N-acetylcysteine

While psychedelics are an important component of the dawning mental healthcare revolution, non-psychedelics will also play key roles in both treatment and prevention of new cases. To this end, Neuronasal, Inc. is developing well-known and FDA-approved OTC compound N acetylcysteine (NAC) as a promising treatment for mild traumatic brain injury (mTBI) using intranasal administration for direct nose-to-brain delivery.

History

NAC was introduced in the 1950s as a mucolytic agent for chronic pulmonary disease. Today, the drug is widely approved and used in this capacity for conditions such as pneumonia, bronchitis and cystic fibrosis.

But NAC’s therapeutic applications extend well beyond its mucolytic properties.

For instance, intravenous high-dose NAC is the standard treatment for
acetaminophen intoxication. In addition, recent studies have found favourable evidence for the use of NAC in several neurologic and psychiatric disorders, such as Alzheimer’s disease, cocaine addiction, bipolar disorder, depression, and schizophrenia, among others.

How does NAC work – and is it safe?

NAC is a precursor of glutathione (GSH), a critical intracellular antioxidant that prevents damage caused by reactive oxygen species (ROS). ROS are
generated as a result of brain injury (e.g. mild traumatic brain injury (mTBI)), which triggers a series of molecular events leading to neuroinflammation and neuronal death in the brain.

Since
NAC acts as a source of cysteine, the levels of which are the rate-limiting step in GSH production, its administration allows depleted GSH pools to replenish. In addition, NAC has direct anti-inflammatory properties and serves as an antioxidant and free radical scavenger. Finally, NAC is an inhibitory glutamatergic modulator, limiting neuro-excitotoxic effects resulting from excessive glutamate release.

Overall, NAC is known to be very safe and comes with few side effects at low doses. However, at the very high oral doses required to produce meaningful drug levels in brain, side-effects like nausea, vomiting, diarrhea, rash and fever have been observed. High-dose intravenous treatment often leads to dizziness and headache. Additionally,
up to 18% of patients receiving intravenous infusions have reported anaphylactoid reactions, presenting with rash, hypotension, or wheezing.

Therapeutic potential

Concussions and other forms of TBI represent a significant and urgent unmet medical need.

With no currently approved treatments, most patients suffer acute symptoms including headache, nausea, fatigue, depression, anxiety and irritability. In addition,
approximately half of the 2.5 million people who are concussed every year in the United States alone develop long-term cognitive impairment. An ongoing NINDS-funded track-TBI initiative has recently revealed that concussion is associated with substantial increases in the rates of major depressive disorder, post-traumatic stress disorder, and other psychiatric and non-psychiatric conditions.

“When you have a mild traumatic brain injury, you’ve got a bunch of things going on. The first event is a physical insult to the brain. If nothing else happened, it would probably result in relatively mild damage,” said Thomas Bradshaw, CEO of Neuronasal, in an interview with FierceBiotech. “But what is caused by [the brain] banging around is a biochemical cascade. Glutathione levels go down and you get microbleeds and swelling … when you have microbleeds, you’re having a reaction to that as well.” 

Fortunately,
NAC shows particular promise as a therapeutic agent in mTBI, especially for the secondary phase described by Bradshaw, wherein the triggered intracellular signaling pathways lead to neuroinflammation, oxidative stress, inhibition of neurogenesis, mitochondrial dysfunction, glutamate excitotoxicity, loss of cholinergic circuits and apoptosis.

Crucially, vitro cellular models showed that apoptosis, mitochondrial fragmentation and autophagy, mediated by oxidative stress, were
alleviated by NAC. Another study showed that early post-injury treatment with NAC reversed the behavioral deficits associated with TBI in rodents. This strongly suggests that NAC should be effective at halting the worst damage caused by ROS released in cases of mTBI.

Initial testing in humans by the US Army has reinforced this hypothesis:
In soldiers exposed to explosive blast injury, treatment with high oral doses of NAC (as compared to placebo) increased the probability of symptom resolution at 7 days from 41.9 to 86.2% when administered within 24 hours post-blast.  

Neuronasal’s potentially ground-breaking, proprietary treatment includes the intranasal delivery of low doses of NAC to patients with acute mTBI by way of an easy-to-use device. This is important because it is expected to produce meaningful drug levels at the sites of injury in the brain, while avoiding the side effects associated with the very high doses of oral or intravenous NAC that would otherwise be required. Moreover, intranasal NAC is well suited for outpatient treatment, whereas intravenous NAC infusions typically require several days of inpatient care.

Conclusion

Given its apparent efficacy in disrupting the underlying neurochemical cascade responsible for the most damaging long-term outcomes of mTBI, intranasal NAC has the potential to change disease trajectories for the millions of people with no other treatment options.

“It’s clear that concussions and other mTBIs are more than just uncomfortable,” said Dr. Matthias Luz, Chief Medical Officer of ATAI Life Sciences. “In the hours and days after trauma, these injuries trigger a pathophysiological cascade that can result in significant long-term sequelae and sometimes even life-limiting conditions if not adequately addressed. NAC appears to have the potential to disrupt this deleterious chain of events following mTBI.”

Results from Neuronasal’s pilot study on the intranasal delivery of NAC should be available in mid-2020, to be followed by a comprehensive phase I study that will conclude in 2021. The aim of these initial trials will be to demonstrate the efficiency of intranasal NAC delivery as measured by magnetic resonance spectroscopy and to identify the optimal drug-device combination