Musings and commentary by Keeper of the Trout
Phalaris staggers is a serious, and sometimes fatal, disorder that occasionally shows up in sheep, and far more rarely cattle , grazing on Phalaris aquatica (P. tuberosa) [Note 1]. It occurs less frequently with other Phalaris species, and almost never with Phalaris arundinacea.
When it does occur, as in the case of P. aquatica, losses can be quite high.
Although Phalaris staggers have been described in the literature for over half a century and intensely `studied' for several decades, the actual causative factors for this syndrome are, at best, poorly understood and, in most cases, misrepresented. The research surrounding Phalaris staggers is still characterized by far more confusion, worthless data, questions and conjecture than either understanding or answers.
Phalaris staggers has two primary manifestations.
One is an acute form, characterized by hyperexcitability and a syndrome of variable symptoms such as a rapid nodding of the head. This may terminate in either the rapid collapse and death of the animal or else its, usually, full and rapid recovery without incident (some workers further divide this into peracute and acute staggers)
There is also a chronic form from which the animal only slowly, and often never fully, recovers. It is characteristically accompanied by degenerative changes in the liver and portions of the central nervous system. The chronic form may also result in death; occasionally quite some time later.
Animals often stumble and collapse, when chased, due to an inability to unflex their joints, or standing animals may collapse, suddenly, without warning.
Rendig's characterization of the chronic form: "...unsteady, stumbling gait. Restlessness, hyperexcitability, twitching of the ears, head bobbing, jaw tremors, heavy breathing and an excessively high pulse rate" (In-depth descriptions of staggers can be found in our references.)
Despite its frequent presentation as an established fact, the causal link between 5-MeO-DMT and Phalaris staggers is currently supposition rather than proven.
Superficial evidence of symptomology has been repeatedly used to claim this despite the complete and utter failure to produce chronic stagger effects, or degenerative damage such as lesions in the livers or nervous systems of animals, by administration of pure DMT and/or 5-MeO-DMT (even if given in fatal doses).
I see roughly ten serious problems (give or take a couple) with the still encountered notion that any of the dimethylated tryptamines are the causative agents for Phalaris staggers: (and most especially with particular regards to 5-MeO-DMT and the chronic form) [Festi and Samorini's work suggests this may be an attempt to kill an already dead issue. My apologies if this turns out to be the case]
1) Rendig et al. found a poor correlation between alkaloid levels and appearance of staggers symptoms. The peak of alkaloid levels appeared to be at the beginning of the Phalaris grazing season while the incidence of staggers was mid-season (Winter). Years when the appearance of staggers was highest showed no higher levels of alkaloids than other years.
Similarly, in Australia, Oram observed that the periods of toxicity corresponded to those periods when tryptamine levels could be demonstrated to be at their lowest [Deaths occurred only in July and Sept. (Winter) while tryptamine levels were highest in April (Autumn).]. Another telling point is that 2 out of the 3 cases of the fatal poisonings which they observed, during their study, happened on the lowest tryptamine producer. When comparing said low tryptamine strain to two high tryptamine strains that had either shown less deaths or only acute cases with rapid recovery, they found TWICE as much total base (at the time of toxicity) in the low tryptamine producer with tryptamines comprising only 3% of the total as opposed to 25% in the latter two (Seedmaster and Sirocco).
Culvenor and coworkers noted that no significant differences had been observed in the alkaloidal composition or content of supposedly toxic or nontoxic pasturage. In their quantitative analysis of P. tuberosa from a variety of locations, slightly higher alkaloid concentrations were reported from fields with no apparent toxicity than from fields where either staggers or sudden death had occurred.
Culvenor noted that many assays were done on dried grass which may produce results not reflecting those found in forage.
It should also be remembered that some assays looked only at total base content as estimated by spectrophotometry or titration with p-toluenesulfonic acid and, in most cases, made no attempt to evaluate the actual alkaloid composition or the relative proportions of its components (some simply divided their subjects into 3 groups based on their reaction with Xanthydrol: No ring substitution, like DMT, [purple], Ring methoxylated, like 5-MeO-MMT or 5-MeO-DMT, [blue] and Gramine [no reaction or pink depending on how the assay is run].), others regarded their total basic fraction as tryptamines (ignoring the potential presence of β-carbolines which would have also been present in the isolated fraction they quantified) and still others relied on assay procedures (tlc and uv absorption) which could have easily confused DMT and 5-MeO-DMT with their corresponding β-carbolines.
2) Rendig et al. mentioned that when V.E. Mendel and G.L. Crenshaw extracted juice from fresh P. minor and infused it into fistulated cattle for 20 days they were unable to produce any symptoms similar to those previously noted in cattle grazing on the grass itself.
When injecting sheep with DMT, 5-MeO-DMT and Bufotenine, Rendig and coworkers were able to induce profound disturbances that were similar to some of the acute stagger symptoms. All animals recovered fully within several hours and showed no lasting symptoms. They were completely unable to produce the persistent chronic staggers seen in sheep grazing P. aquatica var. stenoptera. [Gallagher's work produced exactly the same limited range of results.] While therefore strongly indicated for a possible role in manifesting some of the symptoms expressed in the acute form, evidence is against their involvement in any other aspect of staggers.
