Endogenous Psychoactive Tryptamines Reconsidered - An Anxiolytic Role for Dimethyltryptamine (DMT)

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Endogenous psychoactivetryptamines reconsidered: an anxiolytic rolefor dimethyltryptamine

Michael S. Jacob, David E. Presti

Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200, USA

Received 15 October 2004; accepted 4 November 2004

Summary

The presence of the potent hallucinogenic psychoactive chemical

N,N

-dimethyltryptamine (DMT) in thehuman body has puzzled scientists for decades. Endogenous DMT was investigated in the 1960s and 1970s and it wasproposed that DMT was involved in psychosis and schizophrenia. This hypothesis developed from comparisons of theblood and urine of schizophrenic and control subjects. However, much of this research proved inconclusive andconventional thinking has since held that trace levels of DMT, and other endogenous psychoactive tryptamines, areinsigniﬁcant metabolic byproducts. The recent discovery of a G-protein-coupled, human trace amine receptor hastriggered a reappraisal of the role of compounds present in limited concentrations in biological systems. Interestinglyenough, DMT and other psychoactive tryptamine hallucinogens elicit a robust response at the trace amine receptor.While it is currently accepted that serotonin 5-HT

receptors play a pivotal role in the activity of hallucinogenic/psychedelic compounds, we propose that the effects induced by exogenous DMT administration, especially at lowdoses, are due in part to activity at the trace amine receptor. Furthermore, we suggest that endogenous DMT interactswith the TA receptor to produce a calm and relaxed mental state, which may suppress, rather than promote, symptomsof psychosis. This hypothesis may help explain the inconsistency in the early analysis of endogenous DMT in humans.Finally, we propose that amphetamine action at the TA receptor may contribute to the calming effects ofamphetamine and related drugs, especially at low doses.



2004 Published by Elsevier Ltd.

Introduction

Scientiﬁc knowledge pertaining to the chemical

N,N

-dimethyltryptamine (DMT) began inconspicu-ously with its synthesis by Manske[1]in 1931. Morethan two decades later, in the 1950s, DMT wasidentiﬁed as one of the active compounds in a po-tent psychoactive snuff prepared from the seedsof the Amazonian plant

Anadenanthera peregrina

[2–4]. This snuff, variously called

cohoba

and

yopo

, is used by Amazonian tribes in shamanic rit-uals.

Epena

, another intoxicating Amazonian snuffprepared from the bark resin of plants of the genus

Virola

and also used ritualistically, was shown inthe 1960s to contain DMT[2–4]. DMT has sincebeen described in hundreds of organisms: fungi,marine sponges, tunicates, frogs, legumes, andgrasses[5]. DMT is perhaps most well known forits presence in the plant

Psychotria viridis

, which

0306-9877/$ - see front matter



2004 Published by Elsevier Ltd.doi:10.1016/j.mehy.2004.11.005

Corresponding author. Tel.: +1 510 643 2111.

E-mail address:

presti@socrates.berkeley.edu(D. E. Presti).Medical Hypotheses (2004)

xxx–xxxhttp://intl.elsevierhealth.com/journals/mehy

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is used in combination with the vine

Banisteriopsiscaapi

, to prepare the hallucinogenic brew

ayahua-sca

yage´

, used by indigenous peoples in the Ama-zon basin in shamanic ceremonies[6]. The potenthallucinogenic effects of pure DMT in humans wereﬁrst reported by Szara[7]in 1956. Then, in 1965,DMT, tryptamine and 5-hydroxy-

