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Controversies on selegiline/(-)-deprenyl’s  pharmacological spectrum after more than 50 years of its development

Joseph Knoll


The behavioral studies initiating the development of selegiline/(-)-deprenyl (DEP). I started in the early 1950s with two students, Károly Kelemen and Berta Knoll, research to investigate the manipulability of mammalian behavior.

We developed a useful model, the ‘glass-cylinder-seeking’ behavior, to study the development and the final irreversible fixation of an acquired drive in the brain of rats. The discovery that the rat, one of the most teachable mammals, is readily capable to acquire an unnatural drive, whereas the indocile mouse is devoid of this ability; furthermore, the successful demonstration of significant differences in the EEG arousal reaction in rats with extinguishable and non-extinguishable conditioned reflexes, and many more unexpected data (Knoll et al. 1955 a, b, c, 1956; Knoll 1956,1957; Kelemen et al. 1961; Knoll B. 1961,1968), gave me the inspiration to realize that the development of mammalian brains capable to fix unnatural drives created the manipulability of behavior which rendered community life possible.

I formulated my theory regarding the peculiar role of acquired drives in the evolution of mammalian life in my first monograph (Knoll 1969). To develop the full possibilities of this approach, I tried thereafter to clarify during a 36-year research period the key important brain mechanisms which determine the life of mammalian species capable to fix acquired drives, and summarized my expounded theory in a second monograph (Knoll 2005).

A detailed analysis of the glass-cylinder-seeking drive inspired the conclusion that in the mammalian brain capable to acquire drives, untrained cortical neurons (Group 1) possess the potentiality to change their functional state in response to practice, training, or experience in three consecutive stages, namely getting involved either (i) in an extinguishable conditioned reflex (ECR) (Group 2); or (ii) in an inextinguishable conditioned reflex (ICR) (Group 3); or (iii) in an acquired drive (Group 4).

Vertebrates can be divided into three groups according to the mode of operation of their brain: (a) those that operate with innate drives only (the majority); (b) those with an ability to acquire drives (a minority); and (c) the ‘group of one’ that operates almost exclusively with acquired drives (Homo sapiens sapiens).

With the evolution of brains capable of acquiring drives, species appeared whose members could manipulate each other's behavior and act in concert. This was the condition sine qua non for the evolution of social living, a form of life that enabled the species to surpass qualitatively the performance of any given individual. It goes without saying that training members in the skills needed to act in concert improved the quality of life. It is hard to overestimate the significance of human’s ability to manipulate the brains of animals with limited ability to fix acquired drives (domestication).

Due to the practically unlimited ability to fix acquired drives, humans possess the most manipulable brain among all living creatures on earth. The home/school/society triad manipulates the members of the society from birth until death, and the individuals behave accordingly.

The human being, a building block in the creation of human society, the most gigantic man-made product on earth, was born with a brain knowing nothing whatever about the real world, but with full capability to invent a non-existing, myths-directed world (and believe in it). Thus, Homo sapiens sapiens, the only surviving human species after the extinction of Homo sapiens fossilis, created necessarily with the chaos function of the human cortex the myths of supernatural forces which brought into being the still existing myths-directed human society.

For sake of survival, it was, of course, from the very beginning of vital importance to get acquainted with the creative and controlling forces of nature. The power of thinking in orderly rational ways, the capacity to explore the natural mechanisms (science), is that physiological reality which determines the conscious fight of the individual to find and fix acquired drives that optimally fit their natural endowments. Homo sapiens sapiens appeared around 150,000 years ago; reached full behavioral modernity around 50,000 years ago; and piled up little by little proper knowledge regarding the natural forces. Science and technology developed slowly until the age of enlightenment and achieved thereafter a dramatic speed. A crucially important step forward was the separation of Church, by its nature the main creator and guardian force of the myths-directed era of the human society, and State, interested by its nature in supporting with passing time more and more the rationally directed human activities. The ultimately unavoidable transition of human society from the myths-directed era into the rationally-directed one will finally lead to a reasonably and harmoniously operating global human world. Just comparing in the highest developed countries the quality and duration of the life of individuals, and the characteristics of social life, prior to the age of enlightenment with the conditions today, the trend of development is clear. The aim set by the brilliant pioneers of the age of enlightenment, their prudence recommendation: Sapere aude (Dare to go independent), is as timely as it was then. If masses learn how the brain works, they will resist traditional methods of manipulation.

