Let’s go on a trip with Ayahuasca. What does Ayahuasca have to do with Parkinsonism?

History doesn’t repeat itself, but it rhymes. Concocting a synthetic derivative of a desirable drug, created to evade regulation or the law, sounds like a story out of a 2019 headline. But it would be naive to think this is a unique point in drug abuse history. In fact, it’s happened before (and will likely happen again). 

Beginning in the late 1970s, a ‘designer drug’ version of meperidine was a growing part of drug culture in Northern California.[1] This analog of meperidine known as MPPP (1-methyl-4-phenyl-4- propionoxypiperidine) was originally described in 1947.[2] But because it was never put to market, it did not go through any sort of regulatory processing and scheduling as a controlled drug. Although not necessarily legal, MPPP was not itself illegal and this iteration of designer drug production was underway.

In 1986, a CDC MMWR report alerted medical professionals, and the public, to the emergence of “frozen addicts.”[3] Several patients admitted to hospitals and psychiatric facilities were observed to have symptoms consistent with Parkinson’s disease.[4-7] However, all of these patients in question were younger than the typical Parkinson’s patient diagnosed at the time. It wasn’t until further investigation revealed that they all had recent exposure to a “synthetic heroin” product, MPPP.[1] 

Although MPPP itself wasn’t to blame for Parkinsonism, a contaminant producing a toxic component known as MPP+ was.[8] MPP+ is the stuff of nightmares. Let’s look at the beast in the face and learn a little more about it.

The MPPP batches that resulted in Parkinsonism were found to be almost entirely MPTP (1-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine).[8-11] As a result of an error in the production of MPPP, MPTP was formed. MPTP itself is actually not toxic. But once it reaches the CNS, MAO-B biotransformed it into MPP+. While this transformation took place in astrocytes, MPP+ is subsequently released from this site but then selectively taken up by dopaminergic substantia nigral neurons.

In this region, once MPP+ reaches sufficient concentrations it inhibits Complex 1 of the mitochondrial electron transport chain.[8] Subsequent deficiency in ATP leads to free radical generation, oxidative stress and cell death. Thus the destruction of dopaminergic cells in the substantia nigra region directly led to the rapid development of Parkinsonism.

While this cautionary tale may seem like a tragedy, it actually led to profound discoveries and advances in the management of Parkinson’s Disease. For example, had the first documented producer and user of the contaminated MPPP product (Barry Kidston) been taking an MAO-B inhibitor like selegiline, we may have avoided developing Parkinsonism. Extensive research conducted after the identification of these cases directly led to the development of MAO-B agents (rasagiline and selegiline) for the treatment of Parkinson’s Disease.

Take a trip with me: Ayahuasca

Drug culture and experimentation with mind-expanding or altering substances has never been more mainstream than it is today. When listening to popular podcast hosts like Joe Rogan and Tim Ferriss, it’s clear that we’re well into reemergence of drug culture. I’m personally hopeful of this discourse, provided it yields more thoughtful and academic research. That would certainly improve upon the n=1 reports that are ubiquitous.

Ayahuasca, a hallucinogenic brew used in some South American cultures is one of these such drugs. While the adaptation of ayahuasca to other geographic regions has become popular, the components of the brew tend to change. Traditionally, ayahuasca is made from a mixture of Banisteriopsis caapi vine and Psychotria Viridis leaves.[12] B. caapi provides beta-carboline alkaloids (harmaline, harmine, and tetrahydroharmine). Whereas P. viridis contributes N,N-dimethyltryptamine (DMT). 

Under ‘typical’ circumstances, DMT is not bioavailable when taken by mouth. However, when co-ingested with a monoamine oxidase inhibitor-A (MAO-A), it becomes well (and rapidly) absorbed.[12] The hallucinogenic effects in terms of onset and duration, from enteral DMT in this combination resemble that of inhaled (smoked) DMT. The application of this pharmacokinetic drug interaction from cultures who have not been exposed to this science is fascinating.

A quick google of where to get your hands on some locally will reveal a number of providers of a guided spiritual experience. While their intentions are what they are, the term ayahuasca stops being a description of a specific brew and becomes a general term describing some oral hallucinogens. Some substitutions may not yield terribly different results (Peganum harmala aka Syrian Rue, for B. caapi) others will have different ingredients altogether. Brews have been reported to include everything from tobacco plants (Nicotiana tabacum), or Datura suaveolens (Brazillian Angel Trumpets- in the nightshade family). Synthetic versions of DMT and harmaline have been used in this setting as well (yay designers).

The beta-carbolines found in Ayahuasca can give you one hell of a trip. By causing inhibition of MAO-A in the gut, DMT can then be absorbed when ingested.[12] While these beta-carbolines can have some desirable CNS effects themselves, there exists the potential for significant harm. While the popularity of ayahuasca continues to grow, it will be interesting to observe whether an adverse event found in animal models holds true in humans. [13-15] That, of course, is Parkinsonism. 

