Binge eating and phenylalanine and opioid receptors.
This got long again. Eating disorders in general are also discussed and pdf resources are linked near the end.
“The researchers [(Alamshah, et al., 2017)] found that the single-dose of phenylalanine reduced food intake, increased levels of GLP-1 and decreased levels of ghrelin. Repeated administration also caused weight loss in the obese mice. The researchers also observed that the rats were moving around more, which might encourage them to lose weight.” [… testing in petri dishes….] “They found that phenylalanine interacted with a receptor called the calcium sensing receptor (CaSR), and that it was CaSR in turn causing levels of GLP-1 to increase and appetite to decrease.”
The research team of Alamshah, et al., found the single dose of phenylalanine had an anorectic effect by stimulating the CaSR.
“Our data provide evidence that the anorectic effects of l-Phe are mediated via the [calcium-sensing receptor] CaSR, and suggest that l-Phe and the CaSR system in the GI tract may have therapeutic utility in the treatment of obesity and diabetes.” […] “…stimulated GLP-1 and PYY release, and reduced plasma ghrelin, and also stimulated insulin release and improved glucose tolerance in rats.”
“High-protein diets suppress food intake and reduce weight gain or increase weight loss.3, 4 The expression of the promiscuous amino-acid-sensing receptors, the umami taste receptor T1R1/T1R3, the G-protein-coupled receptor family C group 6 member A and the calcium-sensing receptor (CaSR)5, 6 in the gastrointestinal (GI) tract has led to the suggestion that they may sense to the amino-acid products of protein digestion to mediate satiety.6 There is in vitro evidence that these receptors may be involved in gut nutrient sensing,7, 8, 9 but their role in nutrient sensing and satiety in vivo has been little investigated.10 The CaSR is named for its well-characterised role in calcium homeostasis, but in fact this receptor regulates a number of cellular processes, including cell proliferation and differentiation.11, 12, 13 Calcium is the major activating ligand, but the CaSR also allosterically binds aromatic l-amino acids and, less potently, aliphatic amino acids.14, 15” (Alamshah, et al., 2017)
*The rest of this post is about a different aspect of phenylalanine that may impact appetite than the calcium receptor, CaSR, that also can bind with certain amino acids, discussed by Alamshah, et al.. They are suggesting that the literal presence of amino acids in the gut is activating CaSR receptors in a way that may signal the brain that there is an adequate and satisfying amount of protein in the gut to stop eating now. (Alamshah, et al., 2017)
Other ways phenylalanine may effect appetite and weight
Phenylalanine is involved in the opioid receptor control of weight and appetite due to its presence in a hormone called “7-d-phenylalanine-alpha-melanocyte-stimulating hormone (NDP-α-MSH, also called melanotan I)”. (Baldini and Phelan, 2019)
Hunger and appetite control are very complex with many chemicals interacting to modulate eating behaviors including α-melanocyte-stimulating hormone (α-MSH). Stimulating melanocytes would also increase production of melanin for a better suntan. For appetite effects the alpha-MSH binds to melanocortin-4 receptors (MC4R) on neurons of the paraventricular nucleus (PVN) and reduces appetite. (Baldini and Phelan, 2019) Activation of the MC4R neurons of the PVN also can help weight control by their promotion of brown adipose tissue which releases energy as extra warmth. (Singh, et al., 2022) Spending more time in cold climates can increase brown fat and the high dose niacin protocol is also increasing heat production by mitochondria.
“In the melanocortin pathway, the fed state is signaled by abundance of circulating hormones such as leptin and insulin, which bind to receptors expressed at the surface of pro-opiomelanocortin (POMC) neurons to promote processing of POMC to the mature hormone α-melanocyte-stimulating hormone (α-MSH). The α-MSH released by POMC neurons then signals to decrease energy intake by binding to melanocortin-4 receptor (MC4R) expressed by MC4R neurons to the paraventricular nucleus (PVN). Conversely, in the ‘starved state’ activity of agouti-related neuropeptide (AgRP) and of neuropeptide Y (NPY)-expressing neurons is increased by decreased levels of circulating leptin and insulin and by the orexigenic hormone ghrelin to promote food intake.” (Baldini and Phelan, 2019)
. . . Suggesting that sunshine is also important for a well regulated appetite. In my personal experience with binge eating problems (emotionally related but also genetic issues tip me towards bunging or anorexic appetite), traveling in southern states during the winter left me feeling healthy and thin and since then I have had a problem with a return of binge eating tendencies in the autumn. I am going to try full spectrum lighting this winter and see if that helps, or go find a suntanning booth somewhere.