Knowledge arrived already to the level which meets the claim to bring to an end the myths-directed era, the first part of human history. After all, time is ripe to call into existence the rationally directed, global, homogeneous human society; the birth of the European Union illustrates for example an evident step forward in the right direction. However, only a smaller part of the human world-population (7.5 billion) lives, at present, in highly developed countries, where the overwhelming majority of citizens believe in democracy, freedom of speech, women’ rights, gay rights, etc. Billions still live in countries where the home/school/society triad manipulates the members of the society from birth until death according to the same myths that shaped the lives of the society centuries ago.

In our animal model, we manipulated the behavior of our rats to fix in their brain the ‘glass-cylinder-seeking drive’. Finally, the rat behaved as one possessing a fanatical desire to reach the unnatural goal: to find in an unknown environment the glass cylinder with a side opening and open at bottom and top, and jump to the rim of the 30-cm-high glass-cylinder. When such a rat has been deprived of food for 48 hours and then food was offered within the usual setup that contained the glass-cylinder, the rat looked for the glass-cylinder and left the food untouched. Similarly, when a receptive female was offered to a sexually fully active glass-cylinder-seeking male rat in the usual setup, the male looked for the glass-cylinder and neglected the receptive female. Thus, the same basic mechanism manipulates the behavior of the domesticated animals and humans. However, in striking contrast to the human brain with practically unlimited capacity to fix acquired drives, this ability in animals is strictly limited (Knoll 1969, 2005).

The brain of a suicide killer is furtively manipulated. The properly acquired drive develops as a result of long-lasting training. The subject always acts under coercion, under severe mental pressure. Nevertheless, it is the nature of acquired drives that if the manipulation was fully successful the individual ultimately behaves as one possessing a fanatical desire to reach the acquired-drive-motivated goal. Thus, the expert’s opinion that the global war on terror is a 7th-century clash involving 21st-century weapons is correct. However much time is still needed to arrive to the ratio-directed era of human history, to reach it is sooner or later an imperative necessity.

The billions who remained during the history of mankind untouched by their wartime killings of the masses of their innocent peers and were ready to die in the name of “God”, “fatherland” and so on, illustrates the consequences of the practically unlimited capacity of the human brain to fix acquired drives. Even in the dark history of mankind, the Holocaust, the extermination of millions within a few years with unprecedented success, due to a systematically planned and executed evil mass manipulation of tens of millions, was a unique event. This horrifying recent example, as well as the war on terror now in progress, testifies to the fact that the potential to misuse the physiological endowments of the human cortex is practically unlimited.

Only a global change of education, based fully on the exact knowledge of the brain mechanisms that enable the manipulation of individuals, can lead, at some point in the future, to the desired rationally directed society (Knoll 2005).

Brief history of the development of DEP. We used in our behavioral studies in the 1950s amphetamine or methamphetamine to stimulate the catecholaminergic machinery, the key important activator of the cortex. Since as soon as we surpassed the 1-2 mg/kg dose, the drug-induced continuous, irresistible release of catecholamines resulted in aimless hypermotility which blocked purposeful behavior, I started a structure-activity-relationship study to develop a better variant. In the early 1960s, monoamine oxidase (MAO) inhibitors represented a new type of central stimulation, so I decided to start the structure-activity-relationship study with methamphetamine containing a propargyl-group attached to the nitrogen. This group was known to form a covalent binding with the flavin in MAO and block the enzyme irreversibly.

Out of a series of newly synthesized patentable, racemic methamphetamine derivatives, I selected E-250 (later named deprenyl) as the most promising to get rid of the catecholamine-releasing property. The first paper describing the beneficial pharmacological profile of the racemic E-250, as a new psychic energizer, was published in 1964 (in Hungarian) and in 1965 (in English) (Knoll et al., 1964, 1965). The (-) isomer [(-)-deprenyl (Selegiline)] was the finally developed drug.

(-)-Deprenyl (DEP), the b-phenylethylamine (PEA)-derivative which catalyzed in the early 1990s the discovery of the catecholaminergic activity enhancer (CAE) effect and opened my mind to the key importance of enhancer regulation in brain work, is now a drug used worldwide to treat Parkinson’s disease (PD), Alzheimer’s disease (AD), and major depressive disorder (MDD). Since maintenance on a low, 1 mg/day, dose slows aging related decay of the catecholaminergic brain engine, DEP is successfully employed by healthy, aging population to improve the quality of life in their middle or late years (Knoll 2012).

After more than 50 years in research and therapy, it is timely to throw light upon the still improper evaluation of the pharmacological spectrum of DEP and the possible origin of the controversies.

The gradual recognition of the complicated pharmacological spectrum of DEP.