After undergoing N-methylation at the second position, harmaline/harmala/tetrahydroharmine can form analogs of one hell of a scary compound: MPP+.[13] These analogs of MPP+ produced from N-methylation of the beta-carbolines found in Ayahuasca are N(2)-methyl- and N(2,9)-dimethyl-tetrahydro-β-carbolines.[13] N(2)- and (9)- methylnorharmanium ions induce Parkinsonism findings in mice. This observation in animals could be an explanation of why in many people who ingest ayahuasca, a noticeable (albeit temporary) tremor is often observed, perhaps attributable to this effect. Oh boy, here we go. 

One explanation why we have not observed similar Parkinsonism from ayahuasca could be that N-methylated β-carbolines are removed by CYP 2D6.[13] So when ingested orally, the first-pass metabolism takes out the possibility of a toxic product reaching the CNS. Although this could be highly dependent on the 2D6 polymorphism subtype. Furthermore, beta-carbolines inhibit not only MAO-A but perhaps also MAO-B. By inhibiting MAO-B, it may spare the production of MPP+ related metabolites in the CNS. A selegiline like effect, if you will. Lastly, most biotransformation of the beta-carbolines occurs OUTSIDE of the CNS, thus sparing any potential effect on dopaminergic neurons.

Ayahuasca has been described as having the opposite effect in aiding Parkinson’s related symptoms. [17] This effect may possibly be due to beta-carboline anti-oxidant properties against reactive oxygen species (ROS). [18] It’s not clear whether these are truly conflicting, if not opposing effects observed, or just our lack of knowledge altogether. 

For history to repeat itself in this scenario, well-intended attempts to concoct ayahuasca with other than traditional components could lead to disastrous effects. While the traditional ayahuasca brew could possess protective effects, when substituting one or more ingredients, the protection could be lost. While the clinical implications are unknown, so too is the timing with which this could occur. Something that is for certain, however, is that history rhymes. At least now, we may recognize it.

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Reference:

  1. https://www.acsh.org/news/2017/01/12/frozen-addicts-garage-drugs-and-funky-brain-chemistry-10728
  2. Ziering A, Lee J. Piperidine derivatives; 1,3-dialkyl-4-aryl-4-acyloxypiperidines. J Org Chem. 1947 Nov;12(6):911-4.
  3. Centers for Disease Control (CDC). MMWR Morb Mortal Wkly Rep. 1984 Jun 22;33(24):351-2.
  4. Ballard PA, Tetrud JW, & Langston JW (1985) Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): Seven cases. Neurology, 35, 949–956.
  5. Stern Y, Tetrud JW, Martin WR, Kutner SJ, & Langston JW (1990) Cognitive change following MPTP exposure. Neurology, 40, 261–264. 
  6. Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, & Kopin IJ (1979) Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res, 1, 249–254.
  7. Langston JW, Ballard P, Tetrud JW, & Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science, 219, 979–980. 
  8. Langston JW. The MPTP Story J Parkinsons Dis. 2017; 7(Suppl 1): S11–S19.
  9. Langston JW, Irwin I, Langston EB, & Forno LS (1984) 1-Methyl-4-phenylpyridinium ion (MPP+): Identification of a metabolite of MPTP, a toxin selective to the substantia nigra. Neurosci Lett, 48, 87–92.
  10. Markey SP, Johannessen JN, Chiueh CC, Burns RS, & Herkenham MA (1984) Intraneuronal generation of a pyridinium metabolite may cause drug- induced parkinsonism. Nature, 311, 464–467.
  11. Heikkila RE, Manzino L, Cabbat FS, & Duvoisin RC (1984) Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl- 1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature, 311, 467–469.
  12. Simão AY, Gonçalves J, Duarte AP, Barroso M, Cristóvão AC, Gallardo E. Toxicological Aspects and Determination of the Main Components of Ayahuasca: A Critical Review. Medicines (Basel). 2019 Oct 18;6(4).
  13. Handforth A. Harmaline Tremor: Underlying Mechanisms in a Potential Animal Model of Essential Tremor. Tremor Other Hyperkinet Mov (N Y). 2012; 2: 02-92-769-1.
  14. Boulton SJ, Keane PC, Morris CM, McNeil CJ, Manning P. Real-time monitoring of superoxide generation and cytotoxicity in neuroblastoma mitochondria induced by 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline. Redox Rep. 2012;17(3):108-14. 
  15. Bringmann G, Feineis D, God R, Peters K, Peters EM, Scholz J, Riederer F, Moser A. 1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) and related derivatives: chemistry and biochemical effects on catecholamine biosynthesis. Bioorg Med Chem. 2002 Jul;10(7):2207-14.
  16. Gearhart DA, Neafsey EJ, Collins MA. Phenylethanolamine N-methyltransferase has beta-carboline 2N-methyltransferase activity: hypothetical relevance to Parkinson’s disease. Neurochem Int. 2002 Jun; 40(7):611-20.
  17. Djamshidian A, Bernschneider‐Reif S, Poewe W, Lees AJ. Banisteriopsis caapi, a Forgotten Potential Therapy for Parkinson’s Disease? Mov Disord Clin Pract. 2016 Jan-Feb; 3(1): 19–26.
  18. Kim, H.; Sablin, S.O.; Ramsay, R.R. Inhibition of monoamine oxidase A by β-Carboline derivatives. Arch. Biochem. Biophys. 1997, 337, 137–142.

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