It should be noted, that the exact cause of the illness, i.e. pathogen responsible for syphilis (Trepanoma pallidum) has only been discovered by Erich Hoffmann and Fritz Schaudin in 1905 and the first serological test detecting the presence of the bacteria (along with bacteria responsible for tuberculosis and typhus) has been developed by August Paul von Wassermann, Albert Neisser and Carl Bruck in 1906. This means that all previous methods of treatment were more or less shots in the dark, with no real method of checking the efficacy other than the observation of symptoms.

As early stage syphilis was characterized by the emergence of skin lesions, it comes as no surprise that the physicians decided to treat it with methods that were used with at least some success to treat dermal condition, what was proposed by e.g. Giovanni da Vigo. This explains prevalence of mercury that, due to bactericidal and bacteriostatic properties was often used in this capacity. Although form of administration varied, from fumigation to unguents, the latter were most common (we might only surmise that survival rate of the former was not too high given that although relatively harmless in its metal form, mercury in volatile state is very toxic). One of the most popular treatments was 'grey paste' (unguentum cinereum), also known as 'Neapolitan unguent' or 'Saracen unguent' made from metallic mercury mixed with tallow in 1:3 ratio and used since at least early 12th century as evidenced by writings of Rogerius of Salerno. This therapy, although quite efficient for treating dermal lesions what could have been construed as general efficiency (contributing to its usage until 1930s), did very little to actually cure the general infection and could only postpone the onset of usually terminal symptoms of late-stage syphilis, most notably neural degeneration. The same can be said of guaiacum poultices that were also used to treat this disease. Additionally, topical administration was usually accompanied with cauising profuse sweating, usually by increasing temperature of the surroundings what could have contributed to the mercury poisoning. Salivating was also considered a sign of healing, even today it is known as one of the symptoms of heavy metal poisoning. Thomas Sydenham, 17th-century physician even considered salivation a necessary phenomenon of healing, although Francois-Xavier Swediaur, who lived in the next century noticed that 'the stronger the salivation, the less efficient mercury treatment seems to be'.

In he fist half of 19th century another element gained popularity in the treatment of syphilis. In 1820 Charles Coindet from Geneva used potassium iodide in treatment of late and intermediate symptoms to some succes, and a year later, Christian Martini, German physician from Luebeck proposed administration of iodine in treatment of syphilitic ulcers of the throat. Iodine and potassium iodide was also used by Jean Lugol since 1831 in treatment of late-stage syphilis. William Wallace, Irish physician from Dublin performed extensive research in early 1830s and in 1836 described 139 cases of recovery from part-primary syphilis. The problem was, that although much more effective than mercury in alleviation of late symptoms like bone deterioration, did not possess antibacterial properties and thus were unable to cause full recovery. But given that elimination or even delay of the symptoms were noticeably increasing the quality of patient's life, in 1866 Étienne Lancereaux claimed that 'the two substances, iodine and mercury are incontestably the chef agents which we are now able to oppose the ravages of syphilis'.

Arsphenamin, better known under trade name Salwarsan (also Preparation 606 or Ehrlich-Hata Preparation) has been developed by Paul Ehrlich and introduced in 1909 after anti-syphilitic properties of arsphenamine has been discovered by his colleague, Sahachiro Hata. It was initially considered quite promising, although Heinrich Loeb from the hospital in Mannheim noticed that 11 out of 187 patients relapsed and the therapy had serious side effects while at the same time showing little efficacy in treating late-stage syphilis. Nevertheless, Salwarsan and Neo-Salwarsan, being good bacteriostatics have shown curative properties, especially in the first-stage syphilis. It should also be noted that the anti-syphilitic therapy usually involved administration of Salwarsan along sublimate, or mercury (II) chloride, a potent toxin that could have been responsible for many experienced adverse effects. Furthermore, at last one of the side effects (vein damage) was caused not by the medicine itself, but the presence of sodium hydroxide added to Salwarsan prior to injection. This has been alleviated by the introduction of Neosalwarsan in 1912 and Solu-Salwarsan some time later that used different method of administration.

Constantin Levaditi, Romanian microbiologist who for a time also worked with Ehrlich, in his article published in 1921 recommended usage of bismuth in syphilis treatment. This method, although less popular, was shown to be less efficient albeit carried much lower chance for adverse effects.

It should be noted however, that the pharmacological therapy prevalent between 1910s and 1930s were rather long and usually included the initial, intensive phase lasting for about 2 years, supportive phase lasting for 5 years and prophylactic phase that was basically required until patient's death. This was caused by bacteriostatic rather than bactericidal properties of the treatments used and while effective, length of the therapy sometimes caused patients to drop out, what often could lead to relapse.

Enter Alexander Fleming and his discovery of antibiotic properties of penicilin that revolutionized treatment of bacterial infections. Initially constrained to military personnel, penicilin treatment became introduced to general population of patients in 1943 by an American physician John Friend Mahoney. Due to extreme efficiency and relative lack of side effects in comparison with previous methods it quickly established itself as a primary syphilis therapy that later came to include other antibiotics.

So, summing it up, although pre-antibiotic syphilis therapies were able to alleviate some symptoms, often quite efficiently, they could have not lead to full recovery because they were not eliminating the underlying cause of the ilness.