Recognition that DEP is the unique MAO inhibitor free of the ‘cheese effect’. In 1963, a calamitous number of clinical reports (Womack, Foster, Maan, Davies) appeared in The Lancet concerning patients treated with MAO inhibitors (tranylcypromine, nialamide, pargyline) who developed temporary clinical symptoms (hypertension, palpitation, neck stiffness, headache, nausea, vomiting), similar to a paroxysm produced by pheochromocytoma.

Blackwell realized that these hypertensive crises are associated with the ingestion of high amounts of tyramine in cheese, and MAO inhibitors impede metabolism (a.k.a. the “cheese effect”) (Blackwell 1963).This was for me a highly important, thought-provoking perception, because when Blackwell’s paper appeared, I was working on the manuscript of the first DEP papers (at that time we used the original code name: E-250), and the detailed pharmacological analysis clearly indicated, already in 1965, that DEP is the first MAO inhibitor free of the cheese effect and the prima-facie experimental evidence was published three years later (Knoll et al. 1968).

Unfortunately, 1960s Hungary was isolated from the western world’s mainstream science. Our results remained largely unnoticed. I asked Ervin Varga in 1964, who worked as psychiatrist in our University Clinic, to test the antidepressant effect of racemic E-250. He published a preliminary note (in German) on the promising results of the running clinical trial with racemic E-250 on depressed patients (Varga 1965). Varga wrote with his coworker the first paper, in English, describing that racemic E-250 is an efficient, prompt acting antidepressant (Varga and Tringer 1967). In 1971, they wrote the first paper demonstrating that DEP is a potent antidepressant (Tringer et al. 1971).

In retrospect, it is surprising that although our first papers on racemic E-250, which proposed to use the new compound as an antidepressant, appeared in 1964/1965; the first clinical studies which supported the proposal were published by Varga in Hungary between 1965-1971; the first clinical trial abroad proving the antidepressant effect of DEP was published in the USA (Mann and Gershon 1980), and a couple of studies corroborated the finding thereafter (see Knoll 2012 Chapter 8); selegiline (DEP) with the indication to treat major depressive disorder was only first registered in 2006 in the United States and, based on a transdermal selegiline study in outpatients (Bodkin and Amsterdam 2002), marketed as the first transdermal antidepressant (Emsam).

Ervin Varga found that in harmony with our rat experiments, DEP is free of the “cheese effect” also in humans. As cited as a personal communication in the discussion of our 1968 paper, he stated “Even provocative cheese consumption failed to produce headache or hypertensive crisis” (Knoll et al. 1968; p. 111). Varga moved to the USA, where he still lives, and he discontinued his clinical studies with DEP. His convincing preliminary study, which confirmed that DEP is devoid of the “cheese effect” was never completed and has remained unpublished. It marks the era in Hungary in the 1960s, referred to in the discussion of the Knoll et al. 1968 paper, during which two other Hungarian studies are mentioned, which confirmed that DEP was devoid of the “cheese effect” (Kardos and Füredi 1966; Juhász personal communication). None of them were completed, but later performed studies with DEP confirmed these observations (Knoll 2016).

Sandler and his co-workers in London demonstrated that after pretreatment with DEP parkinsonian volunteers who had received levodopa or levodopa+carbidopa suffered no adverse pressor reaction after challenged with oral tyramine in considerably greater amounts than the dose likely to be encountered in a normal diet (Elsworth et al. 1978; Sandler et al. 1978). Thus, they finally, acceptably confirmed that DEP is an MAO inhibitor free of the cheese effect, which aligned with our findings in animal experiments and with preliminary studies of Hungarian clinicians.

Because of the serious side effects of levodopa in Parkinson’s disease, Birkmayer and Hornykiewicz attempted to achieve a levodopa-sparing effect with the concurrent administration of levodopa with an MAO inhibitor. As such combinations frequently elicited hypertensive attacks, they soon terminated this line of clinical research (Birkmayer and Hornykiewicz 1962). Considering the peculiar pharmacological profile of DEP, Birkmayer in Vienna was the first clinician who dared to combine DEP with levodopa in Parkinson’s disease. The trial, the first clinical study with DEP in the West, was successful. The levodopa-sparing effect was achieved in patients without signs of significant hypertensive reactions (Birkmayer et al. 1977). This study initiated, and a subsequent Lancet Editorial (September 25, 1982) enhanced, the world-wide use of DEP in Parkinson’s disease.



The recognition that DEP is the first selective inhibitor of B-type MAO. In the early 1970s, DEP achieved its place in research and therapy as the first selective inhibitor of MAO-B. Since DEP as a drug (selegiline) is classified in all textbooks only as the prototype of the selective inhibitor of MAO-B, it is still the universal belief among clinicians that selective inhibition of B-type MAO in the brain is fully responsible for selegiline-treatment induced therapeutic benefits. This view is inconsistent with the already proven complex pharmacological spectrum of DEP and this is the controversy which deserves careful consideration.

