N,N-dimethyltryptamine and the pineal gland: Separating fact from myth

This review (2017) critically disputes the hypothesis that DMT is secreted by the pineal gland at birth, during dreaming, and at near-death to produce out-of-body experiences, in light of evidence that naturally occurring DMT concentrations in the brain are not sufficient to produce any psychoactive effects. More sound explanations for out-of-body experiences include the stress-related release of kappa-opioid receptor affine endorphins (similar to Salvinorin A) or excessive release of glutamate (similar to ketamine).

Abstract

“The pineal gland has a romantic history, from pharaonic Egypt, where it was equated with the eye of Horus, through various religious traditions, where it was considered the seat of the soul, the third eye, etc. Recent incarnations of these notions have suggested that N,N-dimethyltryptamine is secreted by the pineal gland at birth, during dreaming, and at near death to produce out of body experiences. Scientific evidence, however, is not consistent with these ideas. The adult pineal gland weighs less than 0.2 g, and its principal function is to produce about 30 µg per day of melatonin, a hormone that regulates circadian rhythm through very high affinity interactions with melatonin receptors. It is clear that very minute concentrations of N,N-dimethyltryptamine have been detected in the brain, but they are not sufficient to produce psychoactive effects. Alternative explanations are presented to explain how stress and near death can produce altered states of consciousness without invoking the intermediacy of N,N-dimethyltryptamine.”

Author: David E. Nichols

notes

A presentation about this was also given by David Nichols at Breaking Convention.

Summary

Introduction

In the past 20 years there has been a surge of interest in the pineal gland’s ability to produce N,N-dimethyltryptamine (DMT), which is a potent psychedelic when significant dosages are exogenously administered.

Historical background

This review will focus on whether or not DMT is produced in the human body, and whether those amounts are sufficient to affect human physiology.

The pineal gland has a long and mythical history, and has been used by writers, screenwriters and musicians to advance narratives vested in diverse metaphysical perspectives on the human condition.

Strassman has proposed that the pineal gland excretes large quantities of DMT during stressful life episodes, notably birth and death, and that this DMT may affect our lingering consciousness.

One would expect that the loss of the pineal gland would have profound implications for mammalian physiology, but pinealectomized rats do not differ from sham-operated rats in total sleep, rapid eye movement (REM) sleep, super-modal high-amplitude non-REM (NREM) sleep, or circadian rhythm amplitude.

The pineal gland was equated with the eye of Horus in pharaonic Egypt and was considered the seat of the soul in various religious traditions. Scientific evidence, however, is not consistent with these ideas.

The pineal gland is a small neuroendocrine organ that secretes melatonin at night. Melatonin has a high affinity for the human melatonin 2 (MT2) receptor expressed in human embryonic kidney (HEK) cells.

Indolethylamine-N-methyltransferase (INMT)

The key enzyme necessary for the biosynthesis of DMT, INMT, is present throughout the body and has high expression in the lungs. It can also N-methylate other phenethylamine derivatives such as phenethylamine, tyramine, mescaline, and dopamine.

INMT is widely distributed in mammalian tissues, but is not detected in the adult brain. However, INMT is detected in the rhesus macaque spinal cord, pineal gland, and retina using rabbit polyclonal antibodies to human INMT protein.

Barker et al. (2013) used liquid chromatography-tandem mass spectrometry to determine whether DMT was synthesized in the rat pineal gland.

Although INMT was originally discovered to generate methylated metabolites of tryptamine and 5-HT, experimental observations indicate that INMT is less likely to be an important endogenous substrate for the enzyme.

How much DMT would be required for psychoactive effects?

The best data come from the 1994 study by Strassman and Qualls (1994). The breakthrough into the “DMT space” occurs at 60 ng/mL, or 318 nM of DMT base.

We developed an infusion protocol that maintains an effect site concentration of 100 ng/mL in a 75 kg subject.

These data indicate that a pineal gland producing DMT for an out of body experience would need to produce 25 mg of DMT very rapidly, and that human serum contains sufficient L-tryptophan precursor to produce a relevant amount of DMT.

Can DMT be concentrated in the brain?