3) The biggest piece of ammunition (and, quite bluntly, the solitary hinge-pin) in the case against the tryptamines are the reports of Gallagher.
The first of a number of points to be noted concerning the perplexing reports of Dr. Gallagher:
Gallagher's dosages claimed to produce fatalities when injected were literally one to two orders of magnitude smaller than those established by either the US Army or by Ho for DMT, by Ho for 5-MeO-DMT, or by Ho, or Ghosal, for bufotenine.
As examples:
Gallagher purported deaths resulted from dosages greater than 1 mg per kg intravenously. Gallagher stands alone in reporting lethal effects at such low dosages.
Dogs are usually more sensitive to lethal effects of the hallucinogens than are most other animals but Heinzelman & Szmuszkovicz reported NO deaths at 5 mg per kg given intravenously to dogs (This is equivalent to 400 mg of DMT injected intravenously into an 80 kg human.)
According to Sax, the Chemical Systems Laboratory determined an intravenous LD50 of 32 mg/ kg, in mice, for DMT. An intravenous dose of 36 mg/ kg was NOT found fatal to monkeys, according to Heinzelman & Szmuszkovicz 1963. They reported "A dose of 53 mg/ kg [iv] was fatal" and cited unpublished work performed by W.A. Freyburger and B.E. Graham at the Upjohn Company.
Ho reported establishing an intraperitoneal LD50 of 110 mg/ kg, in mice, for DMT.
Both Ho et al. 1970b and also Ghosal et al. 1969 reported an intraperitoneal LD50 of 290 mg/ kg, in mice, for Bufotenine.
Ho gave an intraperitoneal LD50 of 115 mg/ kg, in mice, for 5-MeO-DMT. [I also encountered a note that the oral LD50 of 5-MeO-DMT is four times the intravenous LD50 but the comment lacked details, figures or references.]
Gallagher amazingly did not include any proportions of death/survival in animals given the reputed potentially fatal doses (nor did he include the source of his alkaloids); just that death was a possibility. Either sheep are radically more susceptible to the effects of these compounds than other animals or else the picture has not yet been adequately developed.
Another curious point is that Gallagher appears to have reported equivalent or slightly greater toxicity when using subcutaneous administration rather than an intravenous route. This stands at odds with all other toxicological and pharmacological evaluations of the tryptamines.
Examples:
5-MeO-tryptamine:
LD50 in mice (as hydrochloride);
Oral: 580 mg/ kg;
Subcutaneous: 620 mg/ kg;
Intravenous: 102.5 mg/ kg;
As reported by Mashkovsky & Arutyunyan 1964.
They reported rats showed an LD50 of 50 mg/ kg
intravenously.
Erspamer 1954 determined mice to have an intravenous LD50 of 60 mg/ kg and
rats and mice to have subcutaneous LD50 values of 600 and 750 mg/ kg, respectively.
Serotonin:
LD50 in mice;
Subcutaneous: >868 mg/ kg;
Intravenous: 160 mg/ kg;
while the
LD50 in rats was
Subcutaneous: 117 mg/ kg;
Intravenous: 30 mg/ kg; as reported by Erspamer 1954.
LD50 in mice (as hydrochloride);
Subcutaneous: 601 mg/ kg; Intravenous: 81 mg/ kg;
as determined by Mashkovsky & Arutyunyan 1964.
While lacking enough information to know with certainty, my best guess is that the discrepancies between these two reports might have arisen from the time of day that administration occurred. Time of day is crucial information in lethal dose figures but is only rarely considered.
If one looks at the information that Gallagher includes, versus what he left out, and compares the space he uses to discuss his lab results with that taken up by his gymnastic theories on why tryptamines should be suspect, his papers rapidly begin to take on the appearance of the results being only selectively presented.
4) Concerns the green pigmentation that has been that correlated with the in vitro administration of DMT and/or 5-MeO-DMT; just as brown pigmentation involving enzymatic preparations of the same tissues is linked with bufotenine and/or serotonin.
While presence of a green pigmentation has been observed in several tissues of sheep which died after grazing Phalaris and developing chronic staggers, at no point can I determine that ANYONE has ever been able to observe this in sheep which suffered acute or peracute episodes and either recovered or died. The presented notion that this is somehow diagnostic of Phalaris toxicity appears in need of better evaluation if it is unsupported by observations involving acute or peracute cases.
The link between formation of a green pigment in vitro when using DMT and/or 5-MeO-DMT with enzyme preparations is fairly well established but the assertion that this is involved in fatalities apparently lacks any evaluation of appropriate control animals or even the direct structural comparison of the pigment produced in vitro with that recovered from sheep suffering chronic staggers. Gallagher felt that the green pigment found in sheep "appears to be at least closely related" to the pigment from sheep with chronic Phalaris staggers but provided no evidence that they were in fact synonymous or even the suggestion that they were actually comparatively analyzed. Surely a direct structural comparison could not be a problem.
The detail that must be stressed here is that Gallagher [Gallagher et al. 1966] was entirely unable to observe the presence of this pigmentation in any examined cases of the acute or peracute forms of Phalaris staggers; both of which were the only two aspects of the disorder he was able to demonstrably link to the tryptamines under laboratory conditions [allagher et al. 1964]. It should also be noted that his linkage of the tryptamines to these two forms of the disorder was based entirely on symptomology [Note 2].