In the same year that we published the unique behavior of (-)-deprenyl (Knoll et al. 1968), Johnston described clorgyline, which came into world-wide use as an experimental tool in MAO research (Johnston, 1968). He namely realized that clorgyline preferentially inhibits the deamination of serotonin, and this important finding was soon confirmed by Hall et al. (1969). Johnston proposed the existence of two forms of MAO, “type A” and “type B”, the former being selectively inhibited by clorgyline and the latter relatively insensitive to it. Johnston's nomenclature has become widely accepted and is still in use. Clorgyline remained the classic experimental tool to analyze A-type MAO.

For further studies, a selective inhibitor of MAO-B was strongly needed. Fortunately, DEP proved to be the missing, selective inhibitor of MAO-B. I presented the finding in my lecture at the First International MAO Meeting in Cagliari (Sardinia) in 1971. DEP is still the classic experimental tool to analyze B-type MAO. The first paper which described this novel property of DEP (Knoll and Magyar 1972) has become a citation classic ten-year later (Knoll J, This Week’s Citation Classic, January 15, 1982).

For several years, the selective MAO-B inhibitory effect of DEP was at the center of our interest. It delayed the discovery of the drug’s enhancer effect. Prior to the discovery of the catecholaminergic activity enhancer (CAE) effect of DEP (Knoll 1998), it was my firm belief that the selective inhibition of B-type MAO is responsible for the drug’s beneficial therapeutic effects. In my lecture at the ‘Strategy of Drug Research’ IUPAC/IUPHAR Symposium in Noordwijkerhout (The Netherlands) in 1982, I presented experimental evidence that preventive daily administration of DEP during the post-developmental phase of life is an unexpected chance to improve the quality and prolong the duration of mammalian life (Knoll 1982).

Since further behavioral studies indicated that important central stimulatory effects of DEP might be unrelated to MAO-B inhibition, it stand to reason to perform a structure-activity-relationship study to throw light on this problem. We developed (-)-1-phenyl-2-propylaminopentane, (-)-PPAP, the DEP-analog containing instead of the propargyl-group, a propyl-group attached to the nitrogen. The propyl-group is unable to covalently bind with the flavin in MAO-B rather than the propargyl-group in DEP. Thus, (-)-PPAP leaves MAO-B activity unchanged, however, as a central stimulant (-)-PPAP proved to be as potent stimulant of the catecholaminergic neurons as DEP (Knoll et al. 1992).

This finding paved the way for the discovery of the enhancer-regulation in the mammalian brain (Knoll 1994, Knoll and Miklya 1994), and to the realization that: i.) β-phenylethylamine (PEA) is a natural catecholaminergic activity enhancer (CAE) substance (Knoll et al. 1996a); ii.) DEP is a PEA-derived synthetic CAE substance (Knoll et al. 1996b); iii.) tryptamine is a natural enhancer substance (Knoll 1994), the realization of which catalyzed the  structure-activity-relationship study resulting in the development of (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP), the tryptamine-derived, presently most potent known synthetic enhancer substance (Knoll et al., 1999).



The recognition that DEP is a PEA-derived synthetic enhancer substance. The high pressure liquid chromatography (HPLC) method with electrochemical detection allows exact measurement of the continuously released catecholamines and serotonin from freshly excised brain tissue. This method ensured us to obtain unequivocal experimental evidence regarding the operation of the enhancer regulation in the life-important catecholaminergic and serotonergic systems of the brainstem. In 1993, we began to use this technique to measure the amount of dopamine released from the striatum, substantia nigra and tuberculum olfactorium, as well as norepinephrine from the locus coeruleus and serotonin from the raphe.

In 1994, we presented the results from the first series of experiments performed with the HPLC method which demonstrated that multiple, small dose administration of DEP keeps the catecholaminergic, but not the serotonergic neurons on a significantly higher activity level, and how DEP’s peculiar enhancer effect is unrelated to MAO-B inhibition (Knoll and Miklya 1994).

In these experiments, the rats were daily treated for 21 days subcutaneously with DEP, PPAP and methamphetamine, respectively. Measuring by HPLC method the amount of catecholamines and serotonin released within 20 minutes from the freshly isolated, discrete brain regions, we measure exactly the part of the surviving spontaneously active neurons. Treating the rats with proper low doses of the enhancer substances we exactly measure the synthetic enhancer-treatment induced increase in the number of spontaneously active neurons.


