red22
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The biosynthesis of DMT is not limited to plants. In fact, it has been found to be endogenously produced in a number of animals, including rabbits,136 rats,137,138 and humans.139 A recent review analyzed 69 published studies from 1955−2010 that attempted to measure putative endogenous psychedelics such as DMT, 5-OH-DMT (i.e., bufotenin), and 5-MeO-DMT in human body fluids (e.g., urine, blood, and cerebral spinal fluid).131 The authors conclude that there is overwhelming evidence that humans produce DMT and 5-OH-DMT, but that data regarding 5-MeO-DMT is less conclusive. Many early studies measuring DMT levels in animals have been criticized for their lack of specificity; however, these early results have been confirmed recently using highly sensitive and specific modern analytical methods such as liquid chromatography tandem mass spectrometry (LC−MS/MS).138 Furthermore, specific diets, antibiotics, and other medications do not seem to influence DMT levels in humans,131 making it likely that DMT is produced endogenously rather than originating from the ingestion of plant material, the production by gut microbiota, or the metabolism of pharmaceutical agents. Now that the presence of DMT in humans has been firmly established, further research needs to be done to determine if endogenously produced DMT can influence brain function or is simply an insignificant metabolic product of tryptophan metabolism.
The enzyme indolethylamine N-methyltransferase (INMT) catalyzes the methylation of a variety of biogenic amines, and is responsible for converting tryptamine into DMT in mammals.140 Homologous proteins to human INMT have been found in several animals141,142 with the human and rabbit forms being 88% identical.140 Human INMT is expressed in most tissues including the brain with the lungs exhibiting the highest levels of expression.140,143 Interestingly, the ex vivo activity of INMT varies as a function of age with INMT preparations from the perinatal period exhibiting the greatest activity.26 This difference in activity does not seem to be a result of changes in enzyme expression as a function of age, but rather from changes in the levels of an unidentified endogenous, dialyzable, peptidic inhibitor of INMT that represses native activity of the enzyme.144,145 In principle, rapid degradation of this inhibitor could allow for precise temporal control of DMT biosynthesis.
Our current understanding of the function (or lack thereof) of endogenous DMT is severely limited by our lack of knowledge regarding exactly when and where this molecule is produced in the body.131 To date, most studies have attempted to measure DMT levels in body fluids (e.g., blood and urine); however, measuring local changes in metabolism within specific regions of the body is likely to yield more useful information due to the rapid metabolism of DMT as well as the fact that INMT activity varies as a function of tissue type (e.g, it is highest in the lungs). Microdialysis experiments are useful in this regard, and one such study recently detected DMT in the pineal gland of rats.138 Several authors have hypothesized that DMT secreted from the pineal gland might give rise to dreams, mystical states, and various sensations associated with near-death experiences.6,146 However, others have argued that the small size of the pineal gland make it unlikely to be able to produce the quantity of DMT estimated to be necessary to produce a mystical experience (ca. 25 mg of DMT within a few minutes for a 75 kg individual).147 As DMT rapidly crosses the blood−brain barrier after entering the bloodstream (vide supra), a large, highly vascularized peripheral organ expressing high levels of INMT, such as the lungs, seems a more likely source of DMT than either the brain or pineal gland. Though challenging, lung microdialysis studies148 would shed light on this issue.
While very little is known about the synthesis and biodistribution of endogenous DMT, it is clear that under normal physiological conditions, DMT is produced in exceedingly small quantities, causing it to be labeled a trace amine. The single most important question for the field to answer is whether or not endogenous DMT is produced in sufficient quantities to have meaningful biological effects. As DMT is an inhibitor of INMT,143,149 it is likely that such product inhibition of the enzyme limits the amount of DMT that can be synthesized rapidly, making it unlikely that the concentration of endogenous DMT could exceed the threshold for inducing hallucinogenic effects or mystical experiences, except for maybe under extreme conditions. However, endogenous DMT does not need to reach high concentrations to exert significant effects on mammalian physiology. Ly and coworkers demonstrated that a subhallucinogenic dose of DMT in rodents (based on allometric scaling of a hallucinogenic human dose)150 can produce long-lasting changes in neural plasticity.46
Currently, we do not know how DMT concentrations change as a function of age, sex, or behavioral state. There is preliminary evidence from the 1970s suggesting that endogenous DMT production in rats increases following stress, specifically after experiencing electric shocks.133 Both our lab and others have demonstrated that high acute doses of DMT result in anxiogenic effects such as increased immediate freezing following foot shocks, decreased exploratory activity in the open field, and less time spent in the open arms of an elevated plus maze.52,98,151,152 However, we have also shown that DMT promotes structural and functional plasticity in the prefrontal cortex46 and facilitates fear extinction learning.52 It is possible that in rodents, endogenous DMT produced during stress serves an adaptive or protective role by (1) potentiating initial fear responses (e.g., increased freezing and reduced time spent in open spaces) and/or (2) promoting structural plasticity in the prefrontal cortex, thus facilitating fear extinction learning and preventing the formation of pathological fear memories. If true, this would have important implications for understanding the pathophysiology of post-traumatic stress disorder. However, it is also possible that stress does not increase endogenous DMT concentrations to levels sufficient for causing changes in behavior or plasticity.