The failure to observe similar pigmentation changes in sheep known to have been afflicted with either acute and peracute staggers strongly indicates a need for further study. At the very least, controlled in vivo studies need to be performed using orally administered pure 5-MeO-DMT and/or DMT.
5) Tissue/enzyme preparations frequently do not realistically reflect the biochemistry of normal in vivo activity.]
As Gallagher's study suggested MAO inhibition by the tryptamines was involved with development of the toxic effects and MAO inhibition is now either known or suspected for the handful of β-carbolines isolated from Phalaris species; the issue rapidly becomes more complex (it seems amazing that he entirely disregarded the β-carbolines since MAO inhibition had already been established for so many others).
Many of Gallagher's arguments appear to be suppositions attempting to force fit the known facts into his conclusions despite the serious holes in his assertions. I do not intend to suggest that cardioactive effects such as heart attacks might not potentially have involved the tryptamines [Note 3] but do not believe they can be singled out and the known presence of gramine [Note 2], β-carbolines and hordenine ignored. Any combination of gramines, tryptamines and/or hordenine, coadministered with MAO inhibiting β-carbolines, could produce life threatening cardiac events if ingested in sufficient quantity. Even so, the answer appears more complicated. Another potential but overlooked factor is the anticholinesterase activity reported from several Phalaris β-carbolines; see Ghosal et al. 1977
6) Regardless of how many published accounts now claim it, lethality, resulting from the oral administration of dimethylated tryptamines has never been established outside of one lone researcher's reports! Quite literally, each and every later worker cite Gallagher as their primary reference.
Many workers, on the other hand, have reported a lack of oral activity for all of the dimethylated tryptamines found in higher plants [Note 4]. This is obviously a premature or limited view since bufotenine DOES have some
activity orally when ingested in large enough amounts as does 5-MeO-DMT. DMT is claimed by Ott to probably be active if enough was eaten but the amount is obviously in excess of a gram and due to the body's intense and aggressive removal of free DMT & immediate metabolism (whether at the synapse or in blood) this conclusion may or may not be accurate.
In the case of DMT, at least a gram (1000 mg) has deliberately and knowingly been orally ingested by a human and produced no effect. [See Ott 1994 and/or Shulgin & Shulgin 1997]
Besides MAO, the body appears to have additional aggressive mechanisms to remove circulating DMT. In fact Sitaram made a comment that metabolism of DMT is so thorough that any DMT present in the urine would be unlikely to have arisen from within the brain. See more details and references in Some Simple Tryptamines. Second edition.
It is perhaps noteworthy though that despite having a longer duration 100 mg of 5-MeO-DMT taken orally has dramatically less potency and little of the sparkle of even 5 mg smoked.
Another important point is there has NEVER been even one reported human death resulting from DMT or 5-MeO-DMT use; even using pure materials. The odd report (1 or 2 third-hand accounts) of elderly shamans dying after being given a dose of snuffs known to sometimes be extraordinarily potent in 5-MeO-DMT content has also been attributed, by Bo Holmstedt, to asphyxiation due to their aged respiratory system not adequately handling the huge amounts forcibly blown up the nose; some reaching as far as the lungs! (While the user was no doubt incapable of responding to their need to breathe during those crucial first minutes.)
[Note: there was in 2004 a report of a human death involving 5-MeO-DMT as part of an ayahuasca analog brew.
Despite many later assertions to the contrary, Gallagher did not include or even mention the death of ANY animals after oral administration of 5-MeO-DMT. [I would suggest a slow and careful reading (or re-reading) of Gallagher by my skeptics.]
7) Gallagher reported a rapid onset of effects by oral administration, was able to kill animals by injection and was able to reproduce many symptoms of acute Phalaris poisoning using DMT, bufotenine and/or 5-MeO-DMT but did not present any case of death that had been caused by the experimental oral administration of DMT or 5-MeO-DMT, was entirely unable to reproduce persistent chronic staggers using pure materials and was unable to reproduce ANY of the observed degenerative changes such as central nervous system lesions.
8) Gallagher claimed an incredibly short onset of 6 minutes after oral administration of 5-MeO-DMT but curiously did not include the dosage given (or its form or even its source). Nor did he mention a lethal oral dose, or even that any deaths resulted when using this route of administration. None of these are points to omit considering what was being claimed.
9) As footnoted at the start of this list, despite sometimes having very high amounts of 5-MeO-DMT, Phalaris arundinacea has, so far as I can determine, only rarely (twice) been implicated in any stagger-like cases during its quite lengthy history of common and widespread use for feeding livestock.
10) While Gallagher claimed an onset of 6 minutes following oral ingestion of 5-MeO-DMT, he also noted that clinical signs of poisoning and/or deaths from grazing on Phalaris required 6-12 hours to appear and even more commonly 12-72 hours [Note 5]. Deaths have frequently been noted to occur some days (up to months) after removal of the sheep from Phalaris pasturage. [5-MeO-DMT and DMT are believed to be almost entirely removed from the system within 2 hours and a similar pattern is believed true for bufotenine.]