The rational scientist will recognize that it is impossible for the pineal gland to accomplish such a heroic biochemical feat. Some have suggested that DMT can be concentrated or accumulated in the brain.

Some reports have suggested that DMT may be actively taken up by the brain, but despite this speculation, DMT disappeared from the brain, liver and plasma within 30 min.

Takahashi et al. (1985) measured the brain/plasma ratio of [11C]DMT after intravenous injection into rats, but did not pretreat their animals with a MAO inhibitor and did not actually analyze tissue for unmetabolized DMT.

Yanai et al. (1986: 144) examined the subcellular distribution of [11C]DMT in male Wistar rats, and found that it was transported readily through the blood-brain barrier.

The brain/plasma ratio is not a specific proof of active transport into the brain, for example, the antihistamine diphenhydramine (Benadryl) is actively taken up into the brain.

A report by Vitale et al. (2011) has been cited as support for the active transport of DMT into the brain, but their conclusions are fatally flawed because they used 2-iodo-DMT rather than DMT itself and failed to identify any metabolites.

Cozzi et al. (2009) proposed that DMT could reach high levels in neurons through a process involving uptake across the plasma membrane, followed by accumulation into synaptic vesicles. They also reported that DMT inhibits 5-HT transport at the SERT in human platelets.

The study by Yanai et al. (1986) did not show that [11C]DMT accumulates in neuronal endings, but it is not clear if vMAT expressed in insect SF9 cells will recapitulate the exact functional properties of the mammalian vMAT within neuronal endings.

SERT substrates such as MDMA reverse the transport direction of SERT, releasing 5-HT from the neuron. This process is termed calcium-independent, carrier-mediated efflux or release.

The SERT (and other monoamine carriers) can be induced to operate in the reverse direction by SERT substrates, including 5-HT, tyramine, and amphetamine derivatives such as para-chloroamphetamine (pCA) and MDMA.

DMT was not found to release neuronal 5-HT, but 5-MeODMT inhibited the uptake of [14C]5-HT in rat striatal and hypothalamic synaptosomal preparations.

Blough et al. (2014) found that DMT was a SERT-selective releaser, but the more likely outcome is that DMT will induce the release of neuronal 5-HT, in a mechanism similar to that of amphetamines such as MDMA.

A key experiment that would resolve this issue definitively involves incubating radiolabeled DMT with synaptosomes from rats treated with a MAO inhibitor.

DMT and the sigma-1 receptor (S1R)

Although the KD for DMT at the S1R was reported to be 14.75 mM, the highest concentrations obtained by intravenous administration in the Strassman and Qualls (1994) study are approximately 30-fold higher than the KD for endogenous DMT at the S1R.

INMT is localized to postsynaptic sites of C-terminals in close proximity to S1Rs in motoneurons. This association may suggest that DMT is synthesized locally to activate S1Rs.

Fontanilla et al. (2009) indicate that DMT injection induces hypermotility in rodents concurrently treated with the MAO inhibitor pargyline, and that this hypermotility is not antagonized by blockers of dopamine or 5-HT receptors.

Endogenous opioid peptides, such as dynorphin, may play a role in regulating stress responsiveness, motivation, and emotion. Dynorphin is an extremely potent agonist at the kappa-opioid receptor, and salvinorin A is a selective and potent agonist at the KOR.

Jimo Borjigin’s laboratory has published some remarkable results relevant to cardiac arrest. They found that the mammalian brain becomes transiently and highly synchronized at near-death, suggesting that the mammalian brain has the potential for high levels of internal information processing during clinical death.

Asphyxia generates a brainstorm, a surge of core neurotransmitters within the cortex, and this surge lasts for 20 min.

Norepinephrine activates adrenergic receptors on cortical pyramidal cells, the same anatomic location as 5-HT2A receptors.

Asphyxia increases 5-HT and dopamine levels, which are important for arousal, attention, cognition, and affective emotion. Glutamate levels also increase, which can lead to out of body and hallucinogenic experiences.

Conclusion

DMT is not produced at concentrations significant to activate CNS 5-HT2A receptors, and is rapidly broken down by MAO if it is produced. Endorphins, especially DYN, are released during stress, and can mediate hallucinations and out of body experiences.