N,N

-dimethyltryp-tamine (bufotenine) were reported as normal con-stituents of human urine and blood[8].Despite DMTs ubiquitous presence throughoutthe plant and animal kingdoms, and even in the hu-man body, it was classified as a Schedule One con-trolled substance with the implementation of theUS Controlled Substances Act in 1970. A ScheduleOne controlled substance is defined by the US gov-ernment as a substance that demonstrates a highpotential for abuse, has no accepted medical use,and lacks accepted safety for use, even under med-ical supervision. The placement of DMT and otherhallucinogenic/psychedelic compounds in ScheduleOne has significantly impeded scientific researchpertaining to these exceedingly interesting, neuro-chemically-active molecules[9,10]. DMT is essen-tially non-toxic to body organs and does not causephysiological dependence or addictive behaviors.Thus, its classification as a dangerous drug is basedprimarily on socio-political reasons rather thanclinical-scientific evidence. DMT is also interna-tionally classified as a Schedule One substance bythe 1971 United Nations Convention on Psychotro-pic Substances.Soon after the discovery of endogenous DMT inhumans, psychiatric researchers began to reportcorrelations between increased levels of DMT inhuman fluids and schizophrenia[11–15]. It wassuggested that excess DMT biosynthesis may pro-mote psychotic symptoms. This proposal (whichis sometimes known as the ‘‘transmethylationhypothesis,’’ because it involves methylatedamines) attracted interest in the 1960s and1970s. In more recent years, the transmethylationhypothesis has been eclipsed by the dopaminehypothesis of schizophrenia, wherein psychoticsymptoms are related to excessive activity in cer-tain dopaminergic circuits in the brain. Recentbiochemical and genetic characterization of anew family of receptors, the trace amine (TA)receptors, found in mammalian central andperipheral nervous tissues, has renewed interestin a potential role for trace amines in psychosis[16]. It is believed that tryptamine, a necessarymetabolic precursor to DMT, can act as a neuro-transmitter at the TA receptor[16]. As DMT alsoshows activity at the TA receptor[17], endoge-nous DMT may function as a neurotransmitter inthe TA system. Ten years ago, a series of dou-ble-blind, placebo-controlled studies of DMT inhumans included analysis of biological responses(neuroendocrine, autonomic and cardiovascular)as well as the subjective effects[18,19]. In thesestudies, administration of a non-hallucinogenicdose of DMT (0.05 mg/kg) produced a relaxedand comfortable mental state in many subjects.We propose that the main effect of endogenousDMT may resemble low-dose, non-hallucinogenicDMT administration, providing a homeostatic re-sponse to

alleviate

, rather than promote, psy-chotic symptoms.

Endogenous human DMT andschizophrenia: the early research

It was originally suggested by Osmond and Smy-thies[20]in 1952 that a disorder in metabolismmight produce a psychotomimetic substance andprompt schizophrenic symptoms. Although Osmondand Smythies proposed that the methylation ofnor-adreneline might produce such a psychotomi-metic substance, Axelrod[21]demonstrated thatmammalian tissue could produce DMT and Osmondand Smythies’ theory was later extended by Bruneand Himwich[22]to include the possibility ofmethylated tryptamines acting as an endogenoustrigger for psychoses. In a short half-page reportin

Nature

, Franzen and Gross[8]reported the pres-ence of

N,N

-dimethyltryptamine in human blood(

g/mL) and urine (

g/24 h).Subsequent research found these levels to be toohigh and that the average concentrations in normalsubjects tended to be around 5

g/mL inblood[12]and 4

g/24 h in urine[23]. (Itshould be noted that the threshold dose to producesubjective effects in humans is about 5

g/kg, which leads to peak blood concentrations of

g/mL[18,24]). After Franzen and Gross’discovery, psychiatric researchers reported in-creases in the urinary excretion of DMT in schizo-phrenic patients[12–15]. Murray et al.[11] found a statistically signiﬁcant increase in the lev-els of DMT in the urine of schizophrenics(

g/24 h), but found that not all schizo-phrenic patients excreted increased amounts ofDMT. The authors concluded that DMT did not playa causal role in schizophrenia, but could be anintermediary factor, exacerbating certain featuresof psychosis. Other research proved inconclusiveand results between studies were often contradic-tory with either no correlation between schizo-phrenia and excreted DMT, or no statisticallysigniﬁcant difference[25–27].2 Jacob and Presti

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DMT is no longer considered to be a likely causeof schizophrenia, but it is still recognized as playinga potential role in psychotic symptomatology. A re-view by Ciprian-Ollivier and Cetkovisch-Bakmas[28]summarizes this updated hypothesis. In theirreview, Ciprian-Ollivier and Cetkovisch-Bakmas re-port results from several studies they completed inthe 1980s wherein they found a signiﬁcant correla-tion between increased urinary excretion of DMTand the severity of psychotic symptoms. Theauthors readily recognize the complexity involvedin schizophrenia, suggesting a complicated interac-tion among biogenic amines, including serotonin,dopamine, and the

-methylated tryptamines. Itis interesting to note that researchers in Finland re-cently found higher levels of bufotenine (a psycho-active

-methyl derivative of serotonin) in theurine of psychiatric patients (up to 3

g/mL[29]).Several challenges have prevented a more pre-cise examination of the role of endogenous DMT ingeneral: (1) the key enzymes that produce meth-ylated tryptamines have not been adequatelycharacterized in vivo; (2) no neurochemical sys-tem has been linked with endogenous, psychoac-tive tryptamines at low, non-hallucinogenicconcentrations; (3) modern analytical techniqueshave not been used to examine the blood and ur-ine concentrations of DMT and its metabolites.The remainder of this paper will address these is-sues, speciﬁcally the ﬁrst two, in light of recentdiscoveries.

