Melanotan-II

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    Melanotan-II

    Melanotan-II
    by Anthony Roberts - Melanotan II is an analog of the peptide α-MSH hormone and they both cause a tanning/darkening effect in the skin. They were inadvertently developed at the University of Arizona during research into skin cancer.

    Although Melanotan-I and Melanotan-II are similar in name they possess different biological properties, and Melanotan II causes an increase in libido not found in the first version.

    Background
    Currently both forms of Melanotan are being tested and developed under the name CUV1647 by the Australian company Clinuvel Pharmaceuticals.

    Action
    Melanotan works by stimulating the body's naturally occurring alpha-melanocyte stimulating hormone (α-MSH), causing Melanogenesis, a process where melanocytes (tanning cells in the skin) produce melanin (pigment). Administering this hormone to the body directly is an effective and safe alternative to tanning by UV exposure without any previously documented toxic effects.

    Technical Data
    Melanotan research has been ongoing at the University of Arizona since the mid 1980's and is currently being headed by Dr. Victor Hruby. Numerous trials and testing have proved Melanotan to be safe and 1,000 times more potent than natural a-MSH. Melanotan is expected to be used in the future as a drug to combat the major health epidemic of melanoma (skin cancer) (1). Scientists found it to be effective by stimulating subjects' natural tanning mechanism and to create a tan without first needing exposure to harmful levels of UV radiation (2). This will eventually (potentially) allow people to obtain a tan and reduce skin damage that can potentially cause cancer of the skin(3). Additionally, Melanotan II was found to cause increased libido and sexual function (4).

    User Notes
    I’ve actually used Melanotan-II, and can say that it works as well as it’s supposed to. I was basically the first person in the performance enhancement community to have the opportunity to use this stuff, before it was released as a “research chemical”. The vials I received were just unlabeled powder, which needed to be reconstituted before injection, and were totally unlabeled.

    I injected 1ml of the stuff, and went about my normal business for the day, and about an hour after I shot it, thought I had given myself razor burn when I shaved my face. I felt a bit hot, and was slightly red. Of course, it was a “sunburn” feeling, which I hadn’t figured out until I started getting tan later that day.

    Melanotan II gives you a nice even tan, and lasts as long as a “normal” tan, based on how dark you get. I used 1 mL the first day, and then 0.5 mL every day for the rest of the week and the following week. That basically made me as tan as I would be in the summer (which was easily maintained with 1mL once a week).

    The prosexual effects are also very pronounced, and you can definitely expect to experience more erections, on the level of a decently dosed cycle of testosterone.




    References
    1. Clinuvel Pharmaceuticals Limited, Clinuvel (formerly Epitan) Melanotan explanational video (wmv)
    2. Melanotan.org, 27, April, 2007
    3. PubChem entry Melanotan 1
    4. PubChem entry Melanotan II, 27

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    Pharmaceutical Names of Actual and Related Peptides: CUV1647, PT-141, Clinuvel, Epitan, Bremelanotide
    Common Brand/Trade/Slang Names: Melanotan, Melanotan II, MT, MTII, MT-II, MT2, MT-2

    Amino Acid Structure:
    Melanotan - Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 or [Nle4, D-Phe7]-alpha-MSH
    Melanotan II - Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2
    Bremelanotide - Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH or cyclo-[Nle4, Asp5, D-Phe7, Lys10]alpha-MSH-(4-10)

    Molecular Formula and Molecular Weight:
    Melanotan – C78H111N21O19 1646.85 Dalton
    Melanotan II – C50H69N15O9 1024.18 Dalton
    Bremelanotide – C50H68N14O10 1025.16 Dalton

