Tuesday, 6 March 2012

Of toad skins and psychiatry

Karma Chameleon @ Paul Whiteley
In the episode 'Missionary: Impossible', a memorable scene sees one Homer Simpson licking toads and experiencing what might be described as an altered state of consciousness.

Joking aside, there is actually some truth in the potential psychoactive properties of some species of frog/toad as exemplified by the Colorado River toad, whose skin excretes quite a potent cocktail of compounds including 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and bufotenin, both with psychoactive properties. Whether you would actually get a 'high' from oral ingestion of such products is entirely another question and one which I am not all that interested in finding out. I should also add a caveat here just in case anyone stumbled on this post looking for something other than autism research: please don't go licking your friendly neighbourhood amphibians. You might just end up with something rather more unpleasant than you bargained for (see here).

Strange then you might think that a compound found on the skin of a toad might also turn up in human urine samples from people with no evident exposure to such amphibians. Stranger still that elevated levels of that compound were reported in certain groups of people, say diagnosed with autism or schizophrenia. But that's exactly what was found by Emanuele and colleagues* a couple of years back, and not for the first** or second time*** as bufotenin entered the autism research arena. One of the earliest entries I've found mentioning bufotenin (and DMT) and autism is this paper by Piggott**** from 1979.

Bufotenin is an interesting compound in terms of its chemistry and biological effects. It has that famous indole ring so characteristic of the amino acid tryptophan potentially hinting at its chemical relations. Its psychoactive, hallucinogenic effect perhaps warrant its inclusion on various controlled drug schedules around the world. In short, it is quite a character. So why then do elevated levels of this compound appear elevated in the urine of some people with autism and other conditions and what are the potential implications?

Well I don't have a reliable answer for the 'why' question but the chances are that some tryptophan chemistry and perhaps a modicum of bacteria might have some involvement. The words indolethylamine N-methyltransferase (INMT) come up quite a bit in relation to bufotenin bioformation and some suggestion that INMT activity might be heightened in certain psychiatric presentations. I recently discussed the tryptophan-bacteria connection in relation to the production of IAG and autism but who is to say that it just stops there.

As to the implications, well there are a few clues from the Emanuele paper which can be summarised:

  • Urinary bufotenin levels were measured in three groups of people: adults with 'severe' autism confirmed by CARS (n=15), adults with schizophrenia (medication free or naive) (n=15) and asymptomatic volunteer control participants (age and gender ratio matched) (n=15) .
  • Blinded analysis of samples for bufotenin was via mass spectrometric analysis (coupled to HPLC) using a previously published method. This means that analysis was pretty reliable.
  • Compared to controls, mean urinary levels of bufotenin were elevated in both the schizophrenia and autism groups (p<0.001 and p<0.05 respectively). Visually, the distribution of results were more pronounced in the autism group, whereas the schizophrenia group showed less overlap with controls. 
  • Based on the measurement of adaptive behaviours using the Vineland Adaptive Behaviour Scale (VABS), a significant positive correlation between urinary bufotenin levels and hyperactivity scores on the VABS was observed for the autism group. No correlations with pertinent schedules were observed for the schizophrenia group.

Accepting that participant numbers in this study were low and the degree of overlap between controls and the autism /schizophrenia groups, these are interesting findings. The obvious question based on the VABS hyperactivity connection is whether bufotenin levels have ever been specifically looked at in cases of AD(H)D - the answer: not to my knowledge (well, not according to PubMed). Whether any of the participants with autism (or schizophrenia) were ADHD comorbid, we don't know. Indeed, I am not an expert on VABS (although have reported on it as part of one study) so cannot readily comment on its 'usefulness' and accuracy to measure hyperactivity. It strikes me that future work in this area perhaps needs to utilise more applicable scales looking at things like inattention and impulsivity also.

The next question is what effect elevated levels of bufotenin might have on a person. The short answer is that nobody really knows outside of the more psychedelic observations. Whilst it would be easy to speculate on the 'recreational' actions of the compound, we are perhaps wise to bear in a mind a few points such as: (a) these studies were looking at urine samples and urine content for bufotenin representing the end point of the metabolic journey, and (b) aside from a few trials administering bufotenin to 'volunteers' to look at short-term effects, chronic (long-term) exposure has yet to be properly mapped out. Bear in mind also that some level of this compound were found in just about everyone examined, so there may potentially be some 'function' for this compound in the complicated tapestry that is human biochemistry. This paper even goes so far to say that it may have some intestinal function.

The report by Emanuele and colleagues is not a new publication but nevertheless has been of some interest to me for a while. Those who follow the autism research scene will remember some rumblings a few years back over a patent***** about a certain peptide called dermorphin, normally found on the skin of some species of South American frogs and with quite some opiate potency, which was suggested to show linkage to some case of autism. As it happens, not much more was ever done on the findings aside from mention in this paper on Rett syndrome and some criticism based on the analytical methods and results obtained. Maybe dermorphin and DPP-IV are fodder for a later post.

To finish, and with no connection at all to this post, a tribute to Robert Sherman whose fame some will not have heard of until you hear this piece of music which he penned.

* Emanuele E. et al. Elevated urine levels of bufotenine in patients with autistic spectrum disorders and schizophrenia. Neuro Endocrinology Letters. 2010;31:117-121.

** Narasimhachari N. & Himwich H. GC-MS identification of bufotenin in urine samples from patients with schizophrenia and infantile autism. Life Sciences. 1973; 12: 475-478.

*** Takeda N. et al. Bufotenine reconsidered as a diagnostic indicator of psychiatric disorders. Neuroreport. 1995;6:2378-2380.

**** Piggott LR. Overview of selected basic research in autism. JADD. 1979; 9:199-218.

**** Shanahan MR. et al. Peptide diagnostic markers for human disorders. Ortho-Clinical Diagnostics Inc. European Patent: EP0969015A2