“MC4R is considered as a target for anti-obesity therapy. However the receptor controls multiple pathways that include, in addition to energy homeostasis, also glucose metabolism, blood pressure and heart rate. In this respect, the first round of peptides being synthesized were 4-norleucine, 7-d-phenylalanine-alpha-melanocyte-stimulating hormone (NDP-α-MSH, also called melanotan I) and MTII (Hadley & Dorr 2006). NDP-α-MSH and MTII have superpotent activity as compared to that of α-MSH, are resistant to proteases and have prolonged activity (Sawyer et al. 1980, Al-Obeidi et al. 1989a , b , Hadley & Dorr 2006) (Table 1).” (Baldini and Phelan, 2019)
The article continues regarding therapeutic use of the findings - difficulties with side effects occurred but patents and clinical trials have been done.
“However, α-MSH and the relatively non-selective synthetic agonists NDP-α-MSH and MTII as well as the more selective agonist LY2112688, have side effects of increasing blood pressure and heart rate in rodents, nonhuman primates and humans (Dunbar & Lu 2000, Hill & Dunbar 2002, Ni et al. 2006, Greenfield et al. 2009, Greenfield 2011, Rinne et al. 2012, Kievit et al. 2013). These effects are likely to be the result of activation of the sympathetic nervous system by the melanocortin receptor agonists (Fig. 4 and related text) and therefore preclude their use to treat obesity (Greenfield et al. 2009). These compounds have been patented and clinical trials have been carried out to study their effects to promote skin tanning and to improve sexual function in male and females (Hadley & Dorr 2006). However, potential risks to develop melanoma related to the use of unlicensed MTII have been reported (Hjuler & Lorentzen 2014).” (Baldini and Phelan, 2019)
Better suntan and a better appetite control seem to go hand in hand.
A synthetic form of [D-Phe7]-alpha-MSH, 4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone, was found to be more biologically active, and more potent, than alpha-Melanocyte-stimulating hormone (alpha-MSH) for changing the coloration of amphibians. (Sawyer, et al., 1980)
This makes sense for seasonal diners who may benefit from overeating when harvest is plentiful and storing some extra calories for the lean winter months that are on the way.
“Although named for its stimulatory effect on pigment cells, melanocyte-stimulating hormone produced in the hypothalamus can also suppress appetite by acting on receptors in the hypothalamus in the brain. This effect is enhanced by leptin, a hormone released from fat cells.”
“Melanocyte-stimulating hormone secretion from the pituitary is increased by exposure to UV light. Unlike most hormones, melanocyte-stimulating hormone release is not thought to be controlled by a direct feedback mechanism.”
(Melanocyte stimulating hormone/yourhormones.info)
“Ultraviolet (UV) radiation is a unique modulator of skin pigmentation influencing tanning pathways. The delayed tanning pathway occurs as UVB produces keratinocyte DNA damage, causing p53-mediated expression of the pro-opiomelanocortin (POMC) gene that is processed to release α-melanocyte stimulating hormone (α-MSH).” (Yardman-Frank and Fisher, 2021)
Food Sources for Phenylalanine
Phenylalanine is an essential amino acid - meaning we can’t make it for ourselves from other amino acids or chemicals, however it is readily available in most all protein foods including beans, nuts and seeds. Meats, fish and beans have a little more than dairy, nuts, seeds and whole grains. People with PKU/genetic inability to digest phenylalanine properly generally need modified foods as phenylalanine is so prevalent. About 50 mg phenyalanine is the average per gram of protein from any protein rich food including grains. Fruits and vegetables have less at ~ 20-40 mg per gram of protein - but they have much lower protein than even grains have. (PKU Dietary Handbook to accompany PKU guidelines, MacDonald, et al., 2020) To have a very low intake of phenylalanine would likely require having a diet high in refined carbohydrates and fruits. White flour and sugars would be lower in protein or have zero protein.
Mixed amino acid supplement
A dietitian who works with people with eating disorders, Margo Gasta, DCN, RDN, recommends a balanced amino acid support product rather than use of phenylalanine as a solo amino acid powder. Possibly like this Thorne product, Amino Complex Lemon NSF, Thorne, but at $36 or more for an 8 ounce container, it might be an expensive way to get more protein in your diet. It contains 100 mg phenylalanine per scoop which would be too much for someone with the genetic condition PKU but might not be much otherwise. Free amino acids can act as signaling chemicals causing activity by cells and therefore caution is warranted but common sense when on a budget is too.
