Science of the Pineal Gland

The pinecone-shaped pineal gland has been a subject of mystique for millennia. It has been associated with the eye of Horus in Egyptian pharaonic culture, the third eye chakra in Hindu tradition, and the "seat of the soul" in Descartes' philosophy. In spirituality, the pineal gland is often described as the connection to a higher truth, intuition, or source. Descartes believed the pineal gland is where thoughts are formed, bridging matter and energy into awareness. The role of the pineal gland was long considered a mystery, but recent scientific discoveries are advancing our understanding of this fascinating organ.


In this article, we discuss:

  • Origins and functions of the pineal gland

  • The role of melatonin and DMT

  • Circadian rhythm and sleep

  • Reproductive roles of the pineal gland

Which neurotransmitters are found in the pineal gland?

This tiny, 150-mg gland packs a lot of neurotransmitters, which have been found to accumulate and play important roles in the pineal gland:

  • Melatonin

  • Norepinephrine (NE)

  • Serotonin

  • GnRH (gonadotropin releasing hormone)

  • TRH (thyrotropin releasing hormone)

  • GABA (gamma aminobutyric acid)

  • Vasopressin

  • Oxytocin

  • VIP (vasoactive intestinal peptide)

  • NPY (neuropeptide Y)

  • Calcitonin gene-related peptide

  • Substance P

  • DMT (dimethyl tryptamine)

The pineal gland synthesizes and secretes a number of important products, the best known of which is melatonin. Melatonin was first discovered and isolated from the pineal gland in 1958[1]. Recently, the proteome of the pineal gland was characterized for the first time, leading to the identification of 5,820 proteins, of which 1,136 may have secretory roles[2].


Does the pineal gland produce DMT?

DMT, famously called the "spirit molecule" by Dr. Rick Strassman, is the only known endogenous psychedelic. It is thought to be released during birth, death, dreaming, out-of-body experiences, and hallucination[3]. People with near-death experiences (NDEs) report very similar experiences to people who take DMT, such as bright light, out-of-body experiences, feelings of security and warmth, and encounters with sentient beings[4].


In a landmark 2019 Nature study, using in situ hybridization, it was found that cells in the visual cortex, hippocampus, pineal gland, and choroid plexus express both enzymes (AADC and INMT) necessary to produce DMT. INMT mRNA was abundantly expressed in the pineal gland in both rats and humans. INMT is widely distributed in mammalian tissues, including the lungs, adrenal gland, thyroid, placenta, heart, pancreas, lymph nodes, retina, pineal gland, and spinal cord ventral horn motor neurons. The high expression of INMT in the lungs relative to the pineal gland suggests the power of breathwork in altering consciousness.

Using microdialysis, Dean et al. detected DMT at levels comparable to other monoamine neurotransmitters. DMT basal concentrations averaged 1.02 nM, compared to serotonin which averaged about 2 nM. This is compared to literature values for brain concentrations of serotonin (0.87 nM), norepinephrine (1.77 nM), and dopamine (1.5 nM). This study was the first time DMT was found in the brains of freely moving and normal behaving animals.


DMT concentrations increased to a greater extent in pineal-intact than pinealectomized rats following cardiac arrest. However, the pineal gland contributed relatively little to total DMT production. The researchers offered the following explanation: the enzymes of the tryptophan to serotonin/melatonin pathway compete with the enzymes of the tryptophan to DMT pathway. TPH (tryptophan hydroxylase) has a higher affinity than AADC for tryptophan[5].

The physiological functions of DMT are still unknown. Future studies should address whether DMT knockout animals exhibit detectable deficits. It is also unknown whether the DMT secreted after cardiac arrest produces psychedelic effects, and whether this occurs in humans as well. The pineal gland produces about 30 μg of melatonin a day; it would need to produce 25 mg of DMT to trigger a psychedelic experience[3].


How did the pineal gland evolve?

Melatonin is an ancient molecule that is found even in photosynthetically active cyanobacteria, where serves as a free radical scavenger and antioxidant[6]. In humans, melatonin is produced within the numerous pinealocyte mitochondria, which greatly outnumber neuronal mitochondria[7].


The pineal organ in lower vertebrates is a photosensor. In these non-mammals, the pinealocytes are very similar to retinal photoreceptors, hence the association with the "third eye." Mammalian pinealocytes have lost direct light sensitivity. Over mammalian cortical evolution, as our brains became more layered and folded, the pineal gland was buried within, now located nearly at the center of the brain.


