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Alpha-MSH: Its Role in Weight, Chronic Inflammation & CFS

Written by Joe Cohen, BS | Last updated:

If you’re having weight problems, chronic inflammation, CFS or CIRS, then a-MSH has a very significant role in your problems.

What is Alpha-Melanocyte Stimulating Hormone (a-MSH)?

Alpha-Melanocyte Stimulating Hormone (a-MSH) is a subcategory of MSH (there’s also beta and gamma MSH).

The two most prominent roles that a-MSH has in human physiology is in causing weight loss (by reducing appetite and increasing energy expenditure) and by increasing tanning.

a-MSH drastically reduces food intake [1].

a-MSH is a hormone that increases melanocytes, which are skin cells that cause you to become tanned.

Different levels of MSH are not the major cause of racial variation in skin color. However, in many red-headed people, and other people who do not tan well, there are variations in their hormone receptors, causing them to not respond to MSH in the blood [2].

MSH is an anti-inflammatory hormone and helps build a tolerance to our own and foreign proteins [3, 4, 5].

Where Most of Our a-MSH is Produced

a-MSH is produced in the hypothalamic arcuate nucleus and in the nucleus tractus solitarius of the brainstem [6], where it functions to reduce appetite and increase energy expenditure [6].

a-MSH is primarily produced by the intermediate lobe of the pituitary in most of the mammals, but in humans, a-MSH detected in the blood probably originates from the Arcuate Nucleus in the hypothalamus [7].

Note: I interchange a-MSH with MSH.

Health Benefits

1) Anti-Inflammatory

MSH is an anti-inflammatory hormone that also functions as anti-microbial and anti-fungal [6].

MSH brings down brain inflammation (from TNF) [8, 9].

MSH causes a lower immune response to lectins (PHA) [10].

Receptors responsive to MSH (MCR1) are found on cells of the immune system, which mediates the robust anti-inflammatory properties of a-MSH, which include the prevention of Th1 responses and the induction of T regulatory (TREGS) responses [11].

2) Improves Blood Flow

MSH improves nitric oxide delivery in our blood vessels [12], which can help with blood flow.

MSH enhances libido, especially in males (through MC3R, MC4R) [2].

In males, it contributes to erections [13, 14]. In females, it contributes to desire and arousal [15]. This is one reason why people with CIRS have a reduced libido.

3) Lowers Blood Glucose

MSH increases insulin sensitivity and lowers blood glucose. It increases glucose uptake by the liver and decreases glucose production from the liver [16].

4) Causes Weight Loss

MSH reduces abdominal fat [16] and may be the most potent weight reducer.

Leptin reduces weight through the melanocortin system (MC4R) [17].

Alpha-MSH helps maintain normal levels of aldosterone secretion in animal models [18].

5) Has Anti-Microbial Properties

MSH is also a broad spectrum anti-microbial hormone [5]. Its anti-microbial nature includes anti-fungal properties [5].

MSH may combat HIV1 [19].

6) Benefits the Vascular System

MSH helps in stroke recovery [10].

Gamma-MSH, which is different but correlated with alpha-MSH, decreases blood pressure [20].

7) Stimulates Thyroid Hormones

MSH stimulates the thyroid hormone precursor TRH (precursor to TSH, via MC4R) [21].

Increases in MSH lead to increased T3 in rats [22].

The Negatives of a-MSH

MSH causes anxiety, which is caused by lowering GABA [23, 24, 25].

MSH in the amygdala (by activating the MC4R) induces anxiety, inhibits appetite and activates the HPA axis [26].

MSH stimulates prolactin secretion (through MC3R) [27].

MSH also causes depression [28, 25].

However, MSH decreases anxiety brought on by inflammation (IL-1b) [29] – presumably by decreasing inflammation.

MSH contributes to opioid tolerance [30].

MSH increases CRH (precursor to ACTH/Cortisol) [31].

MSH decreases ADH/Vasopressin in rat studies [32].