As a final thought, endogenous DMT might play a greater role in neurodevelopment than in adult physiology. First, INMT activity is highest during development.26 Second, Ly and coworkers have demonstrated that DMT is a potent psychoplastogen capable of inducing the growth of dendrites and dendritic spines while also promoting synaptogenesis.46 Moreover, DMT likely mediates its effects on neural plasticity via an evolutionarily conserved mechanism, as psychedelics are capable of promoting neurite outgrowth in both Drosophila and rodent neurons.46 At this point, any potential role for endogenous DMT in normal mammalian physiology should be considered highly speculative at best, and new research in this area is necessary to close this knowledge gap.
Dark Classics in Chemical Neuroscience: N,N-Dimethyltryptamine (DMT). Lindsay P. Cameron, David E. Olson. Jul 23, 2018. ACS Chemical Neuroscience, 9, 10, 2344–2357. DOI: 10.1021/acschemneuro.8b00101 (ENDOGENOUS PRODUCTION IN ANIMALS, pages 2349–2350)
(6) Strassman, R. (2001) DMT: The Spirit Molecule: A Doctor’s Revolutionary Research into the Biology of Near-Death and Mystical Experiences, Park Street Press, Rochester.
(26) Lin, R.-L., Sargeant, S., and Narasimhachari, N. (1974) Indolethylamine-N-methyltransferase in developing rabbit lung. Dev. Psychobiol. 7, 475−481.
(46) Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., Burbach, K. F., Soltanzadeh Zarandi, S., Sood, A., Paddy, M. R., Duim, W. C., Dennis, M. Y., McAllister, A. K., Ori-McKenney, K. M., Gray, J. A., and Olson, D. E. (2018) Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 23, 3170−3182.
(52) Cameron, L. P., Benson, C. J., Dunlap, L. E., and Olson, D. E. (2018) Effects of N,N-dimethyltryptamine on rat behaviors relevant to anxiety and depression. ACS Chem. Neurosci. 9, 1582−1590.
(98) Geyer, M. A., Light, R. K., Rose, G. J., Petersen, L. R., Horwitt, D. D., Adams, L. M., and Hawkins, R. L. (1979) A characteristic effect of hallucinogens on investigatory responding in rats. Psychopharmacology (Berl). 65, 35−40.
(131) Barker, S. A., McIlhenny, E. H., and Strassman, R. (2012) A critical review of reports of endogenous psychedelic N,N-dimethyltryptamines in humans: 1955−2010. Drug Test. Anal. 4, 617−635.
(133) Christian, S. T., Harrison, R., Quayle, E., Pagel, J., and Monti, J. (1977) The in vitro identification of dimethyltryptamine (DMT) in mammalian brain and its characterization as a possible endogenous neuroregulatory agent. Biochem. Med. 18, 164−183.
(136) Mandel, L. R., Prasad, R., Lopez-Ramos, B., and Walker, R. W. (1977) The biosynthesis of dimethyltryptamine in vivo. Res. Commun. Chem. Pathol. Pharmacol. 16, 47−58.
(137) Saavedra, J. M., and Axelrod, J. (1972) Psychotomimetic N- methylated tryptamines: formation in brain in vivo and in vitro. Science 175, 1365−1366.
(138) Barker, S. A., Borjigin, J., Lomnicka, I., and Strassman, R. (2013) LC/MS/MS analysis of the endogenous dimethyltryptamine hallucinogens, their precursors, and major metabolites in rat pineal gland microdialysate. Biomed. Chromatogr. 27, 1690−1700.
(139) Karkkainen, J., Forsstrom, T., Tornaeus, J., Wahala, K., Kiuru, P., Honkanen, A., Stenman, U. H., Turpeinen, U., and Hesso, A. (2005) Potentially hallucinogenic 5-hydroxytryptamine receptor ligands bufotenine and dimethyltryptamine in blood and tissues. Scand. J. Clin. Lab. Invest. 65, 189−199.
