Samuel Gershon: Events and Memories. 5. THA

“Specific” Drug Antagonists to Barbiturates, Morphine and Hallucinogens 

Samuel Gershon

The next opening was provided by a series of compounds synthesized by Prof. Adrian Albert at the Australian National University (ANU) in Canberra. He was synthesizing a series of acridine compounds in collaboration with the Chairman of Microbiology as antibacterial agents and possible use against tuberculosis. As the Department of Microbiology, in the next building to ours, was doing elaborate in vitro work, we planned to evaluate the pharmacologic properties of one compound in the series: THA, or 1,2,3,4 - tetrahydro - 5 - aminoacridine.

We started with little pharmacological knowledge of the compound, but had a very good dog model of morphine’s effects. So we studied it as an analeptic. Given IV to a sleeping morphinized dog, THA produced an immediate arousal and return to clear consciousness.

Our interest in this compound expanded when we were contacted by the US Army to discuss our work with anti-hallucinogens. We arranged to have a detailed discussion with them together with colleagues at the University of Melbourne, who had developed different potential compounds. They were interested in our whole program, but particularly THA, because their main hallucinogenic compounds (referred to as incapacitating agents) were related to the pharmacology of Ditran (JB-329), a mixture of two structurally related isomers of an anti-cholinergic drug (Gershon and Olaria  1960). The following day, the colonel in charge turned up with a research grant for us to sign. After we published a number of papers on THA, I received a letter from a psychiatrist at the University of Pittsburgh asking permission to access my FDA submitted IND on THA (Bell and Gershon 1964; Bell, Gershon, Carroll and Holan 1964; Brinkman and Gershon 1983; Gershon 1960; Gershon 1965; Gershon, Naubauer and Sundland 1965; Gershon and Shaw 1958; Neubauer, Sundland and Gershon 1966 a,b).  He wished to administer THA to cases of imipramine overdose or poisoning, with or without other sedatives. I granted permission and he published papers on the success of the clinical observations. Apparently he also obtained patents for this use of THA, about which I was not fully informed (Soares and Gershon 1995).

Meanwhile, other investigators tried THA administration in Alzheimer’s patients and also patented their findings. THA was then marketed as a treatment for the condition. Their observations amounted to replication of what we had shown previously; THA clearly produced arousal in many different drug-induced and clinical conditions. THA had a new life for several years as a highly touted treatment for Alzheimer’s and it had a significant effect on the established idea that Alzheimer’s was untreatable. This gave rise to the introduction of other potential therapeutic agents and the field regained some therapeutic hope. My belief is that cholinergic antagonists have considerable therapeutic value and deserve further study. Still, great caution must be adopted because the disease has often been present for many years before treatment is attempted.

I must end this section with my belief that all these antagonists have considerable therapeutic value and deserve further study.

References:

Bell C, Gershon S. Experimental anticholinergic psychotomimetics. Antagonism of Yohimbine and Tacrine {THA]. S Med Exp 1964; 10: 15-21..

Bell C, Gershon S, Carroll B, Holan G.  Behavioral antagonism  to a new psychotomimetic—JB 329. Arch IntPharmacodyv 1964; 147: 3-25

Brinkman S, Gershon S. Measurement of cholinergic drug effects on memory in Alzheimers Disease. Neurobiology of Aging 1983; 4: 139-145.                                       

Gershon S. Blocking effect of tetrahydroaminacrin on a new psychotomimetic agent. Nature 1960; 186: 1072-3,1960.

Gershon S. Behavioral effects of anticholinergic psychotomimetics  and their antagonists in man and animals. Recent Adv Biol Psychiatry 1965; 8: 141-9.

Gershon S, Neubauer H, Sundland  DM. Interaction between some anticholinergic agents and phenothiazines. Potentiation of the phenothiazine sedation and its antagonism. Clin Pharmacol Ther 1965; 6: 749- 56

Gershon S, Olaria J. JB-329, a new psychotomimetic, its antagonism to tetrahydroamino-acridane, and its comparison with LSD, mescaline and Sernyl. J Neuropsychiatry 1960; 1:283-9.

Gershon S, Shaw FH. Tetrahydroaminacrin as a decurarising agent. J Pharm 1958; 10: 22-9.

Neubauer,H, Sundland, D, M and Gershon S,     Ditran antagonists in a mixed psychiatric population. J Nerv Ment Dis 1966a; 142: 265-77

Neubauer H, Sundland DM, Gershon S. Sernyl, Ditran and their antagonists: Succinate and THA. Int J Neuropsychiatry 1966b; 2: 216-22.

Soares JC, Gershon S. THA – historical aspects, review of pharmacological properties and therapeutic effects. Dementia 1995; 6:225-34.  

Samuel Gershon
August 6, 2015