Researchers stumped by drug addiction paradox

April 16, 2008 By Lisa Zyga feature
Researchers stumped by drug addiction paradox
Data from the US National Survey on Drug Use and Health 2004: drug use in the last year. Credit: Sullivan, et al. ©2008 The Royal Society.

From chocolate and caffeine to nicotine and cocaine, many of our most addictive foods and drugs come from plant toxins. Considering that plants originally developed these toxins to deter herbivorous predators, it’s ironic that humans and other mammals don’t merely tolerate the toxins, but can crave them and even develop dependencies on them.

This paradox, presented by researchers in a new paper in Proceedings of the Royal Society B, works both ways: supposedly, the plants should never have developed toxins that reward animals for eating them, and humans should never have developed a reward mechanism for toxic plants.

In their study, Roger Sullivan from California State University and the UC Davis School of Medicine, Edward Hagen from Washington State University, and Peter Hammerstein from Humboldt University in Berlin suggest that the most widely accepted evolutionary explanation of human drug reward might not be on the right track, and that the origins of drug addiction may be even more complicated than previously thought.

“The greatest significance of the paper is in defining the paradox, and laying out the arguments in a manner that shows that it is a real conundrum and not a straw man argument,” Sullivan told PhysOrg.com. “The paradox has deep implications for current drug reward theory because it implicitly suggests that many of the key assumptions in current drug reward theory are flawed.”

Throughout history, plants have created their toxins by mimicking their own molecules that regulate metabolism, growth and reproduction. When ingested by herbivores, some of these molecules can interfere with nearly every step in the animal’s neural signaling process.

In current evolutionary interpretations of drug addiction, these toxic substances trigger the brain’s reward center by rewiring the brain’s natural reward circuits, and falsely indicating a fitness benefit and blocking painful feelings. But, as Sullivan, Hagen, and Hammerstein show, this explanation makes several assumptions that contradict evidence from previous studies. Most significantly, it assumes that humans evolved in environments without exposure to drugs, and that the brain never evolved to protect itself from plant toxins.

However, the researchers point to several other studies which show that the detoxification enzymes developed by animals (and which originally evolved in bacteria about 3.5 billion years ago) expanded in animals about 400 million years ago – about the same time that plants were evolving their own toxins. In other words, animals and plants seemed to have coevolved competitive genes in response to each other, which contradicts the evolutionary interpretation.

As the researchers investigated further, they compiled other studies showing evidence that humans inherited these detox genes from their mammalian ancestors. Interestingly, although many modern animal species can tolerate plant toxins, different species possess different detox function levels. Even among humans from different geographic locations, these functions differ. Often, human populations with greater numbers of toxin-metabolizing genes originate from parts of the world that contain an abundance of those plants. For example, human populations in and near Turkey have a very high frequency of enzymes that can metabolize opiates, and the opiate poppy is native to the Turkish region.

To conclude their argument against the evolutionary interpretation, the researchers explain that (pre-human) animals and plants did appear to have evolved the relevant genes simultaneously. If that’s the case, then the brain shouldn’t treat drugs as if they contained a fitness benefit, giving strong support to the paradox.

“We have been surprised by how robust the paradox is – that is, in presenting the arguments at scientific meetings for several years now, no one has been able to refute the basic argument that plant ecological models and neurobiological models of drug use are in direct conflict,” Sullivan said.

Many more questions also remain unanswered, but they may contain clues to an explanation. For example, there is contradictory evidence for whether commonly used drugs have become more or less potent as they’ve been domesticated. Also, as the researchers point out, current models explaining drug reward mechanisms don’t differentiate between different drugs – even though the pathways taken by opiates, cannabis, or any other drug are vastly different. Models of multiple-drug pathways might better explain drug appeal, the scientists suggest.