For example, whereas 2.72±0.10 nmoles/g tissue of dopamine was released within 20 minutes from the freshly isolated striatum of male rats treated subcutaneously with 0.3 ml saline/100g daily measured 24 hours after the last injection, the amount of dopamine released within 20 minutes from the striatum isolated from rats treated with 0.01 mg/kg DEP was 4.42±0.09 nmoles/g tissue. We obviously measure the enhancer-treatment induced transformation of silent neurons into spontaneously working neurons from the freshly isolated striatum.

We measured the dose-related effects of DEP, PPAP and methamphetamine (see Knoll 2016 Table 1).

We investigated methamphetamine’s enhancer effect because it is a synthetic PEA-derivative with the same pharmacological spectrum as its parent compound, PEA, the natural enhancer of the catecholaminergic neurons, being in higher concentrations a potent releaser of catecholamines.

We measured the effect of DEP, the PEA-derived synthetic enhancer substance free of the catecholamine-releasing property, being in higher concentrations a potent selective inhibitor of MAO-B.

We also measured the enhancer effect of PPAP, which acts like DEP, but leaves MAO-B activity unchanged (Knoll et al. 1992).

Like PEA, their parent compound, the natural catecholaminergic enhancer (CAE) substance, the synthetic PEA-derivatives are in low concentration potent CAE substances. As measured 24 hours after the last injection, a three-week daily treatment of male and female rats with 0.01 mg/kg DEP, or 0.1 mg/kg PPAP, or 0.05 mg/kg methamphetamine, kept the catecholaminergic neurons working on a significantly higher activity level, but they did not enhance the activity of the serotonergic neurons (Knoll 2016 Table 1 and 2).

The discovery of the enhancer regulation in the mammalian brain and the development of the synthetic enhancer substances were recently summarized (Knoll 2016). This study presents final evidence that the enhancer effect of DEP and BPAP, the presently known most potent synthetic enhancer substances, are responsible for the prolongation of life in mammals. Rats treated three times a week with 0.0001 mg/kg BPAP, which is the peak dose exerting its specific enhancer effect (Knoll 2016, Fig.24), significantly prolonged the life of rats (Knoll 2016, Fig.28). This study also shows that the 0.25 mg/kg dose of DEP, used from the beginning in the longevity studies (Knoll 1988), has two effects: it is the peak dose which blocks completely MAO-B in the brain, and is also the peak dose which exerts the non-specific enhancer effect of DEP (Knoll 2016, Fig.12). Since the presently used 10 mg daily dose of DEP in therapy was originally selected as the one equivalent with the dose used in animals, it remains for the future to clarify the role of the non-specific enhancer effect of DEP in the therapeutic benefits observed in the last decades.

All in all, the complicated pharmacological profile of DEP was recognized in phases.

The first phase was the structure-activity-relationship study performed in the early 1960s with the aim to develop for the behavioral studies a methamphetamine derivative devoid of the catecholamine-releasing effect of its parent compound. I selected the compound, later named deprenyl, as the most suitable one for further research. Being devoid of the catecholamine-releasing property, DEP was the first MAO inhibitor free of the cheese-effect.

The second phase in DEP-research which attracted international attention started in the 1970s. This was the discovery that DEP is a selective inhibitor of MAO-B.

The third phase in DEP-research, the discovery of the enhancer regulation in the rat brain, started in the 1990s. We realized that β-phenylethylamine (PEA) and tryptamine are endogenous enhancer substances, DEP is a PEA-derived synthetic enhancer substance, and we developed BPAP, the tryptamine-derived synthetic enhancer substance (as the first summary, see Knoll 2005 and as the last summary, see Knoll 2016).

It is not to be questioned that since the early 1960s the DEP story had always a surprise in store. DEP-research forwarded us to the discovery of the enhancer regulation in the mammalian brain, to the realization that the catecholaminergic and serotonergic neurons are enhancer-sensitive units, and to the development of BPAP.

Brief summary of the unique mechanism of the enhancer effect. We selected in shuttle box experiments the peak in vivo enhancer doses for DEP (‘specific’: 0.001 mg/kg; ‘non-specific’ 0.25 mg/kg) and BPAP (‘specific’: 0.0001 mg/kg; ‘non-specific’: 0.05 mg/kg)   for rats (see Knoll 2016, Fig.12 and Fig.24). The essence of the in vivo analysis was the measurement of the acquisition of a two-way conditioned avoidance reflex (CAR) in the shuttle box, and the inhibition of rats’ learning ability with tetrabenazine-treatment (1 mg/kg sc.) which reversibly blocks the vesicular monoamine transporter 2 (VMAT2). Tetrabenazine depletes at least 90% of norepinephrine and dopamine from their stores in the nerve terminals within 1 hour. The lower the degree of saturation in the transmitter pools, the lower is the excitability of the neuron. Due to the weak performance of the catecholaminergic brain engine, activation of cortical neurons remains in tetrabenazine-treated rats below the level required for acquisition of a CAR. However, addition of 0.0001 mg/kg BPAP to 1 mg/kg tetrabenazine fully restored the learning ability of the rats (Knoll 2016, Fig. 24).