(140) Thompson, M. A., Moon, E., Kim, U. J., Xu, J., Siciliano, M. J., and Weinshilboum, R. M. (1999) Human indolethylamine N-methyltransferase: cDNA cloning and expression, gene cloning, and chromosomal localization. Genomics 61, 285−297.
(141) Morgan, M., and Mandell, A. J. (1969) Indole(ethyl)amine N-methyltransferase in the brain. Science 165, 492−493.
(142) Mandell, A. J., and Morgan, M. (1971) Indole(ethyl)amine N-Methyltransferase in Human Brain. Nat. New Biol. 230, 85.
(143) Thompson, M. A., and Weinshilboum, R. M. (1998) Rabbit lung indolethylamine N-methyltransferase. cDNA and gene cloning and characterization. J. Biol. Chem. 273, 34502−34510.
(144) Marzullo, G., Rosengarten, H., and Friedhoff, A. J. (1977) A peptide-like inhibitor of N-methyltransferase in rabbit brain. Life Sci. 20, 775−783.
(145) Wyatt, R. J., Saavedra, J. M., and Axelrod, J. (1973) A dimethyltryptamine-forming enzyme in human blood. Am. J. Psychiatry 130, 754−760.
(146) Callaway, J. C. (1988) A proposed mechanism for the visions of dream sleep. Med. Hypotheses 26, 119−124.
(147) Nichols, D. E. (2018) N,N-dimethyltryptamine and the pineal gland: Separating fact from myth. J. Psychopharmacol. 32, 30−36.
(148) Zeitlinger, M., Muller, M., and Joukhadar, C. (2005) Lung microdialysis–a powerful tool for the determination of exogenous and endogenous compounds in the lower respiratory tract (mini-review). AAPS J. 7, E600−8.
(149) Chu, U. B., Vorperian, S. K., Satyshur, K., Eickstaedt, K., Cozzi, N. V., Mavlyutov, T., Hajipour, A. R., and Ruoho, A. E. (2014) Noncompetitive Inhibition of Indolethylamine-N-methyltransferase by N,N-Dimethyltryptamine and N,N-Dimethylaminopropyltryptamine. Biochemistry 53, 2956−2965.
(150) Nair, A. B., and Jacob, S. (2016) A simple practice guide for dose conversion between animals and human. J. basic Clin. Pharm. 7, 27−31.
(151) Adams, L., and Geyer, M. (1982) LSD-induced alterations of locomotor patterns and exploration in rats. Psychopharmacology (Berl). 77, 179−185.
(152) Wing, L., Tapson, G., and Geyer, M. (1990) 5HT-2 mediation of acute behavioral effects of hallucinogens in rats. Psychopharmacology (Berl). 100, 417−25.
The DMT Debate w/ Dr. Jon Dean (dmtquest.org YouTube channel)
The DMT Debate #2 w/ Dr. Steven Barker (dmtquest.org YouTube channel)
The enzyme indolethylamine N-methyltransferase (INMT) catalyzes the methylation of a variety of biogenic amines, and is responsible for converting tryptamine into DMT in mammals.140 Homologous proteins to human INMT have been found in several animals141,142 with the human and rabbit forms being 88% identical.140 Human INMT is expressed in most tissues including the brain with the lungs exhibiting the highest levels of expression.140,143 Interestingly, the ex vivo activity of INMT varies as a function of age with INMT preparations from the perinatal period exhibiting the greatest activity.26 This difference in activity does not seem to be a result of changes in enzyme expression as a function of age, but rather from changes in the levels of an unidentified endogenous, dialyzable, peptidic inhibitor of INMT that represses native activity of the enzyme.144,145 In principle, rapid degradation of this inhibitor could allow for precise temporal control of DMT biosynthesis.
Our current understanding of the function (or lack thereof) of endogenous DMT is severely limited by our lack of knowledge regarding exactly when and where this molecule is produced in the body.131 To date, most studies have attempted to measure DMT levels in body fluids (e.g., blood and urine); however, measuring local changes in metabolism within specific regions of the body is likely to yield more useful information due to the rapid metabolism of DMT as well as the fact that INMT activity varies as a function of tissue type (e.g, it is highest in the lungs). Microdialysis experiments are useful in this regard, and one such study recently detected DMT in the pineal gland of rats.138 Several authors have hypothesized that DMT secreted from the pineal gland might give rise to dreams, mystical states, and various sensations associated with near-death experiences.6,146 However, others have argued that the small size of the pineal gland make it unlikely to be able to produce the quantity of DMT estimated to be necessary to produce a mystical experience (ca. 25 mg of DMT within a few minutes for a 75 kg individual).147 As DMT rapidly crosses the blood−brain barrier after entering the bloodstream (vide supra), a large, highly vascularized peripheral organ expressing high levels of INMT, such as the lungs, seems a more likely source of DMT than either the brain or pineal gland. Though challenging, lung microdialysis studies148 would shed light on this issue.