*This product is available through my Fullscript account - sign up under my professional account for 20% discount on anything in their catalog. The List price is the manufacturer’s suggested price so other online places can have good deals too. Free shipping for orders over $50. Sign up here: (Fullscript). Citrus bioflavonoids can be helpful for appetite, blood sugar and weight. Your money might go further at a grocery store buying quality meats or beans and organic citrus - mince the peel as a garnish for the protein foods.
“Serving Size: 1 Scoop, Amount Per Serving:
L-Cystine ... 150mg
L-Histidine ... 150mg
L-Leucine ... 1.25g
L-Lysine ... 650mg
L-Methionine ... 50mg
L-Phenylalanine ... 100mg
L-Threonine ... 350mg
L-Tryptophan ... 20mg
L-Tyrosine ... 30mg
L-Valine ... 625mg”
Other factors that may increase binge eating.
Margo has found that intestinal parasites or dysbiosis can be a frequent underlying issue for clients with binge eating. Carbohydrate excess can be common in binge eating which may lead to protein inadequacy and can be triggered by a Candida yeast infection or intestinal worms.
Genetic differences in the endocannabinoid system can increase risk of eating disorders with over or under eating as potential concerns. I have had both issues at different stages of my life, though binge eating was more frequently a problem for me.
Weight may be kept within a normal range by use of excessive exercise or not eating at other times. There are still negative impacts happening to health though from the large swings in food intake. Even healthy food is unhealthy when way too much is eaten at once as it is overburdening the liver.
Too little food in the early part of the day can set someone up for overeating at night however. Excess dopamine from stimulating social media or other habits like use of addictive substances or video gaming can increase appetite and add to that risk of late night overeating.
Trying to stay awake when you should just go to bed may also be a vulnerability for overeating carbs or other foods. A protein snack, splashing some cold water on your face, and taking a quick walk, might help you wake up more if you really do need to stay awake.
Tips about sleepiness and driving are in this post about a sleep platform I built in the back seat of my hatchback car. Coffee and caffeine can not help you stay awake once the body is too sleep deprived. Pull over and snooze a bit. I was able to use my car like a mini-camper and pull over to sleep anywhere I needed to. (Transcendingsquare.com) The sunshine during winter months was wonderful and surprisingly new to me. I had never traveled very far south during winter months prior to 2017. I learned a lot about what my body seems to need for health — and sunshine was a big factor.
Feeling in control over one’s life and self may help under or overeating issues.
Margo Gasta, DCN, RDN, also recommends or has found there is often a need for life coaching or improving time management skills for clients with binge eating disorders. *Webinar with a fee, so I can’t share it, but here are the notes: (part 1), (part 2). Margo Gasta’s website: (nutritionbymargo.com). The course is part of Next Level Functional Nutrition Training (IFMNT) with Susan Allen-Evenson, RD, CCN.
Loss of control and inability to stop eating is common and can feel very disempowering. Why is my body doing this? Why am I doing this to my body?
Answer: Excess dopamine may be why you are suddenly eating mindlessly to the point of feeling way overfull and uncomfortable. But there are other possible reasons too.
Anorexia nervosa, severe undereating, tends to occur in people who are very in control of themselves - possibly overly controlling their body’s needs due to feeling out of control over their larger world with demands from parents or others dictating their lives. They may be using not-eating as a way to have something in their life that IS under their control.
Emotional overeating may feel more like ‘loss of control’ and it may be more of a self sabotage or oppositional defiance about feeling forced to ‘be good’, ‘look good’, ‘starve yourself to fit into clothes’ or some other message that is feeling overwhelming. When told to always be good and never be bad - then being bad can become very desirable. Feeling deprivation can be a risk factor for setting off a binge. A tip that helped me was to always have a snack bag with healthy snacks available, so I would never feel deprived.
An overly controlling parent can lead to a child/adult who doesn’t even know how to listen to their body’s messages about hunger/fullness or other signals. People who weren’t trained how to listen and respond to their own needs may be looking for a practitioner to tell them exactly what to do - but the most helpful practitioner is going to teach you how to LISTEN to yourself and give your body what it wants and needs in the amount that seems satisfying without being too much. Bitter tastes in a meal helps us to feel satisfied, adequate protein and fats are also part of satiety signaling - feeling satisfied after a meal instead of wanting just a little more and a little more.