Based on evidence from previous studies, Sullivan, Hagen, and Hammerstein note that plant toxins may actually have some kind of benefit for animals. For instance, because plant toxins are more harmful to some species than to others, the less affected species might actually consume levels of toxin that are tolerable to themselves but much worse for the parasites or pathogens that feed on them in order to protect themselves. For example, earlier humans that consumed nicotine (in much smaller amounts than today) could have received the benefit of fewer parasitic infections. Of course, the benefits also come with trade-offs.

“The main implications for future research are that neurobiological theorists must consider facts emerging from plant ecology,” Sullivan said. “We are also planning field studies looking for relationships between human drug use and protection from helminth parasites.”

More information: Sullivan, Roger J.; Hagen, Edward H.; and Hammerstein, Peter. “Revealing the paradox of drug reward in human evolution.” Proc. R. Soc. B. doi:10.1098/rspb.2007.1673. (journals.royalsociety.org/content/ql240r18116x5870/)

Copyright 2008 PhysOrg.com.
All rights reserved. This material may not be published, broadcast, rewritten or redistributed in whole or part without the express written permission of PhysOrg.com.

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jimding
4.2 / 5 (5) Apr 16, 2008
Presumably evolution is largely a function of reproductive success. Of course, one must survive to the point that one can reproduce. I don't think there's much debate concerning the reproductive behavior of intoxicated humans. Nor concerning the tendency of humans to cultivate plants that provide intoxicants, whether alcohol or otherwise.
h1ghj3sus
4.1 / 5 (7) Apr 16, 2008
toxin: a poisonous substance that is a specific product of the metabolic activities of a living organism and is usually very unstable, notably toxic when introduced into the tissues, and typically capable of inducing antibody formation.

Why describe these "drugs" as toxins. Our main-stream are remaking our vocabulary. Please be weary of semantics and the ploys of the manipulators. There exists many substances that are nutritional and essential in small amounts but are toxic in large amounts. However, we do not necessarily describe vitamin C as a toxin. Are all of the psychological prescription medicines toxins also?
TheJ3ss3
not rated yet Apr 16, 2008
Perhaps we are looking at evolution from the wrong perspective. What if we humans possessed a Jungian like connection with other creatures on this planet, a sort of unconscious unity. That might help to explain how two entirely different species might evolve to suit each other at the exact same time.

As well I like the idea put forth on the nicotine - parasite relationship. Sort of a pseudosymbiotic relationship. Makes a person wonder how psychoactive compounds have shaped our evolution. Pretty much every ancient culture has used them in religious and spiritual contexts. Prohibition is a relatively new concept regarding wild plants.
Bonkers
3.7 / 5 (3) Apr 16, 2008
Humans unfortunately have an appetite for new experience and intoxication - even toddlers will repeatedly run round in circles till they fall over giggling. This is not a "toxin" argument, it is a "nectar" argument - but self-censorship is rigorously enforced amongst those who desire funding for their research, and the unpleasant notion that we, like our ancestors, enjoy drugs, cannot be tolerated. moderation in all things I say, but don't let religion or political correctness try and redefine what is, after all, only and uniquely Human.
earls
3.3 / 5 (4) Apr 16, 2008
What if... The plants wanted us to enjoy the "toxins" so we kept ingesting them until we died so then we wouldn't be around to consume the plant after so many doses.

Technically, the enjoyable "toxins" hardly work against the plant, as they are mass cultivated for their "toxin" thereby ensuring reproduction. Counter-intuitive, but effective.

I think high and holy jesus said it best however, that it's simply a bastardization of semantics. No "paradox" here.
HeRoze
3.8 / 5 (4) Apr 16, 2008
jimding - spot on! Having a plant produce a substance that people like is not far fetched. Some forms of symbiosis are quite outstanding. I think jimding states the case well - people like plants that make people happy, and people will cultivate them.
Soylent
5 / 5 (3) Apr 16, 2008
"Are all of the psychological prescription medicines toxins also?"

