who read me, there’s a lot we can learn from the old-fashioned trial-and-error experiments of people who are looking to escape the clutches of the “sick care” system.

Here is just a sample of the stories I was able to uncover on the Internet:

“MIF-1 is the holy grail for me after procuring 1g through a source that is not available to me anymore. No side effects, no dangerous health implications, almost no tolerance building, no addictive potential, no strange stimulation or psychedelic quirks, just the best mood you ever had, reliably, and the most interest in other people and the world.” (Source)

“Tasks are easier to approach with less anxiety or thought to potential outcomes, what other people think, what can go wrong? When every task you come across becomes an emotional chore or the threat of failure is overwhelming, then you cant do any tasks no matter what they are. Its much easier to get up and get ready for the day, a welcome change. Overall I find it easier to approach tasks. I am much less critical of myself when getting started on things, now… It has been about two months and I believe the effects are consistent and still present at the same effectiveness” (Source)

“Ran it @ 10mg / day (subQ) during 5 days. I was not depressed at all at the time so my experience is probably not very relevant. I could definitely feel it did something though. It was subtle, and felt somewhat similar to a psychedelic trip afterglow, if it makes sense. It’s not a mood brightener per se, but I felt that it made life more interesting for a few weeks. I’d say it packs some good potential for people who suffer from anhedonia.” (Source)

(NOTE: Anhedonia is defined as a lowered ability to experience pleasure and a decreased interest in previously-enjoyed activities)

“I started taking it a few days ago, and I have noticed that my mood and my motivation is significantly better. And finally, my anhedonia and apathy have improved also. For the first time in years I can experience more pleasure and joy while doing things. I really hope that the effects dont diminish… Its a little bit over a week now and I still feel good regarding depression. Still have a bit anxiety but I also had this before my self-treatment with MIF-1” (Source)

“It has eliminated all the accumulated social defeat stress. It has motivational and nootropic benefits. It diminishes stress reactions, so f.e. my verbal fluency has increased because others do not bother me anymore. I feel content with myself… TL;DR: it is extremely impressive, strong permanent change of sociability/erasure of social defeat stress + acute dopaminergic stimulation. avoid dosing too much, as a reversal after accumulation can happen (long half-life of 5 days), so do cycles of 7daysx30mg and then stop for one to two weeks.” (Source)

I’ll end this off with a testimonial from Christopher of Limitless Life Nootropics, who used this on his wife with phenomenal success:

“When my wife was on MIF-1 for four days, she was cool as a cucumber and her mood was awesome. Two weeks in, my wife is still in a fantastic mood. This peptide is truly amazing for people going through hormonal changes and feeling like they’re about to go off the rails”

Human Clinical Trials

The first clinical trial dates back to 1974, which was a double-blind study involving 18 women ages 35-61 who were given an oral capsule of 60 mg MIF-1 daily, an oral capsule of 150 mg MIF-1 daily, or a placebo.

While the study was small in size, the findings were promising:

  • 4/5 of the patients receiving 60 mg MIF-1 experienced significant improvement in mental depression symptoms (i.e. a >50% drop in the Hamilton score
  • 2/5 of the patients receiving 150 mg MIF-1 experienced significant improvement in mental depression symptoms 
  • 2/4 of the patients receiving placebo experienced significant improvement in mental depression symptoms 

Despite the nonresponders in this study due to various factors such as lack of hospitalization support, it is already clear an optimal dose existed and the majority of MIF-1 recipients had positive benefits.

The second clinical trial happened in 1978 and involved several dosing schemes of MIF-1.

5 patients took 25 mg of MIF-1 orally three times per day, three patients took 75 mg of MIF-1 orally once per day, 6 patients took 250 mg of MIF-1 orally three times per day, four patients took 750 mg of MIF-1 orally once per day, and 5 patients took a placebo once a day.

