From the samples of B. caapi, Lewin extracted an alkaloid that he named “banisterine,” which he then tested on dogs and monkeys. Lewin also described experiments of the ethnologist, Theodor Koch-Gruenberg, who self-administered harmine and reported changes of color perception and mild hallucinations, which, however, did not reach the intensity of mescaline intoxication. [5] He ingested banisterine and felt invigorated and had improved and faster motor control, but did not experience the mind altering state that had been reported by the early travelers in the Amazon. Lewin then administered banisterine subcutaneously (SC) to an obese patient who had hemiplegia who reported immediate improvement in her gait. [5] Encouraged by this response, he then gave SC injections of 25 to 70 mg of banisterine to patients with several different neurological diseases in the Neukoelln Hospital, where some of the patients reported euphoria, warmth, and lightness of the limbs in some cases. [6]

Eduard Merck asked Louis Lewin (1850–1929), a prominent pharmacologist and medical doctor who worked in Berlin and who devised a systemic classification of psychoactive plants and synthetic drugs based on their pharmacological properties for help to analyze the haramala alkaloids. [3] In view of his previous successful collaboration with the company in relation to mescaline, Lewin was offered a consultancy to further investigate the potential of “the devil's vine” (B. caapi) as a medicine. In 1888, Lewin, who had self-experimented with mescaline in his private apartment, was unable to publish his findings because of limited supplies and therefore approached Merck for assistance. This collaboration led to several publications, and a variant of the peyote cactus was named Anhalonium lewinii in recognition of his research.

Another pharmaceutical company, E. Merck (Darmstadt, Germany), was also interested in the medicinal potential of phantasticants such as mescaline and received a large quantity of yagé in 1926 from Colombia. By 1927, they had stockpiled 30 kg of B. caapi extract and 2,000 kg of P. harmala. At that time, it was still thought that these two plants had different pharmacological properties, but in 1928, harmine was shown to be the active alkaloid in both plants. [4]

Use of Harmine in Parkinsonism

Given his observation that B. caapi can facilitate movement, Lewin speculated that the drug may be efficacious in patients with paralysis agitans and postencephalitic parkinsonism. He was nearing retirement and suggested that two younger colleagues from Heidelberg, Karl Wilmans and Kurt Beringer, who had also been supplied with B. caapi samples by Merck should conduct the first empirical trials.

Although, by 1928, Merck reported that P. harmala and B. caapi were chemically identical,[4] Lewin, in contrast to Beringer, was convinced that B. caapi was superior to the extracts of P. harmala. Shortly before his death in December 1929, Lewin presented 3 patients with postencephalitic parkinsonism at the meeting of the Berlin Medical Association, demonstrating a dramatic benefit in neurological handicaps after SC injections of B. caapi. He also regarded banisterine as superior to hyoscine in its ability to alleviate rigor.[3] Given his experiments, he asked for further funding from Merck to import more banisterine from South America, but owing to the recent reports that the alkaloid was not a “rare and extremely precious” commodity, but identical to extracts of the much more common P. harmala, substance funding was denied.

In early 1929, Beringer, whose major research area had been psychosis and mescaline-induced hallucinations, administered 100 mg of banisterine to a laboratory colleague and noted an “uncontrollable tremor in the arms and legs, similar to what we see in parkinsonian patients.” He then treated 15 postencephalitic patients with extracts of P. harmala and noted a dramatic improvement in motor signs in some cases (see Video 1). In one 29-year-old patient with severe postencephalitic parkinsonism, a course of P. harmala extract (12 drops three times daily) led to a marked improvement in rigidity and oromandibular dystonia with the patient reporting “Doctor, I am healthy again.”[7] Beringer concluded that the treatment had the potential of alleviating symptoms of akinesia, rigidity, and oculogyric crisis in patients with postencephalitic parkinsonism and slowness in paralysis agitans. This therapeutic effect was noted to occur after around 30 minutes, but its effect varied and the benefit could last between several hours and a few days.[3]

Merck dedicated the first 19 pages of their “E. Merck's Jahresbericht ueber Neuerungen auf den Gebieten der Pharmakotherapie und Pharmazie 1928” to harmine and marketed the drug for postencephalitic parkinsonism and paralysis agitans in late 1928 in capsules, suppository, and as injectable solution form (Fig. 2). Given that extracts of P. harmala were easier and more easily procurable, “Merck's harmine” did not contain extracts of B. caapi. Decourt and Lemaine reported that “Merck's harmine” was mainly effective in young patients with postencephalitic parkinsonism without tremor. They also reported that, when taken orally, the drug lost most of its efficacy, whereas Beringer noted good effects when it was administered in keratinized capsules.