Generally, yes.
Mercury_01
3.2 / 5 (5) Apr 16, 2008
Ths study wronly assumes that drug "toxins" are always bad for you. I believe, and participate, in a symbiotic relationship with our plant friends. What of the fact that almost every living organism from a sea cucumber to a human has cannabinoid receptors in the nervous system? its obvious from where I stand that cannabis did not evolve it's "toxins" as a defense mechanism. If you doubt this, ask the deer in my back yard, or the parapalegic, or anyone with cancer or aids, ADD, OCD, or any of the myriad medical cannabis patients. and where would our culture be without ergotamine alkaloids? In my opinion, it may have ended in nuclear war
gopher65
3.2 / 5 (6) Apr 16, 2008
There is a fundamental flaw in the thinking of both these researchers and many of the people posting here. These toxins were not "designed" by evolution to create a pleasant effect in human, any more than hanging someone is designed to create euphoria. It is a secondary effect caused by disrupting the brain's normal operating procedures. When these normal processes are disrupted it causes us to lose our sense of reality. It can be a good loss (some narcotics), a bad loss of reality (some other narcotics, like how some people respond to LSD), or completely neutral (most other toxins).

The key thing to remember is that when your brain starts to die your perceive funky things. We just happen to have selected all the plants that produce good psychedelic effects on us. So studies like this one suffer from a simple selection bias. They purposefully ignored all plant toxins that DON'T interact with humans in a positive manner. If they hadn't done so, they'd have found a beautiful little bell curve of toxin interaction effects on humans ranging from horrible to good.
MikeMarianiMD,FAAP
1.2 / 5 (6) Apr 16, 2008
This is all conjecture, revised conjecture or magical thinking.
Good luck.
Have a nice day.
Sean_W
2.1 / 5 (7) Apr 16, 2008
The idea of using consuming plant insecticides to reduce parasite load is an interesting one but it seems suspicious that they would resemble chemicals in the brain. Would the organisms evolution actually reform the chemicals of it's own brain in order to make these natural parasite medicines rewarding? If these chemicals seemed to resemble a special receptor on neurons which only server to stimulate the reward center for that specific chemical then I could see it but I seem to recall reading that they resemble brain chemicals that are doing signaling work already.

The parasite explanation might explain why organisms which were rewarded increased in frequency instead of decreasing, especially where these things grow. But as for the origin, it could have just been that amounts needed to kill insects only mildly inhibited larger animal's neural activity and, as with many such inhibitions, some just happened to inhibit brain areas which told our reward system to stay quiet.
brant
1.5 / 5 (2) Apr 16, 2008
Oh where, oh where has my science gone????
h1ghj3sus
3.2 / 5 (5) Apr 16, 2008
Micro-evolution is a fact and can be readily studied. Some races are affected differently by alchohol than others. To presume that one plant chemical is a defense mechanism and another isn't is speculative, especially when some of the above chemicals are classified as "toxins" or defensive chemicals. One man's trash is another man's treasure.
Psalms 104:14 "He causeth the grass to grow for the cattle, and herb for the service of man."
docatomic
5 / 5 (2) Apr 16, 2008
I favour the symbiotic theory as well, for to me it seems at least possible that a plant species could evolve in a direction leading towards desirability and consumption by an animal species - to so enhance its chances for survival by benefitting from the resultant protection, care, and cultivation.

Did not our feline companion pets evolve in similar fashion, for example?
Jiufe
2.8 / 5 (4) Apr 17, 2008
Hey so I have an ongoing theory that you guys can pick over. So I started thinking about Marijuana and the chemical THC, THC is known for mimicking "feel-good" receptors in the brains cannabinoid receptors, not only that but it causes the user to increase their appetite rapidly, more than coincidentally the best way to gain fat easily is to consume a lot of nutrients in a short amount of time, also the THC stores most easily in fat so I see this as a way of ensuring it has a host for the THC to stay in. Not only that but I was thinking this could be similar to fruit, the plants produce "fruit" chemicals that mimic existing chemicals in the human brain in order to ensure their existence (humans crave the chemical and therefore plant more plants).

