This review (2015) examines Banisteriopsis caapi (ayahuasca) and its active alkaloid harmine as a potential therapy for Parkinson’s disease based on its unique pharmacological profile, which includes selective MAO type A inhibition, serotonin affinity, NMDA receptor
antagonism, and possible antioxidative and neuroprotective properties, and may also cause direct striatal dopamine release.

Abstract

“Review: Banisteriopsis caapi, a liana indigenous to the Amazon basin with metagnomigenic properties and possible anti-depressant effects is one of the natural sources of harmala alkaloids. A summary of early trials with extracts of Banisteriopsis caapi and Peganum harmala (from which harmine was first isolated) in the 1920s and 1930s on various forms of parkinsonism is given as well as a brief overview of the known pharmacological properties of harmine. Despite its earlier abandonment because of perceived weaker efficacy than solanaceous alkaloids like scopolamine and hyoscine we propose that harmine should be reconsidered as a potential rapidly acting anti-Parkinsonian agent.”

Authors: Atbin Djamshidian, Sabine Bernschneider‐Reif, Werner Poewe & Andrew J. Lees

Summary

Harmine, a beta carboline, was first isolated from the seed pots of the Syrian rue Peganum harmala, and is also found in the tobacco plant, passion flower and lemon balm plants, and in the wings of several Nymphalid butterflies.

Louis Lewin, a prominent pharmacologist and medical doctor, was asked by Eduard Merck to analyze the haramala alkaloids and was given a consultancy to further investigate the potential of “the devil’s vine” as a medicine.

Lewin extracted an alkaloid from B. caapi, which he tested on dogs and monkeys. He then gave banisterine subcutaneously to patients with neurological diseases, who reported euphoria, warmth, and lightness of the limbs in some cases.

Use of Harmine in Parkinsonism

Lewin speculated that B. caapi may be efficacious in patients with paralysis agitans and postencephalitic parkinsonism, but Merck reported that the alkaloid was chemically identical to extracts of P. harmala. He presented 3 patients with postencephalitic parkinsonism, demonstrating a dramatic benefit after SC injections of B. caapi.

Beringer administered banisterine to a laboratory colleague and noted an improvement in motor signs in some cases. He then treated 15 postencephalitic patients with extracts of P. harmala and concluded that the treatment had the potential to alleviate symptoms of akinesia, rigidity, and oculogyric crisis.

Merck’s harmine, a drug containing extracts of P. harmala, was marketed in late 1928 for postencephalitic parkinsonism and paralysis agitans. It was effective in young patients with postencephalitic parkinsonism without tremor.

Frank and Schlesinger stated that banisterine improved symptoms in 80% of their patients with postencephalitic parkinsonism. The average daily dose was 20 and 40 mg/day when orally administered, and side effects included yawning, nausea, vertigo, headache, agitation, tinnitus, bradycardia, and orthostatic dysregulation.

Schuster treated 18 patients with paralysis agitans with SC banisterine, but the effects only lasted for a few hours. He and Lewin tried to extend the effect by constriction of the jugular vein.

Ernst Rustige received 27 injections of Merck’s harmine to treat 18 patients, and also capsules for 2 patients. He noted a general improvement of motor function with increased speed of movement in 13 patients, and also noted that patients were pleased with the new agent.

In 1929, Beringer warned about unrealistic expectations for harmine and stated that the effects were variable and short lasting. Furthermore, the SC administration of “Mercks harmine” was not suitable for all patients and the mechanism by which the alkaloid acts was unknown.

Jacobi recommended a combination of harmine with scopolamine, but Schuster noted that harmine was only effective for a few weeks. Merck considered oral administration of harmine to be ineffective, but it did restore inner peace.

Gausebeck compared harmine with scopolamine in 9 patients with postencepahlitic parkinsonism and 1 patient with paralysis agitans, and concluded that harmine was short lasting and mild to modest.

Hill and Worster-Drought treated 38 patients with postencephalitic parkinsonism with “Merck’s harmine”, but none of the patients improved, and all but 1 reported worsening of symptoms. They 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.

Gunn, a British pharmacologist, concluded that harmine was weakly efficacious and inferior to hyoscine, and it was now being used less and less, usually in combination with atropine or scopolamine.

A study in 2001 found that patients with PD improved after the use of ayahuasca, a concoction including B. caapi and other plants, some of which contain dimethyltryptamine. However, tremor at rest, as well as on action and on posture, worsened in all patients.

Pharmacology of Harmine

Harmine, harmaline, 4,9-dihydro-7-methoxy-1-methyl-3H-pyrido (3,4-b) indole, and norharmine are beta carboline alkaloids found in P. harmala and B. caapi. Harmine has been shown to inhibit MAO, increase dopamine release, and reduce cerebral infarct volume and neuronal cell death.

Use of MAO Inhibitors in PD

Harmine, a nonselective MAO inhibitor, has been shown to shorten latency to onset and increase the duration of motor responses after a single dose of levodopa.

Nonselective monoamine inhibitors were reported to have antiparkinsonian effects in the early 1960s, but could not be used safely with low doses of L-dopa because of potentially dangerous hypertensive effects. Moclobemide is a reversible type A inhibitor that is free of cheese effects.

Type B MAO inhibitors have been extensively investigated, but some patients respond spectacularly to selegiline and rasagiline, whereas others do not respond at all or notice worsening of tremor similar to the original observations with harmine.

Harmine and Tremor

Harmine triggers an 8 to 14 Hz tremor in rodents, cats, and monkeys, which can last several hours. In healthy volunteers, high doses of B. caapi can induce a transient coarse tremor.

Harmine induces tremor in rodents by activating the medial and dorsal accessory inferior olivary nuclei and the cerebellum. Several drugs can suppress harmine-induced tremor, including citalopram, imipramine, caffeine, alcohol, primidone, and b-blockers, but may exacerbate neural damage.

Harmine and Depression

Harmine increases brain-derived neurotrophic factor (BDNF) in rats and has been shown to have antidepressant-like effects. MAO-A inhibitors are used to treat depression.

Discarded Therapies

Many treatments and nostrums used to treat PD in the late 19th century and early 20th century have now been discarded on the grounds of lack of proven efficacy.

Apomorphine was shown to improve decerebrate rigidity in 1951 and was used to treat PD patients, but the beneficial effects were brief and accompanied by side effects. In the 1980s, apomorphine was reinvested in and is now an established therapy for refractory motor fluctuations.

The first human studies with L-dopa, the gold-standard therapy in PD, reported conflicting results. Sano and McGeer concluded that L-dopa had little to offer as a therapeutic agent in the treatment of parkinsonism.

Conclusions

Harmine has a unique pharmacological profile with selective MAO type A inhibition, serotonin affinity, NMDA receptor antagonism, and possible antioxidative, as well as neuroprotective, properties. It may also cause direct striatal dopamine release and may be as efficacious as the commercially available selective type B MAO inhibitors.

Supporting Information

Patient 1: Female patient after encephalitis with vigorous eyelid closure tics and oromandibular dystonia. Symptoms disappear after injection.

Patient 2 had severe left-sided akinetic rigid parkinsonism and bucco-linguo-masticatory symptoms. After injection, he had significant improvement in posture and gait, but continued to have intermittent bucco-linguo-masticatory symptoms.