Figure 2. Harmine for postencephalitic parkinsonism and idiopathic PD was produced by Merck and available as capsules, suppository, and SC injections. Original harmine lyophilized powder and harmine vial for SC injections. Pictures taken at Merck (Darmstadt, Germany).

Frank and Schlesinger also stated very good effect in 80% of their patients with postencephalitic parkinsonism. Bradykinesia, drooling, hypomimia, gait, and postural stability improved in 10 of 12 patients. Furthermore, mood improved considerably, and in 1 case euphoria ensued (a patient who was unable to move made a handstand in the hospital); in others, pre-existing anger and aggressive behavior worsened. Tremor was not improved.[8] In their study, parkinsonian symptoms improved within 15 minutes after SC injections and took approximately 20 minutes when administered orally. The duration of the effect lasted between 3 and 5 hours and 3 and 4 days. Often, motor handicap only lessened after repetitive administration of banisterine, but in some, parkinsonism improved after the first dose. The average daily dose, which was used for injections, was 20 and 40 mg/day when orally administered. Side effects usually occurred at higher doses (60 mg) and included yawning, nausea, vertigo, headache, agitation, tinnitus, bradycardia, and orthostatic dysregulation.

Schuster treated 18 patients with paralysis agitans and “similar striatal lesions” with SC banisterine, with doses ranging between 20 and 40 mg. After 15 minutes, he noted improvement on rigidity with only minimal side effects, such as nausea and occasional vomiting. Effects were lasting for 2 to 6 hours and in some up to 7 days.[1] However, effects only lasted for a few hours, and therefore Schuster and Lewin tried to extend the effect of banisterine and “Merck's harmine” by constriction of the jugular vein.[3]

A number of other German centers also reported spectacular results with “Merck's harmine” (see Table 1). “Merck's harmine” was used with success in patients with postencephalitic parkinsonism, paralysis agitans, and pallidal rigidity, but also in patients with carbon monoxide poisoning as well as in those with arteriosclerotic rigidity.[3]

Table 1. Summary of studies performed with banisterine/harmine in patients with parkinsonism between 1928 and 1931 Symptoms No. of Patients Efficacy Authors +++, excellent response; ++, good response; +, mild improvement; +/−, very mild improvement; –, no effect; ––, worsening of symptoms. The majority of these patients were treated with SC harmine/banisterine injections, but in a few exceptions, harmine capsules as well as harmine drops were given.



a Beringer treated more patients between 1929 and 1931. PEP, postencephalitic parkinsonism; PD, Parkinson's disease. PEP 15 +++ Beringer a PEP 30 ++ Rosenberger Parkinsonism 4 +++ Frank, Schlesinger 4 ++ 2 + 2 – PD, chorea minor 2 – 2 –– PEP 1 +++ Fischer 2 ++ PEP 7 ++ Schuster PD 7 ++ PEP 2 – CO 2 poisoning 1 – Self-experiment 1 PEP 13 ++ Pineas Parkinson's disease 5 + PEP 20 ++ Rustige PEP 37 – Hill, Worster-Drought 1 +/− PEP 8 +/− Gausebeck 1 +++ PD 1 +/− PEP 15 + Cooper, Gunn

Ernst Rustige received 27 injections from Merck (3—50 mg) to treat 18 patients and also capsules (3 × 10 mg per day) for 2 patients. He noted a general improvement of motor function with increased speed of movement in 13 patients. In 6 patients rigidity improved, and in 3 of these patients the pronounced rigidity disappeared completely. An objective improvement was observed after 20 to 30 minutes and the effects lasted for a maximum of 1 hour. In 9 patients “Merck's harmine” had a variable effect on tremor with improvement in some, but also worsening in others. Only 4 of the 18 patients did not show any benefit at all from harmine injections.[1] Rustige also injected saline in some patients and reported that only 1 control patient reported improvement, whereas all others reported no effect. However, he also noted that “these patients were pleased, unfortunately overly pleased, with the new agent which would now help them.” They repeatedly showed other patients with pride everything of which they were now capable and were disappointed over the rapid decline of the effect.[3] In 1931, Mueller reported that harmine has been successfully used in all extrapyramidal disorders at Nonne's clinic for the last year and a half. Patients were administered SC injections of harmine in the morning in combination with “Merck's keratinized capsules” at midday for a period of 3 to 4 weeks. They reported that excellent improvement was achieved in 26% of patients and good improvement in 37%.[3]