What you grew up with may have set up disordered eating → a ‘Clean plate club’ and being forced to finish food you don’t want is setting up overeating habits and lack of awareness of true hunger and fullness signaling. Having treats hidden and controlled and limited, but occasionally being allowed to binge when mom and dad were binging - is setting up binging as a lifestyle. Ellyn Satter recommends not using dessert or treats as a reward at the end of the meal. Her book Child of Mine is worth reading if you have disordered eating issues, or are raising children. The site has a lot of resources available. (ellynsatterinstitute.org)
Foods can be ‘addictive’ - sugar acts like cocaine in animal studies on overuse.
Carbs can be calming when stressed too and sweet/salty, greasy/salty, sweet/creamy, can all be combinations that have a pain killing like opioid effect.
Spicy seasonings with glutamate or the artificial sweetener aspartame can also have an excitatory and addictive effect leading to overeating or drinking the product and maybe even being addicted to ‘needing’ that 2 liter of Mountain Dew everyday. *You might be surprised at how many people have a 2 liter Mountain Dew a day habit.
Disordered eating is a huge topic, which I have personal experience with, sadly. Helpful Substack is Ikiquest by David Marlow.
David links to a post with his 10 Rules of Ikigai, (LinkedIn post). “Ikigai is about experiencing your essence (who), and purpose (why), in harmony with whatever you do (what).”
Number 3 is pertinent for overeaters: “Don’t fill your stomach.” I have found it helpful in my own struggles with food to really try to remember and focus on that overfull feeling, to try to remind myself not to do it again. Once in a binge, it is compulsive and hard to stop - the elevated dopamine may be part of that -but you still need to close the package instead of emptying it into your mouth. And as someone who has been both overweight and thin - overweight people don’t realize why a thin person can bemoan gaining 5 pounds (or even be able to tell) or not wanting to overeat and feel stuffed. Clothes and skin that are smaller just don’t want to stretch that much. My waist can change 9 inches between slim and fully bloated - that gets painful. Feeling overfull can also make it a little harder to work at a physical job - the ab muscles are stretched out and the blood flow is being redirected to the digestive system.
Along with not feeling deprived though, it is important to not succumb to shame or hopelessness. Today is a new day, I can try again today to not overeat salty, yummy foods that aren’t very good for me or even when they are good for me.
I will end here as it is long enough. Time for some sunshine!
Disclaimer: This information is being provided for educational purposes within the guidelines of Fair Use and is not intended to provide individual health care guidance.
(Alamshah, et al., 2017) Alamshah A, Spreckley E, Norton M, Kinsey-Jones JS, Amin A, Ramgulam A, Cao Y, et al., (2017). l-phenylalanine modulates gut hormone release and glucose tolerance, and suppresses food intake through the calcium-sensing receptor in rodents. Int J Obes (Lond). 2017 Nov;41(11):1693-1701. doi: 10.1038/ijo.2017.164. Epub 2017 Jul 13. PMID: 28792489; PMCID: PMC5678004. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678004/
(Baldini and Phelan, 2019) Baldini, G., & Phelan, K. D. (2019). The melanocortin pathway and control of appetite-progress and therapeutic implications. J of Endocrinology, 241(1), R1-R33. Retrieved Sep 30, 2023, from https://doi.org/10.1530/JOE-18-0596, https://joe.bioscientifica.com/view/journals/joe/241/1/JOE-18-0596.xml
(Sawyer, et al., 1980) Sawyer TK, Sanfilippo PJ, Hruby VJ, Engel MH, Heward CB, Burnett JB, Hadley ME. 4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity. Proc Natl Acad Sci U S A. 1980 Oct;77(10):5754-8. doi: 10.1073/pnas.77.10.5754. PMID: 6777774; PMCID: PMC350149. https://pubmed.ncbi.nlm.nih.gov/6777774/
(Singh, et al., 2022) Singh U, Jiang J, Saito K, Toth BA, Dickey JE, Rodeghiero SR, Deng Y, Deng G, Xue B, Zhu Z, Zingman LV, Geerling JC, Cui H. Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations. Mol Metab. 2022 Jan;55:101401. doi: 10.1016/j.molmet.2021.101401. Epub 2021 Nov 22. PMID: 34823066; PMCID: PMC8689242. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8689242/
(Yardman-Frank and Fisher, 2021) Yardman-Frank JM, Fisher DE. Skin pigmentation and its control: From ultraviolet radiation to stem cells. Exp Dermatol. 2021 Apr;30(4):560-571. doi: 10.1111/exd.14260. Epub 2020 Dec 24. PMID: 33320376; PMCID: PMC8218595.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218595/