DMT and 5-MeO-DMT are known to be short and extremely short acting, respectively, producing at best a short-lived and very transient tolerance. (Some have reported not even this.)
This delayed onset at least suggests that metabolic products may be the toxic factors; possibly involving gut flora. Some type of metabolic poisoning may also be involved. Sasha Shulgin's comments about the potential dangers of quaternary tryptamines (or tryptophans or any other simple quaternary amine capable of cyclization) getting trapped in nerve cells bears some serious consideration. (Conversation; Mind States, Berkeley, CA 22 November 1997.
Sensitization and some sort of hypothetical delayed toxicity from tryptamine ingestion has been suggested as an explanation for this discrepancy; yet, as there are several months elapsing between the peak tryptamine levels and the peak incidence of `staggers' this would require a serious (and, for the tryptamines, absolutely absurd) period of latency.
Even Gallagher's assertion that exposure to tryptamines somehow causes lasting sensitization to the effects of adrenaline and thus can somehow result in fatality for days after exposure begs to be questioned in light of ANY of the well known and well explored pharmacological actions of these naturally occurring neurotransmitters [Note 6].
None of the dimethylated tryptamines have ever been experimentally determined to induce any type of delayed efforts or toxicity, or any sensitization to themselves, or to any phenethylamines, or, for that matter, to anything else, after their effects have worn off. And, most importantly, while exceptions do exist, animals suffering acute Phalaris poisoning frequently recover fully within several hours.
On the other hand, the animals most seriously afflicted with `staggers' took many hours to `sicken', up to some days to die [up to 5 months according to Festi & Samorini 1994] and survival after developing chronic staggers was often correlated with a poor and incomplete recovery accompanied by the demonstrable development of lesions in the liver and/or central nervous system; none of which could be produced by the experimental administration of even deliberately fatal amounts of 5-MeO-DMT.
Gallagher dismisses the extremely reasonable idea of a more toxic action (chronic staggers) occurring superimposed on a different acute syndrome as being unlikely but presents no justification for his opinion.
Gallagher reported that bufotenine: A) produced the same neurological signs observed in acute Phalaris staggers, B) was more active than DMT in this regard and C) that it readily crossed the blood brain barrier.
In light of bufotenine's reported poor ability to cross the blood brain barrier, this suggests that either the blood brain barrier in sheep is far more transparent than in humans or that something else altered its permeability or that something which is not be apparent is involved.
Additionally, their administration of any of these 3 alkaloids by injection into the jugular cannot realistically be extrapolated as representing an evaluation of their oral ingestion.
Gallagher himself qualifies his work with the statement, "It is considered that, according to the dose and mode of administration, the group of neurological signs exhibited by sheep with acute Phalaris staggers can be produced by the alkaloids present in P. tuberosa. Chronic Phalaris staggers with persistent, degenerative central nervous system lesions has not yet been reproduced by administration of the tryptamine alkaloids"
Not yet" stands as an intact qualifier even now, over three decades later.
I suspect that the often repeated claims that Gallagher provided proof of oral lethality for 5-MeO-DMT arose from someone not only misinterpreting his paragraph discussing lethal administration but also not understanding what parenteral administration meant. I have repeatedly encountered the notion, many times even by trained pharmacologists who should know better, that parenteral means "by the mouth" or "through the intestines; implying an initial introduction through the mouth", when it literally translates as "by the intestines" or "by the bowels", and is used to refer to ANY mode of administration OTHER than by the mouth (this includes injection) [per os, abbreviated p.o., means "by the mouth"] (At least this is what we were taught in "Medical Terminology" class at the University of Texas)
The greatest degree of toxicity appears to involve hungry animals grazing winter growth in Phalaris pastures which had lain fallow for some time and in which the vegetation was new growth less than 9 inches tall occurring in thepresence of old and dead litter from the previous year's growth.
In addition to new growth which often shows high alkaloid levels, old tussocks were also increasingly accessible for forage. This has been suggested as a contributor due to it providing shade (known to increase alkaloid content and especially 5-MeO-DMT content) but it might also be considered that older material will contain higher amounts of β-carbolines, or other metabolic products, as the dimethylated tryptamine content drops.
Consumption of this old material would also significantly increase the likelihood of fungal contaminant ingestion as, if fungal growth were present, it would be maximal on older & dead material..
That foggy or wet weather was observed to precede and/or accompany the most severe outbmoaks would also indicate conditions when active fungal, mold or mildew growth might be expected.
Fungal endophytes of grasses, sedges and other common components of pasturage are both known and have been demonstrated to produce toxic and/or fatal results in livestock. Their potential presence cannot be dismissed or disregarded. The potential role of fungal toxicity in Phalaris staggers is discussed in Festi and Samorini and also in Shulgin and Shulgin.
Another point is that Phalaris staggers not only do not occur on MOST stands of P. aquatica being used for grazing but, even more interestingly, do not appear at all during some years, even on material believed to have caused it during other years. These two points have been repeatedly observed and noted in the literature. In one experimental example, at Davis, California, sheep were deliberately maintained on Harding-grass (Phalaris aquatica var. stenoptera) for 3 years with no occurrence of staggers. (Trial was said to have been conducted by R.M. Love and W.C. Weir.)
