Narcolepsy Type 2, Orexin Levels, & Orexin Agonists: What We Know So Far

The FDA approval of the first orexin agonist for narcolepsy type 1 (NT1) has sparked many questions from our community: Is orexin involved in narcolepsy type 2 (NT2)? Could orexin agonists help people with narcolepsy type 2?

The short answer: Researchers are actively studying this. 

Most people with narcolepsy type 2 do not have the profound orexin deficiency seen in narcolepsy type 1. However, researchers are still studying whether orexin agonists could meaningfully improve symptoms for people with NT2.

In theory, even without an orexin deficiency, activating orexin receptors could promote wakefulness. Treatments can enhance biological pathways that aren’t necessarily deficient.

The longer answer is more complex. This article explores the evolution from “narcolepsy without cataplexy” to “narcolepsy type 2,” including what we’ve learned about orexin and genetic markers, when testing may be considered, and research into the causes of NT2. We also look at what we know so far about the potential of orexin agonists for NT2.

Understanding Orexin and Narcolepsy Type 1

Orexin, also called hypocretin, is a neuropeptide that helps stabilize wakefulness and regulate transitions between wake, sleep, and REM/dream sleep.

People with narcolepsy type 1 have lost most of the brain cells that produce orexin, resulting in very low orexin levels in cerebrospinal fluid (CSF), measurable through lumbar puncture.

Genetic Susceptibility

About 95–98% of people with narcolepsy type 1 carry an immune-related genetic variant called HLA-DQB1*06:02, which can be measured with a blood test. These HLA variants are used by immune cells to recognize other cells and viruses/bacteria. 

This variant isn’t rare, it’s also found in about 25% of the general population. So HLA-DQB1*06:02 strongly increases susceptibility to NT1, but it does not cause narcolepsy on its own.

How Narcolepsy Type 1 Develops

Current evidence suggests that genetic susceptibility combined with environmental factors (like certain flus and upper airway infections) lead to the loss of orexin-producing neurons and the development of narcolepsy type 1 symptoms.

On August 5, 2026, the FDA approved the first orexin agonist for adults with type 1 narcolepsy. This led to a lot of questions from our community about narcolepsy type 2, orexin levels, and whether a narcolepsy type 2 orexin agonist could help.

Narcolepsy Type 2: What We Know So Far

So far, research indicates that for people diagnosed with narcolepsy type 2, the majority have orexin levels in a typical range, but not always, suggesting there is biological diversity underlying this diagnosis.

Currently, researchers divide CSF orexin levels into these categories:

What Research Shows About Narcolepsy Type 2 and Orexin Levels

2012 Stanford Study

A Stanford-led study in 2022 looked at 171 people with narcolepsy without cataplexy who had CSF orexin measured. Among this group:

• 68% had typical CSF orexin
• 8% had intermediate CSF orexin
• 24% had low CSF orexin, despite having no cataplexy at the time of the study

In the low CSF orexin group, all were HLA-DQB1*06:02 positive, suggesting the same underlying biological cause as narcolepsy with cataplexy. Compared with the typical orexin group, the low CSF orexin group also tended to:

• have an earlier age of onset
• report more severe daytime sleepiness
• have more sleep paralysis
• were more likely to be non-White, particularly Black Americans

At follow-up, 33% of the low CSF orexin group had developed cataplexy, on average about 15 years after sleepiness began. Researchers estimated that about half would develop cataplexy in their lifetime, the other half would never develop cataplexy despite orexin deficiency.

2015 Stanford Study

A follow-up 2015 Stanford-led study examined narcolepsy across racial and ethnic groups, including an analysis of people with orexin loss who did not have cataplexy. Its key findings were: 

• Among people with low CSF orexin, 28% of Black participants did not have cataplexy, compared with 8% of White participants.
• Among those with low orexin, Black participants had lower average orexin levels, yet were less likely to have cataplexy than White participants.
• Black participants had an earlier age of onset of sleepiness.

This study showed further evidence that low orexin does not always result in cataplexy and that clinical presentation of low orexin narcolepsy may vary across populations.

Note: The small numbers of Asian and Latino participants prevented researchers from extending their analysis beyond Black and White participants.

2022 Netherlands Study

A Netherlands study examined 355 people who had CSF orexin measured, including people with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH).

A small group (19 people or 5.3%) had intermediate orexin levels (111–200 pg/mL). In this group:

• Nearly 95% were HLA-DQB1*06:02 positive, similar to the low orexin group (98%).
• They were more likely than the typical orexin group to show cataplexy and sleep study features characteristic of narcolepsy.
• They found people without cataplexy who had either low or intermediate orexin levels.
  

Conclusion: Intermediate orexin levels may be clinically meaningful and don’t fit neatly into the low vs. typical orexin divide.

