Pawpaw and Human Toxicity / Neurodegeneration

My reading about annonacin, a neurotoxin found in Pawpaw, has me concerned about pawpaw consumption and long term (not acute) potentially compounding health issues.  I'd like to hear what others know about this.

Annonacin is a chemical compound with toxic effects, especially in the nervous system, found in some fruits such as the paw paw, custard apples, soursop, and others from the family Annonaceae. It is a member of the class of compounds known as acetogenins.

An average-sized soursop fruit contains 15 mg of annonacin, while a can of commercial nectar contains 36 mg and a cup of infusion, 140 μg. Studies in rodents indicates that consumption of annonacin (3.8 and 7.6 mg per kg per day for 28 days) caused brain lesions consistent with Parkinson's disease. An adult who consumes a fruit or can of nectar daily over the course of a year is estimated to ingest the same amount of annonacin that induced brain lesions in the rodents receiving purified annonacin intravenously.

https://en.m.wikipedia.org/wiki/Annonacin

15mg of annonacin a day is likely to be toxic to humans. If I'm calculating correctly...1oz of pawpaw contains 215mg of annonacin. A single pawpaw is probably 2-3 oz, or 430-645mg of annonacin. We don't know if this builds up in our system, or how much per day/week/month is toxic.

Here is a journal article that speaks to Annonacin and Pawpaw specifically:

Annonacin in Asimina triloba fruit: implication for neurotoxicity.

Its conclusion is:

Pawpaw fruit contains a high concentration of annonacin, which is toxic to cortical neurons. Crude fruit extract also induced neurotoxicity, highlighting the need for additional studies to determine the potential risks of neurodegeneration associated with chronic exposure to pawpaw products.

An additional journal article that draws no conclusions, simply discusses the methods for measuring the annonacin levels in pawpaw.  Note that these measurements were with the meat/pulp of the fruit, not the seed/skin/twigs/etc...

Determination of Neurotoxic Acetogenins in Pawpaw (Asimina triloba) Fruit by LC-HRMS

I'd love to grow and enjoy Pawpaws but the jury is still out on whether I should.  Can anyone weigh in on this?

Brain dysfunction of many sorts is increased in Appalachia, but this may just correspond to risk factors such as smoking, drug usage and exposure to mine tailings. There's hardly a health risk out there that doesn't score higher for people within that region than for the country as a whole. And I'm assuming that people there would have a greater opportunity to eat pawpaws. But so many variables I can't imagine it being measurable.

There are many foods that are somewhat poisonous, but also nutritious. Oxalates, cyanide and other toxins are present in many edible things. The dose usually makes the poison. But it could be different when it's something that lingers rather than being washed out of the system.

You're bound to meet some resistance whenever a popular food is presented as a risk. My wife has hugely cut her rice consumption, after learning how nutritionally poor it is. Family members and other people in the Philippines, generally reject out of hand, the idea that a person could eat too much rice. But it's good to examine these things.

This compound has been discussed in other pawpaw threads on permies in the past.  There's some interesting information in this one about the compound in question; specifically, certain sugars (coincidentally, or perhaps not so coincidentally, found in pawpaw fruit) are said to maybe intervene or block the toxic action.  There's even a suggestion that a different sugar (that lacks the blocking action) is used in preparing the standardized extract used in some of the toxicity studies, which might (??? I'm not enough of a scientist to evaluate this bit) call some of the toxicity studies into question.

My prejudices are tickled and pleased by the notion that a fruit that contains some toxins may also contain phytocompounds that protect associated fructivores from harm.  This sort of undocumented nutritional synergies are at the heart of the "eat whole foods" argument, of which I am a partisan.  But I'm fully aware that we tend to believe the things we want to believe, and this is something I want to believe.  

Very interesting topic @Jeremy R. Campbell.  I appreciate you bringing this up as I had never heard of the possibility before.  Thanks for the link @Dan Boone.

Indigenous uses of paw paw
https://www.thecanadianencyclopedia.ca/en/article/pawpaw

I noticed paw paw can be used as sedative. They just make me mellow.

I had not seen this thread earlier and find this interesting.  Has there been any analysis on variation in the annonacin content between different trees as a starting point for breeding it out?  It would be unfortunate if those trees lacking the compound might have fruit less resistant to bugs and fungal disease.  Interesting info!....