What limited data exists suggests that the peak period of toxicity may be correlated to a period of peak β-carboline levels or at least a period of low trpytamine levels. While this may be coincidental in the etiology of Phalaris staggers it cannot be disregarded as it so often has been. (It should be recalled that both N-methyl cations of tryptamines and
betacarbolines are metabolically produced from the simpler tryptamines.)
According to Festi & Samorini 1997 [Note 7], Bourke and coworkers reported being able to induce symptoms of a chronic neurological disorder using the β-carbolines, norharman and harman in a dose of 54 mg/kg given subcutaneously. [Note 8]
I lean towards the thought [Note 9] that the effects might involve a drug interaction due to the presence of monoamine oxidase and/or cholinesterase inhibiting β-carbolines interacting with other components in the grass or diet, but exactly what is interacting with what is not clear. [The role of gut flora in potentially modifying ingested alkaloids must also be considered.]
(An assessment of these suspicions would therefore require evaluation not just of pure compounds but of mixtures.)
While DMT and 5-MeO-DMT may indeed be orally activated by these compounds, and this does fit some of the symptoms of the acute form, and would certainly enhance the risk of cardiac failure, the fact remains that so would gramine and hordenine, both of which are as likely to be present, and both of which are additionally known to be present in rather large amounts in some strains. When combined with MAO inhibitors, hordenine would pose a far more serious cardiac risk than the tryptamines, while gramine produces virtually the same symptoms as dimethylated tryptamines when either is given to animals at lethal levels.
As for real-world support; since MAOIs and hordenine often co-occur in Phalaris arundinacea, as does DMT and/or 5-MeO-DMT and/or β-carbolines, as does gramine and/or most of the above, and no real problem with staggers has ever been noted for this species, it seems unlikely that either a simple MAOI/ sympathomimetic interactionorsimple oral activation of a tryptamine by an MAOI is responsible for producing staggers. [The unreliable appearance of staggers and the delayed, persistent toxicity also casts serious doubts [Note 10]
Fungal products such as the ergot type alkaloids that are known from some fungal endophytes in grasses and sedges, as were mentioned in passing above, not only have threat of inherent toxicity but similarly have the potential for synergistic toxicity and adverse reactions if combined with MAOI's.
Other compounds like ring substituted gramines [Note 11], or the unsubstituted and/or ring-methoxylated tryptophols, indole acetic acids, tryptophans, and also a variety of β-carbolines (some of them quaternary), are all known from Phalaris strains. All are known to be toxic, or at least potentially toxic, to certain livestock even in the absence of MAO inhibitors.
Another potentially toxic factor that appears to have seen neither consideration nor toxicological evaluation is the reported, but apparently intermittent, presence of the N-methyl cations of DMT and 5-MeO-DMT [Note 12]. The first of these has been noted to comprise up to 5% of the total alkaloid content [By Frahn & Illman 1973] during those periods of active growth when they are produced. Neither the parameters surrounding their production nor their levels over the course of the seasons have been adequately elucidated. If these compounds entered into nervous system tissue and cyclized, it would not be surprising if any quaternary β-carbolines that resulted showed neurotoxic results, delayed onset and serious lasting toxicity. Both should be evaluated for their potential for green pigment formation. If they do, it would be surprising if it was not "at least closely related" structurally to pigmentation from 5-MeO-DMT or DMT. While lacking evaluation, these compounds cannot be dismissed without further study.
The contribution of Bromus, Cyperus, Scirpus, Fescue, Paspalum, Sorghum halepense, Tribulus, clovers and the many other possible components of pasturage similarly cannot be dismissed [Note 13].
While much of this is conjecture, it is amazing that this issue stands in need of clarification and resolution despite the fact that so many have apparently come to consider the issue cut and dried in what sometimes seems to be a fairly politicized scientific circus.
This is not an argument for any particular conclusion in this matter other than the obvious one that the issue is not yet closed and desperately needs objective investigation, despite how politically motivated people {Note 14] have presented and/or manipulated the data.
Many studies were undertaken which attempted to negatively correlate tryptamines' toxicity with palatability based on the premise that lowest palatability indicated the greatest toxicity [Note 15] despite the fact they were working with P. arundinacea and all deaths were occurring on P. tuberosa [Note 16]
Purporting to address the `tryptamine problem' intensive breeding efforts to produce low tryptamine strains OF Phalaris ARUNDINACEA were undertaken, in the US, ostensibly to decrease animal fatalities, in spite of the following demonstrable facts:
1. Highest numbers of animal deaths occur during the times when the tryptamine content was proven to be lowest (by separate workers in Australia and US),
2. "Low alkaloid" strains of Phalaris aquatica are found to produce higher numbers of dead livestock than "high alkaloid" strains when compared directly,
3. Phalaris arundinacea has NEVER caused any occurrence of staggers in the US; and only two incidences worldwide [Simpson et al. 1969 & Ulvund 1985] despite it clearly being on record that is has been deliberately cultivated & utilized for forage for over 200 years. According to Marten & Heath 1973, successful reports of its use far out weigh any negative reports. It is widely and successfully used for forage, hay and silage. Its primary weakness appears to be its highly variable palatability.]