The results were quite interesting:

  • 5 out of 8 patients taking 75 mg MIF-1 daily showed improvement in depression symptoms according to the Hamilton and Zung scores, with no meaningful differences observed whether the dose was taken all at once or divided into 3 smaller doses
  • 1 out of 10 patients taking 750 mg MIF-1 daily showed improvement in depression symptoms according to the Hamilton and Zung scores
  • 1 out of 10 patients taking placebo daily showed improvement in depression symptoms according to the Hamilton and Zung scores, faring better than the patient group who took 750 mg once a day in a single dose

Just like the first clinical trial, the lower dose was associated with the most significant anti-depressant improvement.

The third clinical trial took place in 1983, and it was a double-blind study involving 5 females and 15 males (age range was 19-61) who suffered from major depressive disorder. 

Over 28 days, patients received either a 75 mg oral capsule of imipramine daily or a 60 mg oral capsule of MIF-1 daily.

While both drugs proved to be equally effective according to the Hamilton score and the Zung score for measuring depression, MIF-1’s anti-depressant effects proved to be far more rapid and effective in the first 8 days of treatment.

The fourth clinical trial was published in 1994, and it was the first one where MIF-1 was administered as a subcutaneous injection instead of an oral capsule. 

20 patients with major depression were enrolled in this double-blind study and were placed in two separate groups:

  • Group #1 received 10 mg MIF-1 daily for a period of 5 days, and then switched to a placebo for another 5-day streak on the following week. 
  • Group #2 received a placebo daily for a period of 5 days, and then switched to 10 mg MIF-1 daily for another 5-day streak on the following week. 

Measures of depression were done according to the Hamilton score and the Asberg score.

What’s interesting about this clinical trial is that Group #1, as with the other clinical trials, showed significant reductions in their score and outperformed the placebo group (8 out of 9 patients on MIF-1 showed improvement vs. 2 out of 11 patients on placebo).

But when Group #2 finished its second week on their first course of MIF-1, the results between both groups at the end of the study were virtually the same.

Moreover, the duration of improvement in the MIF-1 group lasted anywhere from 1 month to 2 years!

What we have here is an anti-depressant treatment that acts fast, lasts long, AND has a very high response rate!

Stay tuned… because later in the article you’ll see this comes with nearly zero downsides!

The BEST Dosage of MIF-1 For Anhedonia & Depression

The best dosage for MIF-1 is 10 mg injected subcutaneously once a day for five days in a row.

This is the same regimen used in the seminal 1994 paper quoted earlier, and a quick read of the paper’s introduction shows this dose was reached after looking at the results from prior clinical trials.

It also appears to be what other anonymous biohackers have used, and the same has been said by Christopher of Limitless Life Nootropics.

In the case of Chris, however, he waited for two days after the first 5-day cycle before giving his wife another 5-day cycle of MIF-1 (although you can wait as much as 1-2 weeks).

All of this can be explained by early findings with MIF-1 in the 1970s, which showed that more is not necessarily better:

“The inhibitory effect of the peptide increases linearly with increasing doses until an optimum is reached (between 30 and 40 mg/kg i.p.). At still higher doses the peptide is inactive. The same phenomenon is observed with analogues of MIF.”

What we’re describing in layman’s terms is the “inverted U-shaped dose-effect curve”, where a drug’s maximum effect is achieved at a certain dose but then the effect lowers when the dose is further increased.

How long does the effect of Vyvanse last? - Quora

(Source)

Unsurprisingly, by 1980 we had enough data to see this event replicate itself numerous times in both animal and human studies.

And even in 2006, the right dose of MIF-1 more-or-less remains the same if we’re using it as a treatment of depression.

“Five of 8 patients with unipolar or bipolar endogenous depressions taking prolyl-leucyl-glycinamide (MIF-I), 75 mg/day, showed substantial improvement within a few days of beginning treatment compared with similar improvement in only 1 of 10 receiving 750 mg/day of MIF-I and only 1 of 5 patients taking placebo.

The lower dose of MIF-I was associated with significantly greater improvement than both the higher dose and placebo on all of the rating scales used.

The authors suggest that an even lower dose of MIF-I, on the order of 0.1 mg/kg, may have a greater effect as an antidepressant.”

Until we see larger-scale clinical trials done in humans, it’s safe to say there is very little confusion about how to dose and use MIF-1 properly.