    Peptide Hormone Base: alpha-melanocyte stimulating hormone (α-MSH) Delivery Method: Injectable at this time though transdermal, oral, nasal and implanted pellet form are forthcoming Half Life: 30-60 minutes Typical Vial Contents: 10mg lyophilised white powder. Requires reconstitution with bacteriostatic water to provide an injectable solution.
    Background
    Melanotan (MT) and Melanotan II (MT-II) are both analogs of the alpha-melanocyte stimulating hormone (α-MSH) which is produced within the pituitary gland. Along with other melanocortins, they are responsible for various internal human functions including skin and hair pigmentation, appetite, libido and physical sexual arousal. Whilst these effects have been observed in both sexes, it is worth noting that increases in libido and sexual function are exclusive to MT-II. This article will primarily look at the tanning and pigmentation properties of the hormone, though it would be foolish to ignore the other effects which are discussed further in the Side Effects section.

    Prompted by ultraviolet (UV) exposure, α-MSH release consequently stimulates production of melanin from the melanocytes within the skin. Melanin, as I'm sure you are aware, is a brown pigment and responsible for the tanning of the skin. Simply put, more α-MSH means more melanin, resulting in greater skin pigmentation. Since bodybuilding is such an aesthetic pursuit, and with darker skin that accentuates muscularity, it's little wonder that these drugs are in such high demand.

    Currently, analogs based upon MT and MT-II are undergoing clinical trials, with a view to bringing medicinal products to market. These synthetic variants of α-MSH were developed at the University of Arizona during the 1980s. Australian based Clinuvel Pharmaceuticals Limited have marketing rights to MT (CUV1647), with their primary market being individuals with adverse reaction to UV exposure. This includes those with Polymorphous Light eruption (PLE/PMLE) and Actinic Keratosis (AKs or solar keratosis) where skin is intolerant to UV and characterised by severe sores, lumps, itching or burning sensations, or dry skin lesions/growths. You might think that this peptide would be an ideal treatment for pure albinos. However, these individuals are generally not deficient in α-MSH, but instead are have zero melanocyte receptor binding. Therefore, merely increasing circulatory levels of α-MSH or its analogs is futile. Palatin Technologies Inc. based in the United States, has instead focused on an analog of MT-II. Licensed as Bremelanotide (formerly PT-141), this is aimed squarely at the sexual dysfunction market, more specifically, erectile dysfunction (ED) in men. However, early (phase I & II) clinical trials have also been performed using female subjects with results being described by the company as 'encouraging'.

    Both Melanotan and Melanotan II have been shown in the clinical setting to increase pigmentation without exposure to UV, a feature that is also confirmed anecdotally by users that report tanning in areas of the body that would seldom see the light of day! However, the process of tanning is greatly expedited by UV exposure. It is worth noting that tanning effects may not be uniform throughout the skin. This is in part due to the half life and distribution of the drug itself, but primarily in response to the concentration of melanocytes within certain areas of the skin. Most will notice the greatest tanning effect on the face, arms, abdominal region. Interestingly, the genitals have one of the highest concentrations of melanocytes enabling these particular areas to respond very well to the peptide in conjunction with UV exposure.

    As I'm sure you can appreciate, the development of these peptides has not gone unnoticed by the general population and as a result, there has been an explosion of suppliers looking to exploit such demand, with the peptides being formulated and originating largely from China. Although not classed as controlled substances in the UK, they are viewed as medicinal substances by the MHRA (Medicines and Healthcare products Regulatory Agency). While this means that you can legally possess them for personal use, sale or supply is dependant upon whether the product holds a Marketing Authorisation (product licence) valid for the UK. Since I cannot find any evidence of this, nor would I expect to at this juncture of development, suppliers plying their trade within the UK are doing so illegally.

    Suggested Cycles/Uses
    If you look hard enough out there, you will find some weird and wonderful dosaging schedules whereby the user calculates their daily dosage by multiplying their bodyweight by a cofactor. Perhaps this approach has been adopted since this has been the method employed in the ongoing clinical studies. Typically, this type of formula would suggest a dose of 1mg of MT-II per day for someone weighing in at a mere 110lb (50kg). The cynical among us might be forgiven for thinking that these formulae are constructed by those with a personal interest in the sale of the product as I believe this to be more than necessary to achieve a great result. Indeed, there are many instances whereby users feel they have become too dark. While I have no problem with a bodyweight dosage scale in principle, I can't help thinking that it's not only unnecessary (particularly for the mathematically challenged), but also avoids the ability to gradually increase dosages from a relatively low level; something which I would advocate to assess individual tolerance levels to side effects, especially in the case of MT-II.