MSH is Higher in CFS

It makes sense that people with CFS are more likely to have higher MSH. Here’s why:

  • MSH causes flushing, lower blood pressure and increased pain [6], all common symptoms of CFS.
  • Stress increases the likelihood of CFS and the intensity of symptoms [33]. Stress increases MSH.
  • People with CFS are more likely to be thin, and a-MSH causes weight loss.
  • People with CFS are more likely to have intestinal inflammation, which increases MSH.
  • People with CFS are more likely to have anxiety and depression, which can both be caused by MSH.
  • MSH suppresses orexin in animal models [34], which may theoretically lead to fatigue.

Indeed it’s the case that in 55 people with CFS, a-MSH levels were higher than healthy controls.

The stress-induced increase in a-MSH probably originates from the pituitary gland [35].

CFS and “Pituitary Fatigue”

In CFS, there may be a disorder of the hypothalamic dopaminergic neurons, and that this could further affect pituitary hormone secretion. Although the structure of the intermediate lobe is less clear than that seen in rodents,

As time went on in people with CFS, their a-MSH declined. This may be a result of a dysfunction of the pituitary cells that release a-MSH (melanotrophs) because of prolonged stimulation by stress. In a rat model, melanotrophs subjected to continuous stress for more than 5 days showed degenerative features due to hypersecretion of α-MSH, and the raised a-MSH levels fell five days after stimulation [36].

Thus, melanotrophs in humans with CFS are likely to become exhausted and impaired by prolonged stress. It is also possible that the melanotrophs become desensitized following prolonged stimulation, or that the prolonged high level of a-MSH may activate an unidentified feedback system from the periphery.

Hence, people with CFS may have “Pituitary Fatigue.”

MSH is Lower in Chronic Inflammatory Response Syndrome “CIRS”

People who have a multitude of symptoms and blood markers – and who respond to cholestyramine often are suffering from environmental illness.

Dr. Ritchie Shoemaker has coined this CIRS.

People with CIRS often have lower MSH.

Shoemaker says that the normal range is 35 – 81 pg/mL [37].

However, I’m not sure where he gets this information because he doesn’t cite a study backing this range. Actually, I’ve only found studies that contradict this range in healthy people.

In 30 healthy controls, the average was a-MSH level was 14.5 pg/mL [38].

Not a single healthy person had an MSH over 35, so it’s a bit odd that his reference range is 35 – 81 pg/mL [38].

MSH and “Histamine Intolerance”

People with histamine issues are most often underweight, have low blood pressure, experience flushing and have increased pain sensitivity.

While histamine has a role in these, activation of an a-MSH receptor (MC4R) can cause the same symptoms [6].

People with chronic stress and/or inflammation will have the MC4R receptor activated, which then leads to flushing, weight loss, lower blood pressure and increased pain [6].

Factors That Increase MSH

  • Sun/UV [39] – in humans and horses. The light itself may also increase MSH. UVA increases MSH [40] and UVB increases MSH receptors [41].
  • Nicotine activates the MC4 receptors [42], which is the main mechanism of action for MSH [43, 44].
  • Leptin [6]… Leptin directly activates the POMC/CART neurons causing the release of alpha-MSH [45], which in turn decreases leptin, keeping the system balanced [46]. Leptin binds to its receptors on POMC neurons and increases its activation [47].
  • Insulin [48]
  • Eating [7]
  • Stress [35] – POMC neurons in the arcuate nucleus are rapidly activated by acute emotional stress and a-MSH is also increased by stress [26].
  • CRH (rats)
  • STAT3 – increases the POMC [49]
  • Lower dopamine [35, 50] – located in the hypothalamic periventricular region. Some studies show an increase in prolactin response in CFS, which suggests that CFS patients could have lower dopamine function [35].
  • Endotoxins [51]
  • Cytokines [51]
  • Cyclic AMP/Forskolin (cAMP is the cellular medium by which MSH works).
  • Chronic cold in carp [52]
  • Thyrotropin Releasing Hormone (TRH) in horses [53]
  • Adiponectin [48]
  • Resistin [48]
  • Carboxypeptidase E (CPE) [54] – increased by FOXO1 [22]
  • α-amidating monooxygenase (PAM) [54]
  • N-acetyltransferase (NAT) [54]