While very little is known about the synthesis and biodistribution of endogenous DMT, it is clear that under normal physiological conditions, DMT is produced in exceedingly small quantities, causing it to be labeled a trace amine. The single most important question for the field to answer is whether or not endogenous DMT is produced in sufficient quantities to have meaningful biological effects. As DMT is an inhibitor of INMT,143,149 it is likely that such product inhibition of the enzyme limits the amount of DMT that can be synthesized rapidly, making it unlikely that the concentration of endogenous DMT could exceed the threshold for inducing hallucinogenic effects or mystical experiences, except for maybe under extreme conditions. However, endogenous DMT does not need to reach high concentrations to exert significant effects on mammalian physiology. Ly and coworkers demonstrated that a subhallucinogenic dose of DMT in rodents (based on allometric scaling of a hallucinogenic human dose)150 can produce long-lasting changes in neural plasticity.46
Currently, we do not know how DMT concentrations change as a function of age, sex, or behavioral state. There is preliminary evidence from the 1970s suggesting that endogenous DMT production in rats increases following stress, specifically after experiencing electric shocks.133 Both our lab and others have demonstrated that high acute doses of DMT result in anxiogenic effects such as increased immediate freezing following foot shocks, decreased exploratory activity in the open field, and less time spent in the open arms of an elevated plus maze.52,98,151,152 However, we have also shown that DMT promotes structural and functional plasticity in the prefrontal cortex46 and facilitates fear extinction learning.52 It is possible that in rodents, endogenous DMT produced during stress serves an adaptive or protective role by (1) potentiating initial fear responses (e.g., increased freezing and reduced time spent in open spaces) and/or (2) promoting structural plasticity in the prefrontal cortex, thus facilitating fear extinction learning and preventing the formation of pathological fear memories. If true, this would have important implications for understanding the pathophysiology of post-traumatic stress disorder. However, it is also possible that stress does not increase endogenous DMT concentrations to levels sufficient for causing changes in behavior or plasticity.
As a final thought, endogenous DMT might play a greater role in neurodevelopment than in adult physiology. First, INMT activity is highest during development.26 Second, Ly and coworkers have demonstrated that DMT is a potent psychoplastogen capable of inducing the growth of dendrites and dendritic spines while also promoting synaptogenesis.46 Moreover, DMT likely mediates its effects on neural plasticity via an evolutionarily conserved mechanism, as psychedelics are capable of promoting neurite outgrowth in both Drosophila and rodent neurons.46 At this point, any potential role for endogenous DMT in normal mammalian physiology should be considered highly speculative at best, and new research in this area is necessary to close this knowledge gap.
Dark Classics in Chemical Neuroscience: N,N-Dimethyltryptamine (DMT). Lindsay P. Cameron, David E. Olson. Jul 23, 2018. ACS Chemical Neuroscience, 9, 10, 2344–2357. DOI: 10.1021/acschemneuro.8b00101 (ENDOGENOUS PRODUCTION IN ANIMALS, pages 2349–2350)
Code:
https://shaunlacob.com/wp-content/uploads/2020/12/Dark-Classics-DMT.pdf(6) Strassman, R. (2001) DMT: The Spirit Molecule: A Doctor’s Revolutionary Research into the Biology of Near-Death and Mystical Experiences, Park Street Press, Rochester.
(26) Lin, R.-L., Sargeant, S., and Narasimhachari, N. (1974) Indolethylamine-N-methyltransferase in developing rabbit lung. Dev. Psychobiol. 7, 475−481.
(46) Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., Burbach, K. F., Soltanzadeh Zarandi, S., Sood, A., Paddy, M. R., Duim, W. C., Dennis, M. Y., McAllister, A. K., Ori-McKenney, K. M., Gray, J. A., and Olson, D. E. (2018) Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 23, 3170−3182.
(52) Cameron, L. P., Benson, C. J., Dunlap, L. E., and Olson, D. E. (2018) Effects of N,N-dimethyltryptamine on rat behaviors relevant to anxiety and depression. ACS Chem. Neurosci. 9, 1582−1590.
(98) Geyer, M. A., Light, R. K., Rose, G. J., Petersen, L. R., Horwitt, D. D., Adams, L. M., and Hawkins, R. L. (1979) A characteristic effect of hallucinogens on investigatory responding in rats. Psychopharmacology (Berl). 65, 35−40.