    Clinical trials to determine efficacy of the drugs have typically used dosages up to 0.21mg/kg daily for Melanotan (16mg for a 75kg (165lb) individual), and up to 0.03mg/kg daily for Melanotan II (2.25mg for a 75kg (165lb) individual). More typically however, trials have used the dosages of 0.16mg/kg (12mg) and 0.025mg/kg (1.875mg) respectively. At this level of dosage, one such study involving Melanotan indicated the following incidences of side effects from subjects:
    • Nausea 85%
    • Facial Flushing 75%
    • Fatigue 44%
    • Vomiting 26%
    • Injection site reactions 13%
    • Zero incidence of erections
    • No change in vital signs or haematological parameters, blood biochemistry (liver and renal function)
    As is the case with any drug use, the user is ideally looking to minimise unwanted side effects, whilst still achieving an acceptable outcome. With this in mind, I would suggest that a tapering up of dosages is used in order to assess the individual's personal tolerance to the side effects.

    Both MT and MT II can be used for extended periods, whereby there is an initial daily administration of perhaps 2-3 weeks or until desired level of pigmentation has been achieved, followed by a maintenance phase of two injections per week.

    Melanotan:
    Start with a dose of 1mg daily for the first two or three days and, if level of side effects permit, look to increase dosage by 0.25mg every day over the next several days until you reach a daily dosage of 2-3mg. This level should be adequate for most users, though some may wish to increase yet further, perhaps as high as 5mg daily in order to achieve a very deep tan. A maintenance phase as described above is then used.

    Melanotan II:
    Start with a dose of 0.25mg. If side effects (primarily nausea) are not proving troublesome, attempt to increase daily dosage by 0.25mg where possible, until you reach 1-1.5mg daily. Most have found that this level will yield a very pleasing result and I can't see much point in increasing too much further unless a very deep tan was desired. As with Melanotan, once the desired level of tanning is reached, a maintenance phase is used.

    Administration
    Both MT and MT II are currently supplied as white lyophilised powder contained in a sealed multi-use vial. The peptide is susceptible to temperature degradation and should be shipped preferably with an ice pack though contrary to popular belief, the rate of degradation is very slow (weeks) in its powder form, so there's no need to be alarmed if yours wasn't shipped in this manner or you are unable to collect your package from a depot for a day or two. Once delivered, the powder is best stored in a freezer, or refrigerated if this is not possible.

    To prepare for injection, it must be reconstituted with bacteriostatic water. You may use anything between 1ml and 5ml of water for your vial. Dependant upon the amount of water used will determine the concentration of your solution. For example, a 10mg vial of Melanotan II mixed with 1ml of water will provide a solution of 10mg per 1ml (10mg/ml). This means that a 1mg dose will require a shot of 0.1ml. Bearing in mind that the recommended starting dose is 0.25mg, using the example above, the actual volume of the shot would be 0.025ml (¼ of 1 tenth of a ml). This is a very small volume and very difficult to accurately dose even with a 0.5ml insulin syringe. Therefore, at least until your dosages have increased, it is suggested that you use more water for your vial.

    An example of a good solution would be to mix 10mg of Melanotan II powder with 4ml of bacteriostatic water. This now provides:

    10mg/4ml or 1mg/0.4ml or 0.25mg/0.1ml

    0.1ml can be accurately measured using a 0.5ml or 1ml syringe.