DMT biogenesis: new research

The biochemistry of DMT production in vitro wasstudied signiﬁcantly in the 1970s[30].Fig. 1sum- marizes the three short steps necessary for thecomplete biosynthesis of DMT from the readilyabundant amino acid, tryptophan. The decarboxyl-ation of tryptophan by aromatic amino acid decar-boxylase (AADC), produces the trace amine,tryptamine (TYP). 5-hydroxytryptohphan and

-DOPA are the most well known substrates forAADC, en route to the synthesis of serotonin (5-HT, 5-hydroxytryptamine) and dopamine, respec-tively. Nonetheless, tryptophan (as well as othertrace amine precursors such as tyrosine and phen-ylalanine) can act as a substrate for AADC, consis-tent with the observation that AADC is the rate-limiting enzyme in TYP formation[31]. The discov-ery of the trace amine (TA) family of receptors hastriggered a reconsideration of the role of AADC. Infact, the human AADC gene can undergo alterna-tive splicing, fashioning two different isoforms[32]. One isoform, AADC

480

, catalyzes the decar-boxylation of 5-hydroxytryptohphan and

-DOPA;the other, AADC

442

, was unable to decarboxylateeither. It was noted that the substrate for AADC

442

is unclear, but that phenylalanine, tryptophan, andtyrosine may act as substrates[32]. No further re-search has investigated the possibility of a uniqueAADC isoform speciﬁc to the trace amine pathway.The pathway shown inFig. 1concludes with twosuccessive methylation reactions. First, TYP canact as a substrate for indolethylamine-

-methyl-transferase (INMT) and is methylated to give

-methyltryptamine (NMT). Second, NMT can act asa substrate for INMT as well, thus forming DMT.Biosynthesis of DMT is dependent upon the enzy-matic efﬁciency and speciﬁcity of INMT. In prepa-rations of rabbit lung enzyme (the most widelystudied INMT), NMT shows the lowest

(com-monly interpreted as high binding afﬁnity) forINMT, followed by TYP[33,34]. 5-hydroxytrypta-mine (serotonin, 5-HT) shows a higher

in rabbitlung, suggesting a lower afﬁnity of serotonin forthe enzyme[33]. The physiological signiﬁcance ofthese values has been recently brought undercriticism.

Figure 1

Biosynthesis of DMT from the amino acid tryptophan: (1) aromatic amino acid decarboxylase (AADC)catalyzes the formation of tryptamine from tryptophan; (2) indolethylamine-

-methyltransferase (INMT) transfers amethyl group from SAM (S-adenosylmethionine) to tryptamine, yielding

-methyltryptamine (NMT). A repeat of thisreaction (2) with NMT as the substrate transfers another methyl group and yields DMT and two equivalents of SAH (S-adenosylhomocysteine).

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Tags:	summary the presence of the potent hallucinogenic psychoactive chemical n (more tags) summary the presence of the potent hallucinogenic psychoactive chemical n ndimethyltryptamine (dmt) in the human body has puzzled scientists for decades. endogenous dmt was investigated in the 1960s and 1970s and it was proposed that dmt was involved in psychosis and schizophrenia. this hypothesis developed from comparisons o much of this research proved inconclusive and conventional thinking has since held that trace levels of dmt and other endogenous psychoactive tryptamines are insignificant metabolic byproducts. the recent discovery of a gproteincoupled human trace amine receptor has triggered a reappraisal of the role of compounds present in limited concentrations in biological systems. interestingly enough dmt and other psychoactive tryptamine hallucinogens elicit a robust response at the trace amine receptor. while it is currently accepted that serotonin 5ht2a receptors play a pivotal role in the activity of hallucinogenic/ psychedelic compounds we propose that the effects induced by exogenous dmt administration especially at low doses are due in part to activity at the trace amine receptor. furthermore we suggest that endogenous dmt interacts with the ta receptor to produce a calm and relaxed mental state which may suppress rather than promote symptoms of psychosis. this hypothesis may help explain the inconsistency in the early analysis of endogenous dmt in humans. finally we propose that amphetamine action at the ta receptor may contribute to the calming effects of amphetamine and related drugs especially at low doses. (fewer)

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