Many workers appeared to operate as if the causative link between 5-MeO-DMT and Phalaris staggers was already proven (almost as soon as the presence of dimethylated tryptamines was first reported)
When the correlation between tryptamines and staggers began to be questioned, and the lack of staggers occurrence in P. arundinacea noted, the reasons cited for the importance of such programs shifted to focus on addressing diarrhea in lambs, or watery eyes/ rough coats in cattle, and decreased weight gains in both, rather than stagger production, but never failed to mention staggers; stressing the `toxic' nature of the tryptamines and, in most cases, presented the tryptamine/ staggers connection as an already proven fact.
This is so pervasive that in Southon & Buckingham's 2 volume 1989 Dictionary of Alkaloids., under the entry for 5-MeO-DMT (as the methyl ether of bufotenine, O-Methylbufotenine), they flatly assert "Toxic agent causing staggers-like poisoning of sheep in Australia."
Do I really have to say who they cite as their reference?
This should not be a political issue; it is a very serious one both of economics and livestock toxicity. If these are not the areas which are effectively addressed in research, a great disservice is being done to the livestock producers who are depending on agricultural science not only to define the problem but to provide potential solutions.
The ability to reproduce many, but not all, symptoms of one manifestation of the syndrome and absolutely none of the other can hardly be considered to be a successful causal determination. `Almost' is usually considered the same as a miss in science, or a sign that more work needs to be done before making any conclusions. At the very least it would seem sensible that people first attempted to identify exactly what is in the grasses at the time of peak illness/fatalities and then attempt a toxicological assessment with each and all of the isolated components not just a selected few.
Despite much study and the best efforts of many, a clear and accurate understanding of the true origin of Phalaris staggers is lacking.
The majority of the evidence is strongly against chronic Phalaris staggers being a product of tryptamine ingestion but few seem to care for discovering the truth; politics rule.
Consult our forthcoming work on the Genus Phalaris for more details of some perplexingly bad science.
See Festi & Samorini and/or Shulgin & Shulgin 1997 for alternate scenarios that are AT LEAST as plausible, if not far better supported.
The major discrepancies in Gallagher's work that are seemingly contradicted by the rest of the world
1. DMT, bufotenine (5-OH-DMT) and 5-MeO-DMT were all said to be orally active
2. Over 1 mg/ kg was claimed to
"readily" produce death via heart failure if given intravenously to sheep. [Perhaps it is just a coincidence but this is also the usual dosage given in the literature as a normal intramuscular dose for
humans.]
3. Subcutaneous administration was reported to be either equally or more readily fatal than intravenous administration
4. Bufotenine was more active than DMT and readily crossed the blood-brain barrier
5. Oral administration of 5-MeO-DMT took 6 minutes for onset
- A related and reasonable line of thought but in reality one that has not been adequately evaluated yet.
If sufficient β-carbolines were ingested, it is possible that a sheep could ingest enough tryptamines to have coronary problems. But, as mentioned in the text, it has been shown that the times when staggers show up are ALWAYS during periods when the tryptamines are at their lowest, never during the periods when tryptamine concentrations are the highest, and, P. arundinacea is known to sometimes show clones that are consistently high 5-MeO-DMT and/or DMT producers yet has only rarely been implicated in staggers. (Two reports worldwide are all that I am aware of.)
Staggers have NEVER been reported in North America for Phalaris arundinacea [Marten & Heath 1973, page 267], a valuable and common component of both pasturage and hay in many northern states (as well as worldwide in temperate zones from Siberia to Argentina). It has a known history of specific use for this purpose spanning more than two centuries.
Quite literally, only 2 reports have been located anywhere.
One, described by Simpson et al. 1969, was a solitary but serious outbreak of what appeared to be Phalaris staggers with "subacute" and chronic cases in sheep grazing on a mixed pasture in a drained New Zealand swamp that contained (est.) 60% P. arundinacea. (Affecting 80%; killing 17% of the flock.)
A similar appearing disorder observed in a solitary 6 month old lamb grazing P. arundinacea in south-western Norway was reported by Ulvand 1985 and was mentioned on page 237 in Østrem 1987.
Besides the stagger incidences occurring on Phalaris aquatica var. stenophylla in California and the Northwest, referred to and studied by Rendig and coworkers, the only other similar cases of Phalaris related nervous system disorder and/or death in North America appear to have been the nervous disorder that Rendig et al. 1976 mentioned was observed among cattle grazing on Phalaris minor in the Imperial Valley of California in the 1960s, and those sheep deaths in Florida believed to have been caused by the South African Phalaris hybrid `Ronphagrass'; Marten & Heath 1973 cited Rueike et al. 1954.
This suggests that studying Ronphagrass may further the understanding of staggers. - In animals that have been given fatal dosages of gramines or the dimethylated tryptamines, the primary observable difference between the two manners of death is that tremors do not accompany the terminal convulsions resulting from gramine and its derivatives.
- It might seem to be a hair-splitting point but death from fatal doses of dimethylated tryptamines (and gramine) is not due to cardiac arrest but rather is consistently reported in toxiciological studies to be the result of respiratory arrest (which of course is normally followed by cardiac arrest).