However, by late 1929, Beringer was already aware of the unrealistic expectations for the drug and emphasized in his presentations that the effects were variable and short lasting and stated that “aroused hopes in the ill could not be fulfilled.” He also warned about the “exaggerated and extravagant reports in the newspapers,” which, in his opinion, were unrealistic and would lead to patient disappointment. Furthermore, the SC administration of “Mercks harmine” or banisterine, which appeared to be the most effective route of administration, was not suitable for all patients. “Meck's harmine suppositories” were found to be efficacious only in a minority of patients. Although Beringer treated some patients with infusions of Peganum extract and noted alleviation of tremor, he suggested that atropine and scopolamine may be more suitable given that their effects were more predictable than harmine. He wrote that: “The brilliant successes are currently a minority and are matched by an equal number of complete treatment failures. In between lie a bulk of cases where only a moderately significant improvement of varying practical and therapeutic degree can be achieved. The reason for this unreliability of the therapeutic effect (…) is unknown as is the mechanism by which the alkaloid acts.”[3]

Given the lack of response of tremor, Jacobi recommended a combination of harmine with scopolamine.[3] Schuster also noted that “Merck's harmine” or banisterine were only effective for a few weeks. Oral administration of harmine seemed to be ineffective, which was considered a severe commercial drawback by Merck. By 1932, Merck's opinion of harmine was far less optimistic. It was stated that “even if the effects of harmine (…) on the symptoms of postencephalitic parkinsonism were not sustained, (…) this temporary symptomatic relief, especially on rigidity, often restores inner peace…”.[3]

Almost 30 years later, in 1958, the Austrian neurologist, Birkmayer, contacted Merck to reassess the use of harmine for Parkinson's disease (PD).[9] However, his request was rejected owing to the known lack of oral efficacy recorded in the company's files.

By 1930, it was generally agreed that hypokinesia, drooling, mood, and sometimes rigidity improved with banisterine and parenteral “Merck's harmine,” but that rest tremor sometimes worsened.

Around that time, a German physician, Dr. Halpern, involved himself in self-experimentation and noted a sensation of lightness in his body with increased aggression.[2] After he took 40 mg of harmine by mouth, he reported that “When lying on a sofa, the light headedness increased to a feeling of floating sensation and the weight of the body was subjectively less. These clinical observations should be compared to the state of levitation frequently reported to occur with the crude drug ayahuasca or caapi … … the author who is normally not belligerent started a fight with a man in the street where he was the one who attacked even though according to the circumstances the prospect for the attacker was unfavourable.”

Gausebeck compared the effect of harmine with scopolamine in 9 patients with postencepahlitic parkinsonism and 1 patient with paralysis agitans. In 9 of 10 cases, scopolamine therapy was superior irrespective of whether a higher or lower dose (20 vs. 40 mg) of harmine was used. The researcher concluded that the effects observed with harmine injections were short lasting and mild to modest. Furthermore, the oral administration of harmine in combination with scopolamine was not significantly better than scopolamine alone.[10] Dermitzel reported, in 1930, that after 0.2 g of intramuscular injection of harmine, severe intoxication with body cramps, tremor, delirium, and faintness occurred.

In Great Britain, Hill and Worster-Drought treated 38 patients with postencephalitic parkinsonism with “Merck's harmine.” The group contained 16 patients with severe, 13 with moderately severe, and 9 with mild signs of parkinsonism, who were all already receiving treatment with SC hyoscine. After hyoscine withdrawal, 19 patients received harmine orally and 19 SC, but none of the patients improved. In fact, all but 1 reported worsening of symptoms, which only improved after hyoscine was restarted.[11] They concluded that, “Harmine in doses up to 0.04 g given hypodermically has no perceptible objective or subjective effect in ameliorating any of the symptoms presented in the parkinsonian syndrome and is of no value in the treatment of this condition.”[11] They also suggested that the benefits reported by Rustige et al. were likely to have occurred as a result of suggestion rather than any pharmacological effects of the drug. They could also not replicate the experience of Wilmans and Beringer that the effects of harmine increased with length of treatment. However, they failed to take into account the possibility that abrupt discontinuation of hyoscine could cause severe detrerioration of motor handicap in parkinsonism and could have masked any potential benefits of harmine.

Gunn, a British pharmacologist working in Oxford who had published preliminary positive results with “Merck's harmine,” concluded, in 1931, that it was weakly efficacious and inferior to hyoscine.[12]

What 5 years earlier had been heralded as a miracle cure in “Der Kompass” on 1 March 1929 was now being used less and less and usually in combination with atropine or scopolamine.[13] Von Witzleben, who also used the drug, reported that the high hopes for harmine had not been fulfilled.[14] Interestingly, however, on 15 April 1945, Morell asked Stumpfegger to treat Hitler with “Merck's harmine” SC in combination with anticholinergic drops.[15]

The advent of synthetic drugs with pharmacological effects similar to the solanaceous alkaloids finally led to the total abandonment of harmine even in Germany.