Interestingly, vertebrate pineal glands are associated with environment/geographical location: the colder it is and the closer to poles, the larger the gland. South pole seal pineal glands occupy 1/3 of their entire brains, making the organ 27x larger by weight than in humans. Of note, the Earth's magnetic fields are also strongest at the poles[7].

In all mammals, melatonin is released at night, causing sleepiness in diurnal animals. Melatonin usually peaks between 12am and 4am, in the absence of light.

What's the pineal gland's purpose?

The mammalian pineal gland functions to modulate sleep, mood, food intake, breeding and sexual maturation in the context of diurnal and seasonal rhythms[6]. Melatonin is also a potent mitochondrial, liver-protecting antioxidant.


The circadian clock has been described as a tumor suppressor[8]. Circadian disruption can lead to breast cancer, heart disease, obesity, and cognitive impairments. Indeed, smaller pineal glands are seen in obese and insomnia patients. Pineal melatonin also has antioxidative, anti-inflammatory, and anti-apoptotic effects in the CSF[7]. Melatonin scavenges free radicals, inhibits aromatase, is anti-estrogenic, inhibits telomerase, helps DNA repair, supports the immune system, and regulates linolenic acid metabolism; all of these properties support its oncostatic activity[9].


Melatonin was also shown to protect against liver damage caused by cadmium, one of the most toxic metals known to man. Cadmium is most commonly found in atmospheric contamination due to the mining industry and cigarette smoke. Cadmium induces cell death due to superoxide anion (.O2-) production in the mitochondria. Cadmium also induces epigenetic modifications such as acetylation, resulting in downregulated expression of SIRT3 (a longevity protein) and SOD2 (an antioxidant enzyme). Melatonin enhanced activity of SIRT3, decreased acetylation of SOD2, inhibited mitochondrial .O2- production, restored mitochondrial homeostasis, and promoted cell survival[10].


Dietary tryptophan passes the BBB and reaches the pinealocytes. Tryptophan is converted to serotonin in a bright environment; at night, serotonin is converted to melatonin[11]. Foods high in tryptophan include broccoli, oats, mozzarella cheese, cauliflower, lobster, eggs, beef, salmon, crab, cabbage, and beans. Foods that contain melatonin include corn, eggs, salmon, rice, cranberries, peppers, tomatoes, mushrooms (esp. porcini), lentils, pistachios, whole grains, rolled oats, strawberries, cherries, grapes, beans, wine, and St. John’s wort[12].

Circadian secretion of melatonin

Sleep and the unconscious

Sleep, a process of turning inward, allows the body to repair, clear debris, reinforce connections, and surface the unconscious mind through dreams.


Pineal gland melatonin plays a critical role in circadian rhythm, as it is a chemical signal of darkness. Interestingly though, the pineal gland does not synchronize sleep—it relies on the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. Pinealectomy in humans and animals does not abolish rhythms of rest and activity; however, it does accelerate aging and neurodegeneration in animals[7]. The SCN is the primary circadian pacemaker of the sleep/wake cycle and generates the melatonin rhythm.

Interestingly, though, melatonin is inversely associated with REM sleep; it inhibits memory formation by directly acting on hippocampal neurons[13].

Basic circuitry of circadian rhythm

Melanopsin is a blue-light-sensitive photopigment, and it is expressed in a subset of retinal ganglion cells that project to the SCN via the hypothalamic tract[14]. Melanopsin is fundamental for circadian rhythm function and SCN entrainment.


During the daytime, light entering the eyes stimulates photoreceptors in rods, cones, and melanopsin-expressing retina ganglion cells. The melanopsin-containing retinal ganglion cells (RGCs) in the eye convert light signals to electrical signals and activate the master clock, the SCN, which projects to the brain and spinal cord. The SCN releases GABA to the paraventricular nuclei (PVN). GABA is an inhibitory neurotransmitter, so it inhibits the PVN's release of glutamate onto the intromediolateral nucleus (IML) of the spinal cord. This has the effect of inhibiting the sympathetic superior cervical ganglion (SCG) from releasing norepinephrine (NE), which subsequently inhibits the pineal gland. NE and melatonin release are potently inhibited by light.


At night, the RGCs in the eye signal the SCN to release glutamate (instead of GABA) to the PVN, which ultimately excites the PVN, activating the SCG to release norepinephrine, inducing melatonin synthesis in the pineal gland[15].