- This qualification is made as both Psilocin and Psilocybin are orally active. Bufotenine and 5-MeO-DMT also show some oral activity but they are dramatically less active orally than via any parenteral route except perhaps via enema. There is one more possible exception; Lespedamine (1-Methoxy-DMT); but this remains an exception only because it lacks any type of pharmacological evaluation. [See Morimoto & coworkers for the report of its isolation from the Leguminous Lespedeza bicolor var. japonica and the subsequent analysis] Many synthetic tryptamines exist which are orally active but only a few plant-origin tryptamines.
- This delayed onset at least suggests that metabolic products may be the toxic factors; possibly involving gut flora. A metabolic poisoning may also be involved. Sasha Shulgin's comments about the potential dangers of quaternary tryptamines (or tryptophans or any other simple quaternary amine capable of cyclization) getting trapped in nerve cells bears some serious consideration. (Conversation; Mind States, Berkeley, CA 22 November 1997.
The role of gut flora is sometimes quite important in forage toxicity for ruminants. For example, some simple indoles (like IAA and tryptophan) can be metabolized into 3-methylindole by the gut flora of cattle. 3-Methylindole is experimentally proven to be the causative agent of BPE (Bovine Pulmonary Emphysema).
BPE affects cattle and not sheep. Phalaris staggers on the other hand, generally only affects sheep and usually not cattle (but, there apparently have been exceptions in South Australia.
Lee et al. 1956 cited:
McDonald 1942 Austr. Vet. J. 18: 182;
also Lee & Kuchel 1953b J. Dep. Agric. S. Austr. 56: 493 and S
mith 1953 J. Dep. Agric. S. Austr. 56: 434 and
Symons 1953 J. Dep. Agric. S. Austr. 56: 435. in "A symposium on Phalaris tuberosa and phalaris staggers in sheep and cattle.")
A "nervous disorder" was reported in cattle grazing Phalaris minor in California's Imperial Valley during the early 1960s.
Humorously similar to Thompson's title, "Indolealkylamines of Desmanthus illinoensis and Their Growth Inhibition Activity.", which did not feature any indolealkylamines in their list of compounds evaluated for this property, Parmar & Brink's "Tryptamine Levels In Pasturage Implicated In Bovine Pulmonary Emphysema." was based on the work of Dickinson et al. 1967 and Carlson et al. 1968 and 1972 who were able to induce BPE by rumen and intravenous placement of various indole compounds, none of which were tryptamines. [Tryptophan, while structurally very similar to tryptamine, differs in its pharmacology, metabolism and recognition by the body.]
Tryptophan was only able to cause BPE if given orally to cows and did not if injected. 3-Methylindole (3-MI) was additionally shown to be the causative agent and of bovine gut bacterial metabolic origin as tryptophan showed no toxicity in either sheep or goats whereas the injection of 3-MI into in goats induced interstitial pulmonary edema and emphysema.
If ruminant gut flora metabolized tryptamines to IAA, they could potentially form 3-Methylindole from it but, to my knowledge, no one has ever determined (or studied) if pure tryptamines produce BPE.
A seemingly important (and apparently still unanswered) question was raised, by Carlson, of whether the neutral indoles known to be present in cigarette smoke are involved in the production of emphysema in humans.
3-Methylindole, indole and other neutral indoles have been reported in substantial quantities from cigarette smoke. - See Trout's Notes FS-X7 "Some Simple Tryptamines" for references on the natural and normal occurrence of dimethylated tryptamines in human bodily fluids.
For example, normal DMT levels in human plasma are 1% of that experienced by a 160 lb. individual while peaking on 51 mg given IM [i.e. 0.001 µg/ml versus 0.1 µg/ml] according to Clarke 1986. This is in an interesting account of a slightly similar but apparently even more severe neurological disorder in sheep grazing Tribulus terrestris (This poisoning has been reported only in Australia but a different sort of poisoning involving photosensitization, edema and hepatic toxicity is more widespread in animals grazing Tribulus species.)
See Festi & Samorini 1997 for more details; on the subject of Tribulus staggers they cited:
Bourke et al. (1984),
Bourke et al. (1990) and
Bourke et al. (1992).
Concerning Phalaris, Festi & Samorini 1994 also mention:
Bourke et al. (1987),
Bourke et al. (1988) and
Bourke & Carrigan (1992)
While looking forward to reading them, I presently lack these articles so can include no further details.- It should be noted that many of the symptoms of Tribulus staggers, and the eventual cause of death being starvation due to lack of mobility, are more similar to `Guajillo Wobbles' (Limberleg) than to Phalaris staggers.
This locomotor incoordination is known to occasionally occur in animals feeding exclusively on Acacia berlandieri and related species for prolonged periods (during extended droughts when they can become the predominate available vegetation).
While it serves as a nutritious and harmless browse whenever other plants are also available, losses from Guajillo wobbles can be quite high.
N-Methyl-phenethylamine was said to have been proven to be the causative agent by Camp and coworkers.
For more details, see Adams & Camp 1966, Camp & Lyman 1956, Camp & Lyman 1957, Camp & Moore 1960, Camp & Norvell 1966 and Camp et al. 1964.