What do you guys think?
russellharper
4.7 / 5 (3) Apr 17, 2008
It's not a paradox. Addictive drugs in plants are a strategy to combat their most prevalent predators - insects. Insect excretory systems works backwards from mammals. Simplifying considerably, mammals essentially excrete everything as step one, then pull back in everything they recognize as "good" as step two. Therefore anything unrecognized, like toxic substances, gets excreted by default, and the concentrations remain low in their bodies. In insects, step one is "excrete what you recognize as bad" and that's it. Anything new or unrecognized stays in. If the insect doesn't figure out a way to deal with the toxin, it's poisoned for life! It's the basic reason why pesticides work on insects. Anyway, it is an advantage in the plant world to have the particular toxin be addictive to its most common predators - drug dosages logarithmic relationships body mass etc. too early in the AM.
AJW
1 / 5 (2) Apr 17, 2008
Nearly all earth evolution occurred before
humans appeared on the scene. Our ego
centric thoughts are also a toxin.

Create a paradox today, solve it tomorrow,
and get research funds both days.
fleem
not rated yet Apr 17, 2008
Agree with pretty much all the comments debunking this article (Wait, it looks like every single comment debunks it ?!).

I see very little, if any, paradox, and quite a few reasonable explanations. Symbiosis, differences in the abilities of prime predator (insects, dumb animals) and man, etc.
eraser
4 / 5 (1) Apr 17, 2008
Who is to say that plant constituents are evolved strictly to deter predators? The assumption behind the article is that plants don't "want" to be consumed. And yet many of them have evolved to be tasty, nutritious or otherwise desirable -- usefulness as a drug is simply one subset of "desirable" properties a plant can have.
snwboardn
2 / 5 (2) Apr 17, 2008
The plants obviously don't have a choice in what chemicals they produce. Obviously somewhere in the evolution chain a plant started producing tetrahydrocannabinol, which in turn set it above the rest of the plants that didn't produce it. The only questions that need to be addressed is, from what plant did the modern day marijauna plant evolve from, and what made this adaptation key to survival...
1. Does THC help the plant reproduce more?
2. Does THC thwart the plant from being eaten (bacteria, bugs, animals) before it can reproduce?
3. Does THC increase the plants longevity?
superhuman
3 / 5 (1) Apr 19, 2008
Marijuana, opium poppy, coca, all of them benefited from being addictive to humans, but was producing addictive substances also beneficial to plants before animals were able to cultivate them? Probably not. I think drugs were the toxins before and evolved into addictive substances when humans became capable of cultivating plants.

I prise the plants for their gifts!
PPihkala
4 / 5 (1) Apr 19, 2008
Regarding cultivation, animals have done that long before there was a single human here. Just recollect how plants make clearly visible, great tasting fruits to attract animals to eat them. And they use lots of energy and resources to do that. And why? Because they get the animals to distribute their seeds even long distances and the benefit of fertilizer (animal manure) planted next to their dropped seeds. This is co-evolution that is easy to understand. How psychoactive plant originated substances fit into co-evolution is tougher nut to crack. This evolution probably has many faces, many effects that may vary between each studied case.
WolfAtTheDoor
1 / 5 (2) Apr 20, 2008
I wonder sometimes if civilization has some grand, collective physiological mechanics to controlling the population to a sustainable size: self-destructive behavior, proliferation of homosexuality, and infertility. All dynamics that seem to be increasing in recent years.

It's an 'out there' theory, but hey I'm anonymous so what the hell, right?
HenisDov
3 / 5 (2) Apr 20, 2008
I Am Stumped By The Researchers Stumped By Drug Addiction Scene

http://www.physfo...ic=14988&st=195&#entry334377

A. From http://www.physor...887.html

"...it%u2019s ironic that humans and other mammals don%u2019t merely tolerate the toxins, but can crave them and even develop dependencies on them."

B. From http://www.physfo...top...95&#entry331389

"Don't apply anthropomorphic thinking-expectations. Apply genomorphic behaviour expectation.

From genomorphic considerations Survival At ALL circumstances, both with and without insectiside, is best and should be selected. And in the genome cooperative community survival is best when there is cooperation-synergism between individual genes. There is little native genes-cooperation with a single stranger in the community and more cooperation when two different strangers are implanted in the community."