Since BPAP-treatment fully restored catecholaminergic transmission, there is no denying the fact that VMAT2 works again despite the presence of tetrabenazine. Considering the nature of the well documented effects of BPAP on the enhancer-sensitive catecholaminergic and serotonergic neurons, the low dose BPAP-induced elimination of the effect of tetrabenazine is outlining the functionally essential mechanism of the peculiar enhancer effect of BPAP, the molecular mechanism how 0.0001 mg/kg BPAP is capable to keep VMAT2 normally working in the presence of tetrabenazine awaits clarification and is now subject of Western blotting analysis.


Let us discuss the therapeutically important essential functional mechanism of BPAP, the presently known most potent synthetic enhancer substance, analyzing its effect, as an example, on the enhancer-sensitive dopaminergic neurotransmission. Regarding the excitability and function of dopaminergic neurons electrophysiological studies with rodents and primates have shown that these neurons are silent or spontaneously active (Marinelli et al. 2006). DEP or BPAP treatment keeps the catecholaminergic neurons on a higher activity level (Knoll 2005, 2012, 2016). For example: 6.8±0.18 nmol/g wet weight dopamine was released within 20 min from the substantia nigra isolated from saline treated rats and 14.8±0.36 nmol/g wet weight dopamine was released within 20 min from the substantia nigra isolated from rats treated with a single dose of 0.0001 mg/kg BPAP. Similarly, a single dose treatment with 0.0005 mg/kg BPAP increased the release of norepinephrine from the isolated locus coeruleus within 20 min from 4.7±0.10 (saline) to 15.4±0.55 nmol/g wet weight; and a three-week treatment once daily with 0.0001 mg/kg BPAP acted similarly (the brain areas were isolated 24 hours after the last injection) (Knoll 2016, Table 10).


These ex vivo results from studies using isolated discrete rat brain regions are in complete harmony with the results of the in vivo shuttle box experiments and furnish unequivocal evidence that the treatment of rats with 0.0001 mg/kg BPAP transformed the silent catecholaminergic neurons into spontaneous firing entities.


The presently known enhancer-sensitive regulations work in the uphill period of life, from weaning until sexual maturity, on a significantly higher activity level (Knoll and Miklya 1995). Sexual hormones (estrone, testosterone) return the enhancer regulation to the pre-weaning level, putting in action the downhill period of life and the aging-related slow decay of the enhancer regulation continues until death (Knoll et al. 2000). It is obvious that maintenance during the downhill period of life on a proper low dose of a synthetic enhancer substance slows the aging related decay of the enhancer sensitive brain regulations, improves the quality of life in the latter decades, prolongs life and delays or prevents the manifestation of enhancer-regulation-dependent illnesses, signaling that due to aging-related decay the enhancer regulation surpassed already the critical threshold.

For example, we lose 13% of our dopamine in the decade after age 45. In the healthy population the calculated loss of striatal dopamine is about 40% at the age of 75 which is about the average lifetime. As symptoms become visible only after the unnoticed loss of about 70% of striatal dopamine, in diagnosing Parkinson’s disease the neurologist selects subjects with the most rapidly aging striatal dopaminergic system (about 0.1% of the population). Parkinson’s disease is incurable, thus to start treatment as the loss of striatal dopamine exceeds 70%, is too late.

Experimental and clinical studies with (-)-deprenyl/selegiline strongly support the proposal that preventive administration of a synthetic enhancer substance during post-developmental life could significantly slow the unavoidable decay of behavioral performances with the passing of time, prolong life, and prevent or delay the onset of aging-related neurodegenerative diseases, such as PD and AD. In humans, maintenance from sexual maturity on (-)-deprenyl (1 mg daily) is for the time being the only feasible treatment with a promising chance to reach this aim, since selegiline is at present the only world-wide registered CAE substance.

Considering the peculiar pharmacological profile of selegiline, the unusual safety of this drug and the incurable nature of PD and AD, it is unfortunate that we are still in want of a multicenter, controlled clinical trial, designed to measure the prevalence of these neurodegenerative diseases in a cohort treated from at least age 60 with 1 mg selegiline daily.