At a potluck dinner with about 18 people on February 17 , 2024 in North Carolina, one person brought a bag of freeze-dried pawpaws produced by a local farmer. There were no seeds, I'm not sure if there was any skin. I ate one piece about 2 inches long and 1 1/2 inches wide. I left the meeting about an hour later, feeling a little nauseous. About two hours later it was worse and I vomited. Felt a little queasy in the morning, fine later in the day.  On asking around we found that all of the others who ate one or two pieces were also sick that night while none of those who did not try the pawpaws were affected. Found a few mentions of the toxin annonacin from pawpaw, one article said it was contained in the skin and seeds but I could not find a single scientific reference that had tested the skin. Could freeze drying have extracted toxin from the skin into the pulp? I found one article about toxicity of pawpaws but cound not access it. Most scientific journals have been bought out by corporate raiders who bleed them for profit by charging up to $50 to read an eight-page article. Knowledge for ransom is now big business.

Cecil,  Sorry to hear about your experience, but grateful for you posting it here.  I've been fascinated in trying to grow pawpaw but have heard mixed reviews on what to expect in both growth in the north and palatability of the fruit.  

Please note the 'warning' section in the following link regarding dehydrated pawpaw:  https://www.tyrantfarms.com/how-to-eat-and-process-pawpaw-fruit/#warnings-about-eating-pawpaw-fruit

Within that article is, additionally, this PDF newsletter report (see p. 2):  https://southcenters.osu.edu/sites/southc/files/site-library/site-documents/HORT/newsletters/pawpaw/NL_Fall2013.pdf

Thanks for the contribution of your story.

drying and cooking are known to increase digestive issues with pawpaw, definitely.

As others have said, it's a known fact that you should never freeze-dry, or otherwise dry, pawpaws. I do not believe this is related to annonacin or neurotoxins, there is some more acute digestive problem that occurs. It is sometimes reported in other types of processed pawpaw, and less commonly (but still occasionally) with fresh fruit.

Winn Sawyer wrote:As others have said, it's a known fact that you should never freeze-dry, or otherwise dry, pawpaws. I do not believe this is related to annonacin or neurotoxins, there is some more acute digestive problem that occurs. It is sometimes reported in other types of processed pawpaw, and less commonly (but still occasionally) with fresh fruit.

I agree. I tried drying some pawpaws that were known to be low annonacin cultivars and some that were not. I did not notice a difference in the results.

I just looked at the study and it said 0.0701mg
Per gram, there are 28g in an ounce so that adds up to 1.96mg of annonacin per ounce, not 206mg. So if a fruit is 3 ounces then that would be 5.88mg per fruit according to that study. Compared to soursop which has 15mg per fruit according to info on wikipedia. So that would make it much less than soursop and therefore safer to eat. But it’s all over the internet how much is in soursop but it’s hard to find stuff telling you how much is in pawpaw. Hopefully this study is correct and Pawpaw is the safer fruit.

John Weiland wrote: Has there been any analysis on variation in the annonacin content between different trees as a starting point for breeding it out?

i’ve been told that the older varieties ‘sunflower’ and ‘mango’ have some of the lowest annonacin content among tested varieties. i don’t recall where that info came from, though!

Lots to consider here.

Kaas, Hollis & Pantelyat 2020 say of Annona muricata (soursop) and Asimina triloba (pawpaw):

"Notably, annonacin represents 0.007% of pawpaw fruit pulp by weight, which is higher than other analyzed sources (soursop pulp contains only 0.002% annonacin)."

They are quoting Potts et al. 2012 which gives that figure for Asimina triloba (pawpaw): "The average concentration of annonacin in the fruit pulp was 0.0701 ± 0.0305 mg/g."

That error bar covers c. 68% of expected variation, that's 0.04 - 0.1 mg/g.  But the more fruit, and the more varieties, you eat, the more likely you are to hit a high annonacin one. For a Gaussian distribution, 2.5% (25 in 1000) of fruit will have above 0.1 mg/g.

So if I ate 100g of raw pulp from a pawpaw fruit about twice a week all year, I'd expect 2 or 3 of them in the year to have 10 - 13 mg of annonacin each.  

Moderation, and knowing how to find the low annonacin varieties, seems wise.

References

Kaas B, Hillis AE, Pantelyat A. Progressive supranuclear palsy and pawpaw. Neurol Clin Pract. 2020 Apr;10(2):e17-e18. doi: 10.1212/CPJ.0000000000000704. PMID: 32309040; PMCID: PMC7156197.
https://pmc.ncbi.nlm.nih.gov/articles/PMC7156197/

Lisa F. Potts, Frederick A. Luzzio, Scott C. Smith, Michal Hetman, Pierre Champy, Irene Litvan,
Annonacin in Asimina triloba fruit: Implication for neurotoxicity,
NeuroToxicology,
Volume 33, Issue 1,
2012,
Pages 53-58,
ISSN 0161-813X,
https://doi.org/10.1016/j.neuro.2011.10.009.
(https://www.sciencedirect.com/science/article/pii/S0161813X11001975