The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it.

Luis de Lecea, Thomas Kilduff, and colleagues reported the discovery of the hypocretin system at the same time as Takeshi Sakurai from Masashi Yanagisawa's lab at the University of Texas Southwestern Medical Center at Dallas reported the discovery of the orexins to reflect the orexigenic (appetite-stimulating) activity of these peptides.

In 1996, scientists from the Scripps Research Institute reported the discovery of several genes in the rat brain, including one they dubbed "clone 35."

A majority of these projections reached the limbic system and structures associated with it (including the amygdala, septum, and basal forebrain area).

To this end, they used transgenic cell lines that expressed individual orphan receptors and then exposed them to different potential ligands.

[17] This precursor protein is known as prepro-orexin (or preprohypocretin) and is a 130 amino acid pre-pro-peptide encoded by the gene HRCT and located on chromosome 17 (17q21).

[23] Many studies support that the orexin neurons regulate brown adipose tissue (BAT) activity via the sympathetic nervous system to enhance energy expenditure.

Studies indicate that a major role of the orexin system is to integrate metabolic, circadian and sleep debt influences to determine whether an animal should be asleep, or awake and active.

[32] Narcolepsy results in excessive daytime sleepiness, inability to consolidate wakefulness in the day (and sleep at night), and cataplexy, which is the loss of muscle tone in response to strong, usually positive, emotions.

In fact, orexin-deficient people with narcolepsy have increased obesity rather than decreased BMI, as would be expected if orexin were primarily an appetite stimulating peptide.

[36] Furthermore, genome-wide analysis shows that, in addition to the HLA variant, people with narcolepsy also exhibit a specific genetic mutation in the T-cell receptor alpha locus.

[39] However, some studies suggest that the stimulatory effects of orexin on feeding may be due to general arousal without necessarily increasing overall food intake.

Ghrelin is a short-term factor secreted by the stomach just before an expected meal, and strongly promotes food intake.

In order to make up for this lack of energy, many people use high-carbohydrate and high-fat foods that ultimately can lead to poor health and weight gain.

[45][46][47] For example, lab rats given drugs which targeted the orexin system lost interest in alcohol despite being given free access in experiments.

[54] The finding suggests that boosting levels of orexin-A could elevate mood in humans, being thus a possible future treatment for disorders like depression.

Proper functioning of orexin has been shown to have a large degree of control over behaviors that are motivated by a need to survive, such as searching for food when an organism is starving.

Orexinergic neurons in the lateral hypothalamic group are closely associated with reward related functions, such as conditioned place preference.

Orexin producing neurons in these areas have been found to be primarily indicated in seeking behavior when externally stimulated by environmental signals such as stress.

[82] In 2016, the University of Texas Health Science Center registered a clinical trial for the use of suvorexant for people with cocaine dependence.

[84] Intranasal orexin is able to increase cognition in primates, especially under sleep deprived situations,[85] which may provide an opportunity for the treatment of excessive daytime sleepiness.

[86] A study has reported that transplantation of orexin neurons into the pontine reticular formation in rats is feasible, indicating the development of alternative therapeutic strategies in addition to pharmacological interventions to treat narcolepsy.

[87] Orexins are also thought to have potential implications in learning and aiding in fending off diseases such as dementia and other disorders that impair cognition.