All drugs used today harshly change in their pharmacologically effective dose the physiological milieu of the highly sophisticated living material, so they are in principle unsuitable for lifelong daily administration, the uniqueness of the enhancer effect is evident. In the extremely low dose range in which they exert their specific enhancer effect, the enhancer substances selectively transform the lower performing enhancer sensitive neurons into better performing ones, thus they do not change the physiological milieu. It is obvious that their safety margin is exceptional.

Lifelong preventive medication requires unique drug safeness. Due to their peculiar mechanism of action and safety margin, only the synthetic enhancer substances meet this requirement. BPAP on rats exerts its specific enhancer effect in a subcutaneous dose as low as 0.0001 mg/kg and even the subcutaneous administration of 20 mg/kg is tolerated without any sign of toxic effects.

Since DEP (Selegiline), is at present the only synthetic CAE substance in clinical use, it is reasonable to suggest a daily 1 mg dose to serve as a preventive agent from sexual maturity to slow the aging of the catecholaminergic brain engine. As repeatedly demonstrated, DEP is a perfectly safe option for this purpose. Nevertheless, BPAP, the therapeutic efficiency of which still needs establishing, overshadows the potency of DEP. BPAP, the highly potent and selective synthetic enhancer substance, is an ideal experimental tool for detecting unknown enhancer-sensitive brain regulations. Since our knowledge regarding the enhancer regulation is in its infancy, we see just the peak of the iceberg. The prospects of revealing by the aid of BPAP unexplored enhancer regulations in the mammalian brain are quite promising.

Reasons for the need to evaluate the share of DEP’s ‘non-specific’ enhancer effect in the therapeutic benefits observed since decades in patients treated with the usually used 10 mg daily oral dose of DEP. There is recent convincing, unequivocal experimental evidence on rats that the generally used parenteral dose of DEP (0.25 mg/kg) which blocks selectively MAO-B activity in the brain is also the optimal dose which exerts the ‘non-specific’ enhancer effect ( see Knoll 2016, Fig. 12).

Since the oral 10 mg daily dose of DEP was originally selected by us in the 1960s for the first clinical trials as equivalently effective with 0.25 mg/kg dose of DEP in rats to block selectively MAO-B activity in the brain, and this is still the world-wide used daily dose of DEP in therapy, there can be little doubt that the generally used oral dose of DEP exerts also in humans its ‘non-specific’ enhancer effect. Up to the present, the unknowingness of the enhancer regulation left this point out of consideration. It remains for the future to ascertain the share of the ‘non-specific’ enhancer effect in DEP-treatment induced therapeutic benefits.




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Knoll J. Experimental studies on the higher nervous activity of animals. VI. Further studies on active reflexes. Acta Physiologica Hungarica 1957; 12:65-92.


Knoll J. The theory of active reflexes. An analysis of some fundamental mechanisms of higher nervous activity. Publishing House of the Hungarian Academy of Sciences, Budapest, Hafner Publishing Company, New York. 1969


Knoll J. Selective inhibition of B type monoamine oxidase in the brain: a drug strategy to improve the quality of life in senescence. in: Strategy in drug research (JA Keverling Buisman, editor). Amsterdam, Elsevier; 1982, p.107-35.


Knoll J. Memories of my 45 years in research. Pharmacology and Toxicology 1994; 75:65-72.


Knoll J. (-)Deprenyl (selegiline) a catecholaminergic activity enhancer (CAE) substance acting in the brain. Pharmacology and Toxicology 1998; 82:57-66.


Knoll J. The brain and its self. A neurochemical concept of the innate and acquired drives. Springer, Berlin, Heidelberg, New York, 2005.


Knoll J. How Selegiline ((-)-Deprenyl) Slows Brain Aging. (Bentham e-Books, 2012).


Knoll  J.  Discovery of the enhancer regulation in the mammalian brain and the development of synthetic enhancer substances. A chance to significantly improve the quality and prolong the duration of human life. ( URL:; e-books, 2016).


Knoll J, Magyar K. Some puzzling effects of monoamine oxidase inhibitors. Advances Biochemical Psychopharmacology 1972; 5:393-408.


Knoll J, Miklya I. Multiple, small dose administration of (-)deprenyl enhances catecholaminergic activity and diminishes serotoninergic activity in the brain and these effects are unrelated to MAO-B inhibition. Archives internationales de Pharmacodynamie et de Thérapie 1994; 328:1-15.


Knoll J, Miklya I. Enhanced catecholaminergic and serotoninergic activity in rat brain from weaning to sexual maturity. Rationale for prophylactic (-)deprenyl (selegiline) medication. Life Sciences 1995; 56:611-20.


