My Experience With NSI-189

We're living in unusual times.

The internet has empowered courageous (foolish?) individuals to jump the gun on clinical trials. If a drug looks promising, you can put in a request for a custom synthesis of the compound, assay the purity of the sample via HPLC for $200 in a lab in the US, and ingest said compound. To be fair, this practice is far outside of the mainstream and is mostly restricted to the catacombs of Longecity.

Illegally torrenting music has been a big concern for media companies. Analogously, I wonder whether pharmaceutical intellectual property infringement (at the level of consumers) will ever become a hot button issue. If I ever needed to take a $100,000 cancer drug I might be tempted to ordering a custom synthesis from a greyhat lab in China and take it illicitly.


But this post is about my experience with NSI-189 and not about intellectual property, so I'll try to stay on topic.

NSI-189 will be in phase II clinical trial by the end of 2017. NSI-189 is a neurogenic antidepressant under clinical evaluation by Neuralstem. To reiterate: NSI-189 is not FDA-approved. Let's not forget the things that can go wrong with drugs that aren't fully vetted. Because NSI-189 is not vetted by the FDA and its long-term effects are unknown, taking NSI-189 should be a last resort.

I've been taking NSI-189 for over a year. My experience with NSI-189 has been generally positive. OK, that was an understatement; NSI-189 has been a life-saver.

I'm reporting my experience because I was frustrated by a lack of information about NSI-189 online.

I've experienced a lot of side effects with NSI-189 and it would have been helpful to have been able to validate whether these side effects could be attributed to NSI-189 verses some other cause.

It took me a while to get around to writing this post. So long, in fact, that there are now heaps of information about NSI-189 online. Even so, I've decided to hit publish.

I'll introduce NSI-189 for those who are unfamiliar and then discuss its side effects.

Phase of Clinical Research

As of October 2016, NSI-189 was in phase 1B. However, Neuralstem has already enrolled all participants for phase II, which is slated to start in the third quarter of 2017. For some context, here the phases of clinical drug development that precede FDA approval:

Phase Primary goal Dose Patient monitor Typical number of participants Success rate[2] Notes
Preclinical Testing of drug in non-human subjects, to gather efficacy, toxicity and pharmacokinetic information unrestricted scientific researcher not applicable (in vitro and in vivo only)
Phase 0 Pharmacokinetics particularly oral bioavailability and half-life of the drug very small, subtherapeutic clinical researcher 10 people often skipped for phase I
Phase I Testing of drug on healthy volunteers for dose-ranging often subtherapeutic, but with ascending doses clinical researcher 20-100 normal healthy volunteers (or for cancer drugs, cancer patients) approximately 70% determines whether drug is safe to check for efficacy
Phase II Testing of drug on patients to assess efficacy and side effects therapeutic dose clinical researcher 100-300 patients with specific diseases approximately 33% determines whether drug can have any efficacy; at this point, the drug is not presumed to have any therapeutic effect whatsoever
Phase III Testing of drug on patients to assess efficacy, effectiveness and safety therapeutic dose clinical researcher and personal physician 300-3,000 patients with specific diseases 25-30% determines a drug's therapeutic effect; at this point, the drug is presumed to have some effect
Phase IV Postmarketing surveillance – watching drug use in public therapeutic dose personal physician anyone seeking treatment from their physician N/A watch drug's long-term effects

NSI-189's Mystique

NSI-189 was identified by screening for compounds that enhance neurogenesis. Since enhancement of neurogenesis is the common endpoint of almost all antidepressants - this seems like a good strategy.

But Prozac boosts neurogenesis too, so what's the difference? The appeal of NSI-189 is that its mechanism is uncharacterized. That's not to say that Neuralstem hasn't tried to characterize NSI-189's mechanism of action.

This is slide 17 lifted from Neuralstem's March 2016 corporate presentation:

Neuralstem tested NSI-189 for binding activity against 52 different neuronal targets and found nothing.

All we know is that NSI-189 enhances neurogenesis but we don't known how. This air of mystery has intensified interest in NSI-189. If tomorrow it were disclosed that NSI-189 was just another serotonin re-uptake inhibitor, interest would fade.

A similar thing happened with Prozac. In the 90's the book Listening To Prozac was published, a book which in retrospect seemed to evangelize an antidepressant with questionable efficacy. In 2008, the role of publication biases came to the fore with antidepressant trials.

NSI-189's Side Effects

Most nootropics I've trialled have been virtually free of adverse effects. NSI-189 did cause side effects which convinced me that it was doing something.

I experienced these side effects:

  • intermittent peripheral neuropathy (transient loss of sensation in the hands and feet)
  • increased appetite
  • increased dietary preference for sugar (sweet tooth)
  • fatigue/malaise
  • exercise intolerance
  • post-exercise headaches
  • decreased motivation
  • fugue states where my inner dialogue was absent

Some of these side effects will seem like a major burden. But they were more than offset by the benefits of NSI-189:

  • increased sleep quality and increased sleep duration
  • decreased anxiety
  • decreased social inhibitions
  • increased laughter
  • increased playfulness
  • decreased physical sensitivity to pain
  • decreased blood pressure (I'm normally hypertensive)
  • decreased heart rate
  • an almost disconcerting lack of stress
  • mood stability

NSI-189 and Stress

I found that NSI-189 markedly decreased the stress response. NSI-189's anti-stress effect was so pronounced that I felt strange feeling unaffected by things that would normally be very stressful.

This effect of NSI-189 was both positive and negative. It showed me what it's like to function without an exaggerated stress response. On the other hand, stress can be adaptive. It helps you think more clearly and behave more decisively in crucial situations. That surge of epinephrine and norepinephrine you get before an exam mentally prepares you to perform.

I can speculate that NSI-189 suppresses the HPA axis via an unknown mechanism. But there's really no way to say one way or another without elucidating NSI-189's mechanism in the laboratory. Perhaps NSI-189 antagonizes adrenergic signaling - this might explain its hypotensive effects.

Mood Stabilizing Effects of NSI-189

As with NSI-189's effects on stress, its mood stabilizing effects have both upsides and downsides.

People with bipolar disorder absolutely need mood stability. Mood stabilizers are often prescribed off-label to depressed patients because they can be helpful as augmentation agents.

The Bottom Line

  • Will pharmaceutical intellectual property infringement ever become tempting to consumers? Probably not in the mainstream, but it's interesting to think about.
  • NSI-189 is a novel neurogenic antidepressant.
  • My experience with NSI-189 was overwhelmingly positive; it's the only antidepressant to-date that I've responded to.
  • I found that NSI-189 markedly blunted the stress response, which seems beneficial if you'e HPA axis is out of whack.
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Xavier Kent

I'm interested in nutrition, nootropics, and javascript. I'm a firm believer in getting really good at one thing.


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