C. Remeber, two interdependent organisms are involved in drug addiction

Where is the irony?

Likewise in this case, from the genomorphic considerations of the plant producing the toxin the more toxin seekers-cravers the more enhanced its own survivability.

Whereas in regards to the seekers-cravers, obviously since they do not feed back a rejection-damage to their genome, their base prime organism, why should their genome select an uncalled-for "defense modification-mutation"?.

(If/when our genome eventually selects a specific toxin defense gene it will take, as nature goes, many more years...)

Dov Henis
Zitface
4 / 5 (1) Apr 20, 2008
Russel Harper is right on. The 'paradox' only exists within an obstinately narrow perspective. And what about the theory that cannabis alkaloids promote forgetfulness (in humans)in order to limit the harvesters' return visits to that particular patch?
Bonkers
1 / 5 (1) Apr 21, 2008
Analgesia is the key to opium and cannabis, anything that works on the maddening pain of toothache would have had great value in a primitive world. Coca is perfect for altitude sickness and stamina, the locals don't go for the high cocaine content varieties, there are other alkaloids in there they prefer.

Plants and spices have been traded for millennia, and are the basis of most (all?) modern medicines. The original article just hopes to associate a few popular plants with the words toxin and addiction, whilst admitting it is totally stumped as to the meaning of it all. - a null hypothesis surely ...??
theonion
1 / 5 (2) Apr 22, 2008
The plants obviously don't have a choice in what chemicals they produce...

snwboardn has it right. I have never read, in one location, comments from a more confused band of quasi-intellectuals. If you are to follow the theory of evolution, it is not that the plants decide what makes them more or less fit to survive, but that the qualities of those that do survive are passed on to other generations.
In other words, the plants don't choose, the choice is made for them by nature.
DeeSmith
2 / 5 (2) Apr 25, 2008
Plants produce a variety of secondary metabolites as defense systems; many have multiple activities. For instance, some compounds may attract predators of common insects that snack on leaves. These same compounds may also alter instar gene activation during insect maturation. Many of these secondary metabolites are potent oxidants (and thus also have antioxidant capacity when regenerated by common redox systems present in plants and animals). Generally speaking, most secondary metabolites are directed against insects, not large herbivores. A limited number of compounds induce behavioral modifications. Humans noted medicinal and flavoring qualities of plant secondary metabolites early (prehistory) as hunter gatherers (primary daily activity was plant foraging), that would result in attempts at plant management and later on, domestication of many of these plants. That outcome was NOT deliberate action by plants; anti-herbivory metabolites evolved LONG before bipedal hominids evolved.

Addictive behaviors in modern humans don't occur naturally; they are an acquired behavior of self medication to offset abnormally low stress tolerance (insufficient cellular redox maintenance and altered neurotransmitter activity). The authors assertion of a supposed paradox is strange. Substance abuse is a relatively modern issue. Nicotine, cocaine and cannabis use was limited not widespread, and often restricted by cost and supply. Before widespread cultivation and trade (within the last 500 years out of tens of thousands of years of human history), their use was localized (example: cannabinoid use pre-1500 was confined to India) and often ritualized. Primary example: historic use of hallucinogenic plants by shamans in many regions of the world.

That these behavior-altering compounds are widely abused speaks to the problems of mental health and wellness of modern society.
ofidiofile
1 / 5 (1) Nov 20, 2008
it's been suggested before that feeding is wired into this addiction system. if you don't get hungry, you don't eat; if you don't eat, you get weak and die (either through starvation or predation). everything that we take into our system - including food - is a chemical that starts some kind of chain reaction with the "natural drugs" that regulate our metabolism etc.

many plants likely "take advantage" (through selective processes, not via intention) of this; the ones we like, we propagate. the ones we propagate survive to reproduce, and often even spread as the human animal spreads. it's worked for corn, wheat, soy, cannabis, and so on.

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