Joseph Knoll’s additional response to Hector Warnes’ response 2

Joseph Knoll: The Discovery of the Enhancer Regulation in the Mammalian Brain and the Development of the Synthetic Enhancer Substances


You refer in your comment to the DATATOP study papers of the Parkinson Study Group, published in 1989. In agreement with the still generally accepted view, you refer to the
(-)-deprenyl/selegiline (DEP)-treatment induced delayed need for levodopa-therapy as a consequence of DEP-induced MAO-B inhibition.

We presented in a recent longevity study experimental evidence that rats treated daily with 0.0001 mg/kg (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP), the peak dose which exerts the specific enhancer effect, lived significantly longer than their saline-treated peers and BPAP was more potent than DEP in extending the lifespan of rats (Knoll and Miklya 2016). This was the proof that the enhancer effect is responsible for BPAP-induced life extension.

When the DATATOP study was planned in the late 1980s, DEP’s enhancer effect was unknown. The organizer’s hypothesis for the DATATOP study was the concept that the activity of MAO and the formation of free radicals predispose patients to nigral degeneration and contribute to the emergence and progression of Parkinson’s disease (PD). In accordance with their working hypothesis, they expected that DEP (the MAO inhibitor), α-tocopherol (the antioxidant) and the combination of the two compounds would slow the disease’s clinical progression.

They selected patients with early, untreated PD and measured the delay in the onset of disability necessitating levodopa therapy. In the first phase of the trial, 401 subjects were assigned to a-tocopherol or placebo and 399 subjects were assigned to DEP, alone or with a-tocopherol. Only 97 subjects who received DEP reached the “end” of the trial (i.e., the onset of disability necessitating levodopa therapy) during an average 12 months of follow-up compared with 176 subjects who did not receive DEP. The risk of reaching the end of the trial was reduced by 57% for patients who received DEP and these patients also had a significant reduction in their risk of having to give up full-time employment (Parkinson Study Group 1989). Following the course of changes, the authors concluded in their next paper that DEP, but not a-tocopherol, delayed the onset of disability associated with early, otherwise untreated PD (Parkinson Study Group 1993). Over time, however, the DATATOP study also revealed that DEP did not reduce the occurrence of subsequent levodopa-associated adverse effects in patients. This fact still deserves serious consideration (Parkinson Study Group. 1996).

The outcome of the DATATOP study, the finding that DEP delayed the need for levodopa therapy, but a-tocopherol fell short of expectation, clearly proved for us that DEP exerts an unknown pharmacological effect of basic importance and a-tocopherol is devoid of this effect.

We soon realized that DEP is a PEA-derived catecholaminergic activity enhancer (CAE) substance, an enhancer of the impulse propagation mediated release of catecholamines. A comparative pharmacological analysis of DEP and a-tocopherol proved that a-tocopherol is devoid of the enhancer effect (Miklya et al. 2003). At 0.25 mg/kg DEP selectively blocks MAO-B in the brain and also exerts, in the same dose, the non-specific enhancer effect (Knoll and Miklya 2016). Furthermore, since DEP prolongs the lifespan of rats in 0.001 mg/kg dose, it is obvious that the enhancer effect of DEP is responsible for the observed delay of levodopa need (Knoll 2012). 

This conclusion was also supported by the clinical trial with rasagiline performed by the Parkinson Study Group. The trial revealed that unlike the early selegiline trials, rasagiline failed to demonstrate a decreased need for levodopa (Parkinson Study Group 2002). Even the results of additional studies (Ahlskog and Uitti 2010; Olanow and Rascol 2010) led to the conclusion that “based on current evidence, rasagiline cannot be said to definitely have a disease-modifying effect” (Robottom 2011). Similar to a-tocopherol, neither lazabemide nor rasagiline, the two selective MAO-B inhibitors used in PD, are also devoid of the CAE effect of DEP (Miklya 2014).

Since the mid-1980s, further analysis of the characteristic enhancement of the catecholaminergic brain machinery in DEP-treated rats rendered probable that this effect is unrelated to the selective inhibition of MAO-B. The development of 1-phenyl-2-propylaminopental (PPAP), the DEP-analog devoid of a MAO inhibitory property, and an equally active stimulant of the catecholaminergic neurons as DEP, verified this suggestion (Knoll 1992). The first study which demonstrated that multiple, low dose administration of DEP enhances catecholaminergic activity in the brain and this effect is unrelated to MAO-B inhibition allowed for the discovery of the enhancer sensitive brain regulations (Knoll and Miklya 1994). P-phenylethylamine (PEA) and its best known synthetic derivatives (amphetamine and methamphetamine) are strong releasers of catecholamines from their plasmatic pools. Since the catecholamine releasing effect conceals the detectability of the enhancer-sensitive nature of the catecholaminergic neurons (Knoll 2016, Fig. 8), DEP’s primary physiological function as a natural enhancer substance, as well as the fact that amphetamine and methamphetamine are, like DEP, PEA-derived synthetic enhancer substances, remained unknown.

