Fadogia vindicated?! https://pubmed.ncbi.nlm.nih.gov/35969364/

Well NSI-189 was assessed using both the MARDS and HAM-D-17 scales, and failed to reach clinical significance. However, it did reach clinical significance in the CPFQ (Cognitive and Physical Functioning Questionnaire) and the Symptoms of Depression Questionnaire (SDQ), along with stage two of the The Quick Inventory of Depressive Symptomatology (QIDS-SR). It's a bit more complex with NSI-189, as they only studied 40mg and 80mg, with the larger dose showing less effects. This could mean they are dosing too high, and a 20mg would have met the primary endpoints. It also did show benefits in depressive people, but since the primary endpoints are skewed towards how older SSRIs work, just more strictly applied these days, they didn't reach clinical significance in those. They mentioned that in the study.

https://www.researchgate.net/publication/330258439_A_phase_2_double-blind_placebo-controlled_study_of_NSI-189_phosphate_a_neurogenic_compound_among_outpatients_with_major_depressive_disorder

It is worth noting that, in both trials, relatively broad-scope self-report symptom measures of depression and cognition appear to have outperformed traditional clinician-rated measures which sample only a limited subset of possible symptoms MDD patients report in clinical practice, or even when compared to those listed in the DSM-5. Indeed, it has been argued that the MADRS and HAMD-17 were tailored with the particular symptom and side-effect profile of older agents in mind, namely the tricyclic anti- depressants. The drawback, however, is that these older scales (developed in the 1950s and 1960s) fail to capture improvement on several key domains including cognition, irritability, reverse neuro-vegetative symptoms, and emotional symptoms specific to atypical depression including mood reactivity and rejection sensitivity. Interestingly enough, statistically significant separation on the SDQ was obtained on symptoms captured by the MADRS/HAMD-17 such as low affect, tearfulness, but also others including anxiety, mood reactivity, ability to make decisions, ability to work, functioning, optimism, and outlook on life. Efficacy, as measured on the CPFQ, reflects improvement in cognition during treatment. If these assumptions are correct, it is clear in our opinion, that relying on new technology to screen for antidepressant drugs in the pre-clinical arena but then testing them with scales developed 50-60 years ago falls short of what is needed to move the field forward. What remains unclear is why the 80 mg daily dose did not demonstrate efficacy on any study measure, save for some measures of objective cognition. Although it is possible that doses higher than 40 mg are not efficacious for the treatment of symptoms of MDD, the previous phase 1b trial did not show evidence for differential efficacy across daily doses of 40, 80, and 120 mg (Figs. 5a, d in the respective publication). Unfortunately, doses lower than 40 mg have not been tested in order to help confirm or refute this hypothesis.

The big issue with NSI-189 is Neuralstem itself. They have had failure after failure for years, and investors pulled out big time after the NSI-189 results. They don't have the money to see NSI-189 through, unfortunately.