    Obviously, as your dosages become higher, you may dilute subsequent vials with lower amounts of water to reduce the volume of each shot. I would recommend that when you are using a dosage of 1mg, you reconstitute the vial with 1ml or 2ml of water so that each shot will be 0.1ml or 0.2ml respectively.

    The injection is given into the sub-cutaneous layer which includes adipose tissue (fat), as in the figure below:

    If you are using insulin syringes which have short needles, you will need to enter the skin at 90°. to the skin, otherwise you can inject as shown in the illustration above with a 29 or 30 gauge, 0.5" needle.

    I would suggest that you use standard 1ml syringes to which you can interchange needles as required. By doing so, you are able to attach any gauge/length you want to reconstitute and draw the solution (I use a 25guage 1" needle). Once done, simply attach your suitable needle for the injection. Following the injection, ensure that you pull back the plunger a little to 'reclaim' the solution that is contained within the needle itself. The syringe/needle is then placed in the refridgerator for storage until your next injection is due whereby you will attach a brand new injection needle. This process is repeated until you have administered all of the solution in that particular syringe.

    Alternatively, you may pre-load insulin syringes and refrigerate until needed. However, because they have non-detachable needles, this can be quite cumbersome as they require loading from the rear.

    Instability of the peptide is a much greater issue once reconstituted so you don't want it sitting in the fridge for months on end. Ideally one 10mg vial of MT-II could be shared by two people (each having their own syringe/needles) so even during the maintenance phase of two injections per week of 1mg each; the longest it will be reconstituted for is 2.5 weeks.

    Major Differences
    I'm guessing by now the question on most people's mind would be which of the two is better? The short answer is Melanotan for the obvious reason that it facilitates tanning with limited side effects. It is for this reason that this analogue is being trialled with a view to bringing it to market by Clinuvel. They would be faced with an almost impossible mission had they chosen instead MT-II to develop and place before the regulatory authorities for approval. This is due to the host of extra side effects commonly encountered by users of this analogue, perhaps also coupled with the fact that the side effects that are shared with Melanotan appear more pronounced. However, in terms of monetary cost, and perhaps also a desire to experience and utilise the other side effects, most prospective users will choose Melanotan II.

    Melanotan's peptide structure is very closely matched to that of our endogenously produced alpha-melanocyte stimulating hormone (α-MSH). It is a specific agonist of the melanocortin-1 receptor (MC-1R) which is primarily responsible for skin colour and is found on melanocyte cells.

    Melanotan II on the other hand has a much shorter sequence of amino acids and because of this quite pronounced change in length and structure, is an agonist of the range of melanocortin receptors. Perhaps more importantly, binding at receptors other than MC-1R is far greater than that of Melanotan. This 'shotgun effect' agonism of the full spectrum of different melanocortin receptors results in some effects that are only witnessed from MT-II. Most notably, increases in sexual arousal are due to MT-II's activation of MC-3R and MC-4R.

    Because the amino acid sequence is much shorter in the case of MT-II, there is therefore a much greater density of peptide chains than is present using MT within a given set weight. Although the receptor binding affinity of MT-II may not be quite as effective, there will be much more peptide chains than for MT on a mg for mg basis so effectively you require much less in terms of milligram weight of Melanotan II to achieve similar results. This accounts for the wide difference in suggested dosages for each peptide and of course, makes MT-II a much cheaper proposition.

    Effects / Side Effects
    Melanotan Melanotan II Skin pigmentation Skin pigmentation Nausea Nausea Appetite suppression Appetite suppression Flushing (esp. facial) Flushing (esp. facial)Headache Headache Lethargy Lethargy Itching Itching Dizziness Dizziness New mole appearance or darkening New mole appearance or darkening Hyperpigmentation Hyperpigmentation White patches White patches (Increased libido Physical sexual arousal Anaphylactic shock?) with 2 only

    Of the above listed effects/side effects, it is worth bearing in mind that the prevalence and severity are witnessed to a greater degree from Melanotan II. Indeed, most will find Melanotan very comfortable to use, typically only experiencing minor nausea, appetite suppression and flushing.