Knoll J, Kelemen K, Knoll B. Experimental studies on the higher nervous activity of animals. I. A method for the elaboration of a non-extinguishable conditioned reflex in the rat. Acta Physiologica Hungarica 1955a; 8:327-45.


Knoll J, Kelemen K, Knoll B. Experimental studies on the higher nervous activity of animals. II. Differences in the state of function of the cells constituting the cortical representation of the unconditioned reflex in extinguishable and non-extinguishable conditioned reflexes. Acta Physiologica Hungarica 1955b; 8:347-67.


Knoll J, Kelemen K, Knoll B. Experimental studies on the higher nervous activity of animals. III. Experimental studies on the active conditioned reflex. Acta Physiologica Hungarica 1955c; 8:369-88.


Knoll J, Kelemen K, Knoll B. Experimental studies on the higher nervous activity of animals. IV. A method for elaborating and studying an active conditioned feeding reflex. Experimental analysis of differences between active conditioned defensive and feeding reflexes. Acta Physiologica Hungarica 1956; 9:99-109.


Knoll J, Ecsery Z, Nievel J, Knoll B. Phenylisopropylmethyl-propinylamine HCl (E-250) egy új hatásspektrumu pszichoenergetikum. MTA V. Oszt. Közl. 1964; 15:231,   


Knoll J, Ecseri Z, Kelemen K, Nievel J, Knoll B.  Phenylisopropylmethyl¬ propinylamine (E-250) a new psychic energizer. Archives internationales de Pharmacodynamie et de Thérapie 1965; 155:154-64.


Knoll J, Vizi ES, Somogyi G. Phenylisopropylmethylpropinylamine (E-250), a monoamine oxidase inhibitor antagonizing the effects of tyramine. Arzneimittelforschung 1968; 18:109-12.


Knoll J, Knoll B, Török Z, Timar J, Yasar S. The pharmacology of 1-phenyl-2-propylaminopentane (PPAP), a deprenyl-derived new spectrum psychostimulant. Archives internationales de Pharmacodynamie et de Thérapie 1992; 316:5-29.


Knoll J, Miklya I, Knoll B, Markó R, Rácz D. Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the brain. Life Sciences 1996a; 58:2101-14.


Knoll J, Miklya I, Knoll B, Markó R, Kelemen K. (-)Deprenyl and (-)1-phenyl-2-propylaminopentane, (-)PPAP, act primarily as potent stimulants of action potential-transmitter release coupling in the catecholaminergic neurons. Life Sciences 1996b; 58:817-27.


Knoll J, Yoneda F, Knoll B, Ohde H, Miklya I. (-)l-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain. British Journal Pharmacology 1999; 128:1723-32.


Knoll J, Miklya I, Knoll B, Dallo J. Sexual hormones terminate in the rat the significantly enhanced catecholaminergic/serotoninergic tone in the brain characteristic to the post-weaning period. Life Sciences 2000; 67; 765-73.


Lancet Editorial. Deprenyl in Parkinson’s Disease. The Lancet 1982; Vol.2, No.8300, (September 25) p. 695-96.


Mann JJ, Gershon S. A selective monoamine oxidase-B inhibitor in endogenous depression. Life Sciences 1980; 26:877-82.


Marinelli M, Rudick CN, Hu XT, White FJ. Excitability of dopamine neurons: modulation and physiological consequences. CNS Neurological Disorders Drug Targets 2006; 5:79-97.


Sandler M, Glover V, Ashford A, et al. Absence of „cheese effect” during deprenyl therapy: some recent studies. Journal Neural Transmission 1978; 43:209-15.


Tringer L, Haits G, Varga E. The effect of (-)E-250, (-)L-phenyl-isopropylmethyl- propinyl-amine HCl, in depression, in: V. Conferentia Hungarica pro Therapia et Investigatione in Pharmacologia (G Leszkovszky, editor), Budapest, Publishing House of the Hungarian Academy of Sciences, 1971, p.111-14.


Varga E. Vorlufiger Bericht über die Wirkung des Prparats E-250 (phenyl-isopropyl-methyl-propinylamine-chlorhydrat), in: III. Conferentia Hungarica pro Therapia et Investigatione in Pharmacologia (B Dumbovich, editor), Budapest, Publishing House of the Hungarian Academy of Sciences, 1965, p.197-201.


Varga E, Tringer L. Clinical trial of a new type of promptly acting psychoenergetic agent (phenyl-isopropylmethyl-propinylamine HCl, E-250). Acta Medica Hungarica 1967; 23:289-95.


Joseph Knoll

August 4, 2016