Thursday, 23.03.2017

Reply (Joseph Knoll)

This is a reply to Donald F. Klein's Comments

I would like to thank Dr Donald Klein for his comments and questions. It seems to me that the catecholaminergic activity enhancer (CAE) effect of selegiline, discovered in the mid 1990s, remained unknown because I introduced the compound in 1972 as the first selective inhibitor of B-type MAO, and in humans a daily 10 mg dose is needed to completely inhibit the enzyme in the brain. Thus, selegiline, now registered in more than 60 countries, marketed under more than 100 trade names to treat Parkinson's disease (PD), Alzheimer's disease (AD) and major depressive disorder, cited in thousands of papers and described in the textbooks as the selective inhibitor of MAO-B, is used in this high dose, whereas its main, CAE effect is exerted in a low dose. In addition, the dose-effect relation regarding the CAE effect is unusually complicated. In the rat for example, the peak dose of the 'specific' CAE effect is 0.001 mg/kg, and 0.25 mg/kg blocks the activity of MAO-B in the brain. In this high dose selegiline exerts its 'non-specific' CAE effect. As a matter of fact, the share of the ‘non-specific’ CAE effect of selegiline in the therapeutic benefits observed in patients treated with the usually used 10 mg daily dose remains to be clarified in the future. It is clear by now that selegiline is primarily a β-phenylethylamine (PEA)-derived CAE substance and blocks MAO activity in high doses only.

The catecholaminergic brain engine is the most rapidly aging system in our brain. We lose 13% of our striatal dopamine in the decade after age 45. The aging of the brain engine is primarily responsible for the decay of behavioral and sexual performances over time, and plays a role in the manifestation of neurodegenerative diseases. I wrote this book to put facts and arguments together, which highlights that selegiline, due to its CAE effect, slows the aging of the catecholaminergic brain engine, and as a consequence of this effect, selegiline significantly prolongs the life of different mammalian species. Experimental and clinical studies with selegiline strongly support the proposal that preventive administration of a synthetic CAE substance during post-developmental life could significantly slow the decay of behavioral and sexual performances with the passing of time, prolong life and prevent or delay the onset of aging-related neurodegenerative diseases. In humans, the maintenance from sexual maturity on 1 mg selegiline daily is currently the only feasible preventive measure with a promising chance to accomplish this aim. However, a proper trial on healthy volunteers is still missing. Let us hope all is not lost that is delayed. Since INHN published the “Information on Contents” and “Author's Statement”| of my three monographs (, Publications: September 5, 2013; January 23, 2014; and February 27, 2014) and also ''The history of selegiline/(-)-deprenyl the first selective inhibitor of B-type monoamine oxidase (MAO) and the first catecholaminergic activity enhancer (CAE) substance'' ( Archives: Miklya Collection), there is now available the summation of my research started in the early 1950s which ultimately led to the discovery of the enhancer regulation in the mammalian brain. At present we see only the tip of the iceberg. We learned that PEA and tryptamine are native CAE substances and developed a PEA-, and a tryptamine-derived synthetic CAE substance, selegiline and (-)-BPAP, respectively. We use them to study the enhancer regulation in the brain. Selegiline is at present the available drug to test exactly the preventive anti-aging effect of a safe synthetic CAE-substance. Klein's remark ''….conducting a life extending trial in humans is a far from easy task…...'' is only too true, but the stakes are tremendous. In the Epilogue of my book (p 92) I mention that though ''never marry your hypothesis'' was and has remained my leitmotif, the outcome of the first longevity study (Knoll J. ‘The striatal dopamine dependency of lifespan in male rats. Longevity study with (-)-deprenyl.’ Mechanisms of Aging and Development, 1988, 46:237-262) fascinated me so greatly that I decided, at age 64, to undertake a self-experiment. I am on 1 mg (-)-deprenyl daily since January1, 1989. After the lapse of 25 years, my self-experiment augurs so far well. I wish to thank Dr Donald Klein again for his comments, which coming from a leading expert in our field might be helpful in disseminating the CAE problem to a wider audience and foster additional interest.


Joseph  Knoll

May 1, 2014