    Although side effects do become less troublesome with each administration of MT or MT-II, most users will experience at least some of the side effect to varying degrees, most commonly nausea, appetite suppression, facial flushing and dull headaches. These will typically become apparent within a few minutes of administration but can last for many hours. In the case of MT-II, increases in libido are often seen in conjunction with outwardly physical signs of sexual arousal whereby the male user experiences prolonged periods of increased blood flow to the penis. This particular side effect does not diminish in severity over time and instances of occurrence are to be expected throughout the period of MT-II use. As I'm sure you can appreciate, this aspect may prove embarrassing and perhaps quite uncomfortable, so I must stress again the importance of building dosage up gradually to assess personal tolerance and susceptibility.

    Some users will notice the new appearance of freckles as these particular areas of skin have increased melanin. The good news is that as the tan is developed, the visual appearance of them will diminish, probably completely. Moles commonly become darker too as these are actually highly concentrated clusters of melanocytes. Both of these occurrences will reverse some time after discontinuation of the peptide and suntanning is ceased.

    In addition to freckles and mole changes, there are fairly rare reports of a phenomenon called hyperpigmentation. This is typified by blotches of darkened skin, normally much larger than regular moles. Not all incidences of hyperpigmentation are attributable to increased melanocyte activity even though their appearance may only become apparent during melanocortin receptor agonism by Melanotan I or II. This condition is specifically referred to as diffuse hyperpigmentation, with many possible underlying causes or disorders including Addison's disease, haemochromatosis, hyperthyroidism and certain medications which may induce phototoxic reactions.

    Previously unseen white spots or white patches of skin may also become apparent as the tan deepens. Again, this is not thought to occur as a direct result of using Melanotan, rather it merely uncovers the underlying condition. There are a range of actual causes. White spots (typically 2-5mm in size) may be the result of Idiopathic guttate hypomelanosis where there are reductions in the number of melanocytes and melanin in those particular areas. Larger white areas of skin may be due to Tinea versicolor which is a fungal infection caused by the yeast Malassezia furfur which is found on the skin and is not normally troublesome. Treatment would normally include an oral or topical anti-fungal though it may take many weeks for the skin tone to become consistent with surrounding areas.

    It has been suggested that due to the greater difference of MT-II to our own α-MSH, there is a greater chance of the body to view the peptide as a 'foreign body' and produce an allergic response. This could potentially trigger anaphylaxis, a potentially life threatening situation whereby large amounts of histamine are produced by the body which can lead to a host of effects including severe bronchoconstriction and rapid drops in blood pressure.