(131) Barker, S. A., McIlhenny, E. H., and Strassman, R. (2012) A critical review of reports of endogenous psychedelic N,N-dimethyltryptamines in humans: 1955−2010. Drug Test. Anal. 4, 617−635.
(133) Christian, S. T., Harrison, R., Quayle, E., Pagel, J., and Monti, J. (1977) The in vitro identification of dimethyltryptamine (DMT) in mammalian brain and its characterization as a possible endogenous neuroregulatory agent. Biochem. Med. 18, 164−183.
(136) Mandel, L. R., Prasad, R., Lopez-Ramos, B., and Walker, R. W. (1977) The biosynthesis of dimethyltryptamine in vivo. Res. Commun. Chem. Pathol. Pharmacol. 16, 47−58.
(137) Saavedra, J. M., and Axelrod, J. (1972) Psychotomimetic N- methylated tryptamines: formation in brain in vivo and in vitro. Science 175, 1365−1366.
(138) Barker, S. A., Borjigin, J., Lomnicka, I., and Strassman, R. (2013) LC/MS/MS analysis of the endogenous dimethyltryptamine hallucinogens, their precursors, and major metabolites in rat pineal gland microdialysate. Biomed. Chromatogr. 27, 1690−1700.
(139) Karkkainen, J., Forsstrom, T., Tornaeus, J., Wahala, K., Kiuru, P., Honkanen, A., Stenman, U. H., Turpeinen, U., and Hesso, A. (2005) Potentially hallucinogenic 5-hydroxytryptamine receptor ligands bufotenine and dimethyltryptamine in blood and tissues. Scand. J. Clin. Lab. Invest. 65, 189−199.
(140) Thompson, M. A., Moon, E., Kim, U. J., Xu, J., Siciliano, M. J., and Weinshilboum, R. M. (1999) Human indolethylamine N-methyltransferase: cDNA cloning and expression, gene cloning, and chromosomal localization. Genomics 61, 285−297.
(141) Morgan, M., and Mandell, A. J. (1969) Indole(ethyl)amine N-methyltransferase in the brain. Science 165, 492−493.
(142) Mandell, A. J., and Morgan, M. (1971) Indole(ethyl)amine N-Methyltransferase in Human Brain. Nat. New Biol. 230, 85.
(143) Thompson, M. A., and Weinshilboum, R. M. (1998) Rabbit lung indolethylamine N-methyltransferase. cDNA and gene cloning and characterization. J. Biol. Chem. 273, 34502−34510.
(144) Marzullo, G., Rosengarten, H., and Friedhoff, A. J. (1977) A peptide-like inhibitor of N-methyltransferase in rabbit brain. Life Sci. 20, 775−783.
(145) Wyatt, R. J., Saavedra, J. M., and Axelrod, J. (1973) A dimethyltryptamine-forming enzyme in human blood. Am. J. Psychiatry 130, 754−760.
(146) Callaway, J. C. (1988) A proposed mechanism for the visions of dream sleep. Med. Hypotheses 26, 119−124.
(147) Nichols, D. E. (2018) N,N-dimethyltryptamine and the pineal gland: Separating fact from myth. J. Psychopharmacol. 32, 30−36.
(148) Zeitlinger, M., Muller, M., and Joukhadar, C. (2005) Lung microdialysis–a powerful tool for the determination of exogenous and endogenous compounds in the lower respiratory tract (mini-review). AAPS J. 7, E600−8.
(149) Chu, U. B., Vorperian, S. K., Satyshur, K., Eickstaedt, K., Cozzi, N. V., Mavlyutov, T., Hajipour, A. R., and Ruoho, A. E. (2014) Noncompetitive Inhibition of Indolethylamine-N-methyltransferase by N,N-Dimethyltryptamine and N,N-Dimethylaminopropyltryptamine. Biochemistry 53, 2956−2965.
(150) Nair, A. B., and Jacob, S. (2016) A simple practice guide for dose conversion between animals and human. J. basic Clin. Pharm. 7, 27−31.
(151) Adams, L., and Geyer, M. (1982) LSD-induced alterations of locomotor patterns and exploration in rats. Psychopharmacology (Berl). 77, 179−185.
(152) Wing, L., Tapson, G., and Geyer, M. (1990) 5HT-2 mediation of acute behavioral effects of hallucinogens in rats. Psychopharmacology (Berl). 100, 417−25.
The DMT Debate w/ Dr. Jon Dean (dmtquest.org YouTube channel)
The DMT Debate #2 w/ Dr. Steven Barker (dmtquest.org YouTube channel)
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