The later realization that tryptamine is, like PEA, a natural enhancer (Knoll 1994) signaled the elaboration of BPAP as the most selective and potent synthetic enhancer substance currently known (Knoll et al. 1999).

Since in 1989, when the DATATOP study was performed, we all were convinced that the selective inhibition of MAO-B in the brain is responsible for DEP’s unique pharmacological effects, but our further studies disaffirmed this view. I hope that clinicians will seriously consider that DEP is a PEA-derived synthetic enhancer substance which exerts its specific enhancer effect in a very low dose (0.001 mg/kg) (Knoll 1998); and the development of BPAP, the trypamine-derived, selective and most potent synthetic enhancer (Knoll et al. 1999) confirmed the importance of this new line in brain research. Furthermore, the proof in our recent longevity study that compared the low dose of the synthetic enhancers with their specific enhancer effect, and very high doses of DEP (0.25 mg/kg) and BPAP (0.05 mg/kg) exert their non-specific enhancer effect and prolong the life of rats is, from a practical point of view, important information. Since 0.25 mg/kg DEP is the peak dose in rats and 10 mg DEP daily is the optimum dose in patients to selectively block MAO-B activity in the brain and the same dose of DEP is also the peak dose with the non-specific enhancer effect, it remains for the future to exactly verify the participation of the non-specific enhancer effect and MAO-B inhibition in patients treated with 10 mg DEP daily.

Thank you Dr. Warnes for your valuable comments. I fully agree with you that the Reeve et al. review is an illuminating study which convincingly clarifies the relationship between aging and PD. I appreciate that you already tested the DEP transdermal patches and found them effective in a group of depressive patients.

Since DEP is still the only synthetic enhancer in clinical use, it remains for the future to finally test the already available synthetic enhancers, like PPAP and BPAP, in patients. BPAP, an extremely safe compound, proved to be in animal experiments the most effective synthetic enhancer substance. Since we recently detected that a previously unknown enhancer-sensitive tumor-manifestation-suppressing (TMS) regulation works in the rat brain (Knoll et al. 2017), the selection of a pilot group of patients with de novo diagnosed malignant tumor to test the appearance of the dramatic TMS effect of BPAP treatment observed in rats could be a reasonable first approach to appraise the significance of BPAP in suppressing the manifestation of malignant tumors.



Ahlskog JE, Uitti RJ. Rasagiline, Parkinson neuroprotection, and delayed-start trials: still no satisfaction? Neurology 2010; 74: 1143-1148.

Knoll J. Pharmacological basis of the therapeutic effect of (-)deprenyl in age-related neurological diseases. Medical Research Review 1992; 12: 505-524.

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. 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, 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. Longevity study with low doses of selegiline/(-)-deprenyl and (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP). Life Sciences 2016; 167: 32-38.

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: 1723-1732.

Knoll J, Baghy K, Eckhardt S, Ferdinandy P, Garami M, Harsing LG Jr, Hauser P, Mervai Z, Pocza T, Schaff Z, Schuler D, Miklya I. A longevity study with enhancer substances (Selegiline, BPAP) detected an unknown tumor-manifestation-suppressing regulation in rat brain, Life Sciences 2017; 182: 57-64.

Miklya I. Essential difference between the pharmacological spectrum of (-)-deprenyl and rasagiline. Pharmacological Report 2014; 66: 453-458.

Miklya I, Knoll B, Knoll J. A pharmacological analysis elucidating why, in contrast to
(-)-deprenyl (selegiline) α-tocopherol was ineffective in the DATATOP study. Life Sciences 2003; 72: 2641-2648.

Olanow CW, Rascol O. The delayed-start study in Parkinson disease: can’t satisfy everyone. Neurology 2010; 74: 1149-1150.

Parkinson Study Group. Effect of (-)deprenyl on the progression disability in early Parkinson's disease. New England Journal of Medicine 1989; 321: 1364-1371.

Parkinson Study Group. Effect to tocopherol and (-)deprenyl on the progression of disability in early Parkinson’s disease. New England Journal of Medicine 1993; 328: 176-183.

Parkinson Study Group. Impact of deprenyl and tocopherol treatment of Parkinson’s disease in DATATOP patients requiring levodopa. Annals of Neurology 1996; 39: 37-45.

Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO study. Archives of Neurology 2002; 59: 1937-1943.

Robottom BJ. Efficacy, safety, and patient preference of monoamine oxidase B inhibitors in the treatment of Parkinson’s disease. Patient Preference and Adherence 2011; 5: 57-643.



Knoll J, Miklya I, Ferdinandy P, Schuler D, Schaff Z, Eckhardt S. Arylalkylamine compounds for use in the prevention or treatment of cancer. WO 2016088112 A1.

Knoll J, Miklya I, Ferdinandy P, Schuler D, Schaff Z, Eckhardt S. Compounds for use in the prevention or treatment of cancer. US 2017/0319535 A1.


May 3, 2018