Hexarelin is often presented as a "soft" peptide that only slightly boosts its own growth hormone. In fact, its pharmacology is broader: it affects several hormonal axes and has a distinct target in the cardiovascular system. The editors analysed which unwanted effects were recorded in studies, which can be predicted from the mechanism of action and where the available knowledge ends.
Where side effect data comes from
For registered drugs, the profile of side effects is formed on the basis of large clinical trials and subsequent post-marketing surveillance. Hexarelin did not go through such a path, so a complete list of undesirable reactions, as in the instructions for the drug, does not exist for it.
Available data come from three sources. The first is small studies of the 1990s and 2000s on volunteers and patients, where hormonal changes and tolerability were recorded. The second is knowledge about the effects of growth hormone and IGF-1, which can be partially extrapolated. The third is data on other ghrelin receptor agonists.
In human studies, hexarelin was generally well tolerated, and no serious adverse events were reported with short-term use. However, "satisfactory tolerability" in a short study of a few dozen participants is not at all the same as proven safety.
Therefore, in this article we divide the effects into those directly recorded for hexarelin and those expected from the mechanism of action. Such a distinction helps to avoid both intimidation and unfounded optimism.
Hormonal effects beyond growth hormone
The best documented “side” effect of hexarelin is non-selectivity. In addition to growth hormone, the peptide increases the levels of prolactin, adrenocorticotropic hormone (ACTH) and, accordingly, cortisol. This has been shown in endocrine studies by Italian groups and summarized in a review by Ghigo et al. (1997).
The increase in prolactin in the studies was moderate and transient. However, with frequent repetition of stimulation, manifestations characteristic of hyperprolactinemia are theoretically possible: a decrease in libido, a violation of the menstrual cycle in women, and in men - suppression of sexual function. This has not been studied systematically with long-term use of hexarelin.
Cortisol is a stress hormone with a catabolic effect. Its increase partially "competes" with the anabolic effects of growth hormone, and chronic activation of the stress axis can affect sleep, blood pressure, and glucose metabolism. It is for this reason that newer secretagogues, such as ipamorelin, were developed to avoid effects on ACTH and cortisol.
| Effect | Level of Evidence for Hexarelin | Possible manifestations |
|---|---|---|
| Increase in prolactin | Shown in human studies | Decreased libido, cycle disruption (with long-term use - theoretically) |
| Increase in ACTH and cortisol | Shown in human studies | Influence on sleep, pressure, glucose |
| Increase in appetite | Expected from the mechanism (ghrelin receptor) | Increased hunger, usually less than from GHRP-6 |
| Sensation of heat, redness of the face | Described for releasing peptides in studies | Transient flushing after administration |
The effect on appetite is associated with the fact that hexarelin activates the receptor of the "hunger hormone" ghrelin. According to comparative works, this effect in hexarelin is less pronounced than in GHRP-6, but it cannot be completely excluded.
Effects associated with growth hormone and IGF-1
Since the main effect of hexarelin is to increase growth hormone, it is logical to expect side effects characteristic of an excess of this hormone. They are well known for their clinical use of recombinant growth hormone and research on its abuse in sports.
Fluid retention and swelling, especially of the hands and feet, is one of the most frequent reactions to an excess of growth hormone. It can be accompanied by a feeling of stiffness, tingling in the fingers and symptoms of carpal tunnel syndrome due to compression of the median nerve by swollen tissues.
Joint and muscle pain is also typical of elevated growth hormone levels. The mechanism is associated with fluid retention in joint tissues and changes in connective tissue metabolism.
Growth hormone has an anti-insulin effect, therefore, with frequent stimulation, an increase in glucose level and a decrease in sensitivity to insulin are possible. For people with prediabetes, type 2 diabetes, or metabolic syndrome, this effect is potentially most important. At the same time, due to tachyphylaxis and feedback, hexarelin is unlikely to increase growth hormone as much as direct administration of the hormone, so the severity of such reactions is probably less.
Local reactions and product quality risks
Any subcutaneous injection can cause local reactions: redness, itching, compaction, small bruises. For the most part, they go away on their own, but their frequency increases when the injection technique is violated and non-sterile solutions are used.
For hexarelin, this risk is further enhanced by the fact that there is no registered medicinal product on the market. All available products have the status of "reagents for research" and do not undergo pharmaceutical control of sterility, the content of bacterial endotoxins and impurities.
- Infectious complications: abscess, phlegmon, in rare cases — systemic infection.
- Pyrogenic reactions: fever, chills, aches due to endotoxins even in a sterile solution.
- Unpredictable effects: other active substance, incorrect concentration, peptide breakdown products.
- Immune reactions: impurities and aggregates may increase the risk of allergic reactions.
Therefore, some of the "side effects" experienced by users may not be related to hexarelin per se, but to the quality of the specific product. For a person, the difference is imperceptible, but it is fundamental for risk assessment.
Who is at high risk
There are conditions in which stimulation of the growth hormone axis is potentially more dangerous. For recombinant growth hormone, they are reflected in the contraindications of the official instructions, and it is logical to take them into account for any substances that increase its level.
Such conditions include active malignancies or a history of cancer, as IGF-1 stimulates cell proliferation. It is also diabetes and impaired glucose tolerance, diabetic retinopathy, severe acute diseases.
People with heart diseases should be mentioned separately. Although hexarelin has been studied as a potential cardioprotectant, its long-term cardiovascular effects in humans have not been studied. For patients with hypertension, arrhythmias or heart failure, any experiment without medical supervision is unacceptable.
Finally, adolescents with open growth zones, pregnant women, and lactating women are groups for which no data are available at all. For athletes, an additional risk is a violation of anti-doping rules, since hexarelin is permanently prohibited by WADA.
Editorial conclusions
The best-documented adverse effects of hexarelin are increases in prolactin, ACTH, and cortisol, i.e., the effects of its nonselectivity. It is also possible to affect appetite and transient hot flashes.
The mechanism of action results in the effects characteristic of an excess of growth hormone: swelling, pain in the joints, symptoms of tunnel syndrome and deterioration of glucose metabolism. Their frequency with the use of hexarelin has not been systematically studied.
A significant part of the real risks are quality problems: the lack of guarantees of sterility, purity and content of the active substance in products of the unregulated market.
We also advise you to read materials about the long-term risks of hexarelin, about the results of its research on humans and animals, as well as about the storage and stability of the peptide.
List of used literature
- Ghigo E, Arvat E, Muccioli G, Camanni F. Growth hormone-releasing peptides. Eur J Endocrinol. 1997;136(5):445â460.
- Ghigo E, Arvat E, Gianotti L, et al. Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man. J Clin Endocrinol Metab. 1994;78(3):693â698.
- Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998;139(5):552â561.
- Rahim A, O'Neill PA, Shalet SM. Growth hormone status during long-term hexarelin therapy. J Clin Endocrinol Metab. 1998;83(5):1644â1649.
- Holt RIG, Ho KKY. The use and abuse of growth hormone in sports. Endocr Rev. 2019;40(4):1163â1185.
- Molitch ME, Clemmons DR, Malozowski S, et al. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(6):1587â1609.