Conditions With Increased MSH

Factors That Decrease MSH


  • Melanocyte-inhibiting factor, which is derived from oxytocin [65]
  • Lower leptin levels [62], which is likely if you’re thin
  • NPY [6] – NPY inhibited the processing of POMC. NPY decreased the amount of a-MSH in the PVN [66]. NPY increased the release of the inhibitory neurotransmitter GABA onto POMC/CART neurons [45].
  • AgRP [6]
  • Ghrelin (by way of NPY/AgRP) [45]
  • PRCP [6]

Conditions With Low a-MSH

  • Anorexia or being very thin (anorexia decreases MSH a lot more) [7]
  • Bingeing on alcohol (in rats) [67]
  • Multiple sclerosis [68]
  • A damaged pituitary or hypothalamus produce less alpha-MSH [69]
  • Acute brain injury [70]


Melanotan II and MSH2-Pro are synthetic analogs of a-MSH. Usage has been shown to produce tanning and has aphrodisiac effects in preliminary studies and clinical trials [71].


MSH acts through a variety of receptors, but the most significant is the Melanocortin 4 Receptor (MC4R).

SelfDecode discusses a variety of SNPs in MC4R, with additional information about this gene.

Variations in these SNPs are associated with weight changes.

Why Some People May Have Low MSH

Interestingly, the body can create antibodies to a-MSH by mistake.

Certain proteins in E. Coli found in the gut (both friendly and disease-causing E Coli) are similar enough to where the immune system confuses the two and creates antibodies to a-MSH [61].

It’s thought that this is one reason for the low a-MSH levels detected in anorexic subjects (because autoantibodies reduce a-MSH) [61].

What’s really interesting is that these antibodies can sometimes improve the function of a-MSH (by being a carrier) instead of reducing it [72].

When antibodies (proteins) attach themselves to a-MSH strongly, they block its function, but when they latch on to it weakly, they help its function [72].

Rats exposed to chronic stress had increased levels of antibodies and they attached more strongly to a-MSH, which reduced its levels [72].

This is one link between stress and inflammation.

Antibodies are also increased by gut inflammation, but it doesn’t cause a stronger binding to a-MSH, which means that it improves its functioning [73].

This is one reason why intestinal inflammation often causes weight loss.

Practical Applications For People Who Can’t Gain Weight

People who can’t gain weight have overactive POMC neurons in the hypothalamus and a-MSH.

That means you need to take action that decreases POMC/MSH.

This includes:

  • Stress reduction
  • Reducing inflammation
  • Reducing leptin – I theorize that leptin is causing a hyper POMC response in people who can’t gain weight.
  • Reducing insulin
  • SIRT1 activators
  • STAT3 inhibitors
  • Rhodiola/adaptogens to increase NPY
  • Increase dopamine with Mucuna

About the Author

Joe Cohen, BS

Joe Cohen, BS

Joe Cohen flipped the script on conventional and alternative medicine…and it worked. Growing up, he suffered from inflammation, brain fog, fatigue, digestive problems, insomnia, anxiety, and other issues that were poorly understood in traditional healthcare. Frustrated by the lack of good information and tools, Joe decided to embark on a learning journey to decode his DNA and track his biomarkers in search of better health. Through this personalized approach, he discovered his genetic weaknesses and was able to optimize his health 10X better than he ever thought was possible. Based on his own health success, he went on to found SelfDecode, the world’s first direct-to-consumer DNA analyzer & precision health tool that utilizes AI-driven polygenic risk scoring to produce accurate insights and health recommendations. Today, SelfDecode has helped over 100,000 people understand how to get healthier using their DNA and labs.
Joe is a thriving entrepreneur, with a mission of empowering people to take advantage of the precision health revolution and uncover insights from their DNA and biomarkers so that we can all feel great all of the time.


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