    References
    Hadley ME, Dorr RT
    Peptides. 2006 Apr;27(4):921-30. Epub 2006 Jan 18
    Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization.
    Hadley ME.
    Peptides. 2005 Oct;26(10):1687-9
    Discovery that a melanocortin regulates sexual functions in male and female humans.
    Zheng H, Patterson LM, Phifer CB, Berthoud HR
    Am J Physiol Regul Integr Comp Physiol. 2005 Jul;289(1):R247-58. Epub 2005 Mar 3
    Brain stem melanocortinergic modulation of meal size and identification of hypothalamic POMC projections
    Grill HJ, Ginsberg AB, Seeley RJ, Kaplan JM
    J Neurosci. 1998 Dec 1;18(23):10128-35
    Brainstem application of melanocortin receptor ligands produces long-lasting effects on feeding and body weight.
    Shrestha YB, Wickwire K, Giraudo SQ
    Neuroreport. 2004 Jun 7;15(8):1365-7
    Action of MT-II on ghrelin-induced feeding in the paraventricular nucleus of the hypothalamus.
    Trivedi P, Jiang M, Tamvakopoulos CC, Shen X, Yu H, Mock S, Fenyk-Melody J, Van der Ploeg LH, Guan XM
    Brain Res. 2003 Jul 11;977(2):221-30
    Exploring the site of anorectic action of peripherally administered synthetic melanocortin peptide MT-II in rats.
    Dorr RT, Ertl G, Levine N, Brooks C, Bangert JL, Powell MB, Humphrey S, Alberts DS.
    Arch Dermatol. 2004 Jul;140(7):827-35
    Effects of a superpotent melanotropic peptide in combination with solar UV radiation on tanning of the skin in human volunteers.
    Dorr RT, Dvorakova K, Brooks C, Lines R, Levine N, Schram K, Miketova P, Hruby V, Alberts DS.
    Photochem Photobiol. 2000 Oct;72(4):526-32
    Increased eumelanin expression and tanning is induced by a superpotent melanotropin [Nle4-D-Phe7]-alpha-MSH in humans.
    Barnetson RS, Ooi TK, Zhuang L, Halliday GM, Reid CM, Walker PC, Humphrey SM, Klienig MJ
    J Invest Dermatol. 2006 Aug;126(8):1869-78. Epub 2006 Jun 8
    [Nle4-D-Phe7]-alpha-melanocyte-stimulating hormone significantly increased pigmentation and decreased UV damage in fair-skinned Caucasian volunteers.
    Dorr RT, Lines R, Levine N, Brooks C, Xiang L, Hruby VJ, Hadley ME
    Life Sci. 1996;58(20):1777-84
    Evaluation of Melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study
    Diamond LE, Earle, DC, Heiman JR, Rosen RC, Perelman MA, Harning R
    J Sex Med. 2006 Jul;3(4):628-38.
    An effect on the subjective sexual response in pre-menopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist.
    Wessells H, Gralnek D, Dorr R, Hruby VJ, Hadley ME, Levine N
    Urology. 2000 Oct 1;56(4):641-6.
    Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction.
    Wessells H, Fuciarelli K, Hansen J, Hadley ME, Hruby VJ, Hadley ME, Levine N
    J Urol. 1998 Aug;160(2):389-93
    Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study.
    Molinoff PB, Shadiack AM, Earle D, Diamond LE, Quon CY
    Ann N Y Acad Sci. 2003 Jun;994:96-102.
    PT-141: a melanocortin agonist for the treatment of sexual dysfunction.
    Wessels H, Hruby VJ, Hackett J, Han G, Balse-Srinivasan P, Vanderah TW
    Ann N Y Acad Sci. 2003 Jun;994:90-5
    MT-II induces penile erection via brain and spinal mechanisms.

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    Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II.

    Wessells H, Levine N, Hadley ME, Dorr R, Hruby V.
    Section of Urology, The University of Arizona College of Medicine, Tucson, 85724, USA. hwessels@u.arizona.edu
    Abstract

    We review our experience with Melanotan II, a non-selective melanocortin receptor agonist, in human subjects with erectile dysfunction (ED). Melanotan II was administered to 20 men with psychogenic and organic ED using a double-blind placebo-controlled crossover design. Penile rigidity was monitored for 6 h using RigiScan. Level of sexual desire and side effects were reported with a questionnaire. In the absence of sexual stimulation, Melanotan II led to penile erection in 17 of 20 men. Subjects experienced a mean of 41 min Rigiscan tip rigidity>80%. Increased sexual desire was reported after 13/19 (68%) doses of Melanotan II vs 4/21 (19%) of placebo (P<0.01). Nausea and yawning were frequently reported side effects due to Melanotan II; at a dose of 0.025 mg/kg, 12.9% of subjects had severe nausea. We conclude that Melanotan II is a potent initiator of penile erection in men with erectile dysfunction. Our findings warrant further investigation of melanocortin agonists and antagonists on penile erection. International Journal of Impotence Research (2000) 12, Suppl 4, S74-S79.

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    What was your ratio in mixing bw to peptide for MELANOTAN II? I saw you injected 1ml the first day etc, bug was the the concentration? Thanks for the info. I want to do the research before I buy. Thanks

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