Clement et al. 1998 disputed this due to a lack of oral reproducibility in well-fed animals (which is NOT a population at any level risk in the real world) and undertook a more detailed study of Acacia rigidula.
In addition to N-Methylphenethylamine, they claimed to have found many alkaloids including Nicotine, DMT, Mescaline, N-Methyl & Dimethylmescaline, accompanied by an assortment of amphetamines and isoquinolines - some of which had not been observed outside of the Cactaceae, many of which were new to the world of nature and a couple of which were new to science. Some of these were said to be only present seasonally.
There are some serious unanswered questions about this work though. Including the purported sources of reference materials and their identification criteria; especially in those two instances where it does not appear that any published synthesis exists. We hope the validity/integrity of Clement's work can someday be established but lack adequate details at the present to make any further comment. - Interestingly, this idea is far more prevalent among those who's interest in Phalaris stems from its entheogenic potential than among those in most mainstream agricultural research circles (who for the largest part can't seem to get beyond Gallagher).
- As does Lee & Kuchel's description of sheep showing such serious chronic staggers they were expected to die, but then seemingly recovered to the point where they appeared normal; said `recovery' lasting for some days or even weeks, before the symptoms once again appeared; sometimes less than before but sometimes even worse. Conversely, other animals seemed to have the course of the illness arrested so that, while they did not get any worse with time, they also showed no improvement (they gave the example of permanently flexed knees). One animal they mentioned died after showing violent symptoms, followed by its collapse, and eventually death several hours later, resulting from the stress of a dipping operation some 21 weeks after suffering from what had appeared to be a mild case of chronic staggers. (from Lee & Kuchel 1953a)
- 5-MeO-gramine was found to be almost toxic as gramine by Ho. Gramine's LD50 in mice was 44.6 mg/ kg if iv and 122 mg/ kg if ip. (Erspamer 1954 and Ho et al. 1970b respectively.) [Erspamer determined an LD50 of 62.9 mg/ kg iv for rats.] 5-MeO-gramine had an LD50 of 130 mg/ kg ip in mice.
- To be fair, the procedures used by most workers would not have detected these compounds (most would not have even recovered them during their isolation efforts.)
- All of these plants are known to contain compounds such as phenethylamines (from hordenine to octopamine), simple indoles, tryptamines, b-carbolines of varying complexity, fungal endophytes, glucosides capable of releasing HCN or other agents potentially toxic to livestock.
- By politically motivated, I am not suggesting that these scientists have had political aspirations or agendas but rather that politics has heavily influenced the picture in promoting favored viewpoints via channeling academic support and project funding to those groups which attempted to prove that the tryptamines were causative factors. If one examines the body of literature it can rapidly be seen that the people who were published were [to say it politely] heavily predominated by those who approached this as if the conclusion of tryptamines being the causative agents was already previously established or at least strongly indicated. In cases such as Oram's where his facts flew directly in the face of Gallagher's assertions, he presented his facts and spent much of the rest of the article apologetically trying to support Gallagher's claims.
The issue is not one of malicious deceit or conspiracy but perhaps one where reason was deferred to accomodate the published assertions of experts?. All that is clear at this point is that Gallagher's material has enough discrepancies to give sufficient cause for questioning the validity of those reported details which appear to clash with any and all other reported assessments.
The experiments, in general, following Gallagher, have been structured not to determine the causes of Phalaris toxicity but instead started with the assumption that the tryptamines were already proven to be the cause, or certain to be proven, and attempted to support this, despite Oram's, and, later, Rendig's, important conclusions suggesting a more complex picture. - This can be shown to be true only if a limited range of examples are included. Gramine is also negatively correlated with palatability; possibly more so than the tryptamines as at least one of the so-called palatable strains, Phalaris arundinacea P.I. 253317 Yugoslavia, has turned out to be a reliable ayahuasca analog source
[Commercially available as "Yugoslavian fresh-cut". Encountered as "Palatable clone #41-5" in the literature.]
[It should also be noted that the basic premise of this line of `study' is flawed. That increased toxicity is directly correlated with lowered palatability, (based on `cafeteria style' feeding trials) assumes that sheep are discriminating enough to choose non-toxic over toxic forage. If this was true, then it would seem that not only staggers but other grazing disorders would be far less of a problem.]
While concentrations of alkaloids can indeed be directly correlated to palatability (due to their taste); this can not be regarded as any sort of an evaluation of their relative toxicity. While the dimethylated tryptamines certainly can be considered toxic, it is only true in the same sense that adrenaline and serotonin are considered toxic. All are natural and normal components within mammalian nervous systems. See Clarke's 1986 second edition, Davis et al. 1989, Franzen & Gross 1965, Oon et al. 1977, Smythies et al. 1979, and their contained references for details. - A rather humorous twist was put on the erroneous equating of these two species by Usdin & Efron who listed 5-Methoxy-N-methyltryptamine (5-MeO-MMT) as a hallucinogen and cited Wilkinson as their lone reference.
Wilkinson determined Phalaris arundinacea to contain this compound, using plants growing wild where he worked (England) and had simply mentioned the reported occurrences of staggers for Phalaris tuberosa (P. aquatica) growing in Australia.