2022 Italy and France Study

A study conducted in Italy and France in 2022 looked at 1,600 people evaluated for narcolepsy and focused on the 45 people (2.8%) with intermediate CSF orexin levels. The key findings were: 

• 64% had cataplexy, while 36% did not.
• 73% were HLA-DQB1*06:02 positive, and these were more likely to have cataplexy and irresistible daytime sleep episodes.
• Lower orexin levels within this intermediate range were associated with more sleep-related hallucinations.

Conclusion: Intermediate orexin levels represent an important “gray area,” where people may show typical features of narcolepsy despite not meeting the current cutoff for low orexin levels.

Summary: What Research Shows About Narcolepsy Type 2 and Orexin Levels

In summary, these studies found:

2012 Stanford: Low orexin can exist without cataplexy.

• Nearly 1 in 4 people studied without cataplexy had very low orexin.

2015 Stanford: Presentation may vary across populations.

• Profound orexin deficiency without cataplexy was more common among Black participants than White participants.

2022 Netherlands: The low CSF orexin (≤110 pg/mL ) cutoff isn’t the whole story.

• People with intermediate orexin levels may show biological and clinical features associated with orexin-deficient narcolepsy.

2022 Italy/France: The intermediate range is an important “gray area.”

• People may show typical features of narcolepsy despite not meeting the current ≤110 pg/mL CSF orexin cutoff for orexin deficiency.

If Narcolepsy Type 2 Is Not Caused by Orexin Loss, What Causes the Symptoms?

Researchers are working to better understand the underlying causes of NT2 and IH, including whether today’s diagnostic categories represent distinct conditions or overlapping biological subtypes. Important research projects underway:

Why Some People Diagnosed with Narcolepsy Type 2 May Actually Have Narcolepsy Type 1

In the U.S., narcolepsy diagnosis usually relies on symptoms and overnight/daytime sleep testing (PSG + MSLT). CSF orexin is rarely measured.

Yet research studies that have measured CSF orexin have consistently identified a small subgroup of people without cataplexy who have low orexin (≤110 pg/mL).

Under today’s criteria, low orexin would qualify them for a diagnosis of narcolepsy type 1, even without cataplexy. But without routine CSF orexin testing, some people diagnosed with narcolepsy type 2 may not know that they actually meet the biological criteria for NT1.

In terms of advocating for yourself, it is important to know what tests are available. If you’re uncertain about your diagnosis, make sure you’ve engaged your healthcare providers to see if one or more of these tests would be helpful in your situation.

– Dr. Chad Ruoff, Types of Narcolepsy broadcast

Can I Get CSF Orexin Level Measured in the U.S.?

Yes, testing for CSF orexin is available but not commonly used in practice, as it involves a lumbar puncture which is considered an invasive procedure. Mayo Clinic Laboratories offers CSF orexin testing (called ORXNA) to clinicians across the U.S. The lumbar puncture can be performed locally and the sample sent to Mayo for analysis.

Mayo Clinic Laboratories website states, “This test may be considered for the diagnosis of narcolepsy type 1, after HLA-DQB1*06:02 positivity is shown, and if a clinical multiple sleep latency test (MSLT) is negative or unavailable due to potential confounding circumstances.”

Important: Insurance coverage varies for CSF orexin testing and the lumbar puncture. Check with your insurance provider in advance about coverage and prior authorization.

Learn more at the Mayo Clinic Labs website.

Can I Get HLA DQB1*06:02 Testing in the U.S.?

Yes, a healthcare provider can order HLA-DQB1*06:02 testing through a commercial laboratory. It only requires a routine blood draw, but insurance coverage may vary and some plans may not cover it. Medicare may be particularly limited.

It isn’t routinely ordered because a positive result cannot diagnose NT1, since about 25% of the general population carries this genetic variant.

However, a negative result may be more informative: since about 95–98% of people with orexin-deficient narcolepsy carry HLA-DQB1*06:02, NOT having it makes profound orexin deficiency much less likely. Generally, in the case of HLA negativity, a lumbar puncture is not performed.

Before testing: Ask your doctor which lab they use and contact your insurance company and/or the lab to confirm coverage and your expected out-of-pocket costs.

Learn more at LabCorp and Mayo Clinic Labs.

Final Thoughts: Narcolepsy Type 2, Orexin Agonists, and Orexin Levels

We set out to answer your burning questions: Is orexin involved in narcolepsy type 2 and could orexin agonists help people with NT2? What we found is a complex, evolving area of great scientific interest and unmet needs. There’s still so far to go to identify the biological causes underlying narcolepsy type 2. 

At Project Sleep, we believe information is power. We have summarized the current evidence in a lay friendly way, knowing that simplification can lose nuance. Please explore the citations below to dig deeper. 

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