MIF-1’s Side Effects & Safety Profile

Due to the majority of MIF-1’s human clinical trials taking place in the 1970s and 1980s, we have limited information available for the peptide’s side effect profile. 

But based on discussions with Chris from Limitless Life Nootropics and the testimonials of the few brave souls who self-experimented with the peptide, here is a list of what may happen:

  • Increased frequency of soft bowel movements
  • Cannot be used if you are currently taking Kratom or opiates of any kind
  • Failure to respond to the peptide
  • Possible placebo effect

But given the lack of toxicity data in animals and the failure to report severe adverse events in human studies, I don’t see any major reason to be concerned about unwanted outcomes.

My only beef with MIF-1 would be the unknown consequences of inhibiting the release of melanocyte-stimulating hormone (MSH), especially given the peptide’s long-lasting effects.

We don’t know if skin pigmentation will be affected, and some peptides such as PT-141 have been reported by users to increase the likelihood of depression.

Likewise, I don’t know if it would be a good idea to use MIF-1 alongside Melanotan 1 and Melanotan 2 due to potential antagonism (i.e. the peptides work against each other).

So it may be wise to avoid using any of the three peptides mentioned while using MIF-1.

Outside of these minor concerns, I don’t think anything should stop someone from using MIF-1 if they feel it is right for them.

Do your own due diligence, start at a lower dose if you feel comfortable doing so, and track your results.

Where To Buy MIF-1 Online

Despite MIF-1’s extremely small size at only 3 amino acids long, you’ll be surprised at how difficult it is to purchase this therapeutic peptide.

There are very few vendors who are even aware of the untapped potential this peptide has… let alone know it exists.

Even fewer will make it available for sale, albeit at a ridiculous cost.

The lowest I’ve seen on the market is $140USD for a 50mg vial of MIF-1, and I’ve seen some prices that go anywhere between $400-600 for the same vial.

I have nothing against pricing high-quality products at what they’re worth, but those costs can only be described as deliberate theft and extortion that go beyond the high costs of peptide synthesis.

And we haven’t even gotten into the topic of peptide purification, peptide quantification, shipping procedures, and long-term storage.

Fortunately for you, Limitless Life Nootropics has MIF-1 in stock for the competitive price of $75-100 per 50mg vial of MIF-1. 

Use code JAY15 to get 15% off your order! 

Nobody else will sell you a peptide of this extreme quality for this cheap.

Ask me how I know!

Additional Reading Resources For MIF-1

MIF-1 may not be a brand-new therapeutic peptide given its discovery in the late 1960s and further study in the early 1970s.

But it certainly is one of the forgotten miracles we’re digging out of the grave and re-exposing to the world at large.

Don’t get me wrong… I always have and always will firmly believe depression is largely a symptom of an unintegrated spirit.

When people fail to release their inner trauma and accept WHAT IS, sadness and apathy are the natural results.

Nothing replaces doing the inner work and raising your consciousness to new levels.

Yet I also believe there is a time and place for proven treatments to speed up the process.

With all of this said, I’ll leave you with some additional reading materials if you want to dive deeper into MIF-1 than I did.

This intriguing 3-part series (Part 1, Part 2, and Part 3) reveals why MIF-1 was just the start of discovering the role our melanocortin system plays in depression, and the future peptides that may be superior to MIF1.

This 24-page literature review covers virtually every study done on MIF-1 in humans and animals, along with its naturally-occurring analogs in the human body. 

Last but certainly not least… for the newbies discovering the wonderful world peptides for the first time, grab my FREE copy of the Top 10 Mistakes People Make When Starting Therapeutic Peptides eBook!

You’ll also be opted into a free email sequence where I give away a 50%-OFF discount code for my premium Therapeutic Peptides course.

As always…

Raise Your Vibration To Optimize Your Love Creation!

PS – If you want to get the “secret” heads-up like I do on underground experimental peptides poised to change the world forever, join The Fully Optimized Health Private Membership Group.

It’s your greatest opportunity to fully optimize your health and gain total access to me and my network of high-level men and women living their highest and best life.

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