Melatonin is lipophilic and can readily pass the cell membrane and may interact directly with intracellular proteins. Pineal melatonin travels via the third ventricle of the cerebrospinal fluid (CSF) and binds to melatonin receptors on the pars tuberalis of the pituitary, playing an essential role in the reproductive rhythm of seasonal animals, and the SCN of the hypothalamus, influencing clock mechanisms. The pineal is also innervated by the parasympathetic system[15].


Gene expression fluctuates daily, exceeding a 24-hour period. Desynchronization can be caused by shift-work, jet-lag, aging, or blindness[14]. Completely blind people have longer than 24-hour cycles, without feedback from light to synchronize the SCN. Melatonin supplementation restored their rhythms to 24 hours[7].


What are clock genes?

Clock genes are ensembles of genes whose cyclic expression and repression give rise to sleep/wake phenotypes. These genes are primarily expressed in hypothalamus but also in the liver, heart, stomach, and gut[8]. Clock genes include the period genes, Per1 and Per2, the cryptochrome genes Cry1 and Cry2, and Clock.


Clock genes are part of a transcriptional-translational feedback loop that cycles about every 24 hours[15]. The process is regulated by proteasomes, which are enzyme complexes that degrade other proteins tagged with the degradation signal. Proteasomes destroy transcription factors needed only for a particular period of time, regulating transcription of clock genes[8].


At night, melatonin inhibits the proteasome, allowing for stabilization of clock gene activators. These activators then bind to the DNA, leading to transcription and translation of clock genes into proteins[7]. These proteins then work in a negative feedback loop to inhibit their further transcription[14]. This cycle of gene expression is critical to an organism's circadian rhythm function and overall sense of well-being.


Key takeaways

  • The pineal gland modulates circadian rhythm, sleep, mood, food intake, fertility, and sexual maturation.

  • At least 13 neurotransmitters have been found in the pineal gland, including melatonin, serotonin, oxytocin, and DMT.

  • Melatonin functions as a free radical scavenger in mitochondria, lending its association to longevity.

  • The visual cortex, hippocampus, pineal gland, and choroid plexus are capable of producing DMT.


This is Part 1 of a 3 part series on the pineal gland:

  1. Overview of the Pineal Gland

  2. Development of the Pineal Gland

  3. Aging of the Pineal Gland


References


1. Shoja, M.M., et al., History of the pineal gland. Childs Nerv Syst, 2016. 32(4): p. 583-6.

2. Yelamanchi, S.D., et al., Characterization of human pineal gland proteome. Mol Biosyst, 2016. 12(12): p. 3622-3632.

3. Nichols, D.E., N,N-dimethyltryptamine and the pineal gland: Separating fact from myth. J Psychopharmacol, 2018. 32(1): p. 30-36.

4. Timmermann, C., et al., DMT Models the Near-Death Experience. Front Psychol, 2018. 9: p. 1424.

5. Dean, J.G., et al., Biosynthesis and Extracellular Concentrations of N,N-dimethyltryptamine (DMT) in Mammalian Brain. Sci Rep, 2019. 9(1): p. 9333.

6. Kiecker, C., The origins of the circumventricular organs. J Anat, 2018. 232(4): p. 540-553.

7. Tan, D.X., et al., Pineal Calcification, Melatonin Production, Aging, Associated Health Consequences and Rejuvenation of the Pineal Gland. Molecules, 2018. 23(2).

8. Vriend, J. and R.J. Reiter, Melatonin feedback on clock genes: a theory involving the proteasome. J Pineal Res, 2015. 58(1): p. 1-11.

9. Touitou, Y., D. Touitou, and A. Reinberg, Disruption of adolescents' circadian clock: The vicious circle of media use, exposure to light at night, sleep loss and risk behaviors. J Physiol Paris, 2016. 110(4 Pt B): p. 467-479.

10. Pi, H., et al., SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin. Autophagy, 2015. 11(7): p. 1037-51.

11. Ozlece, H.K., et al., Is there a correlation between the pineal gland calcification and migraine? Eur Rev Med Pharmacol Sci, 2015. 19(20): p. 3861-4.

12. Meng, X., et al., Dietary Sources and Bioactivities of Melatonin. Nutrients, 2017. 9(4).

13. Emet, M., et al., A Review of Melatonin, Its Receptors and Drugs. Eurasian J Med, 2016. 48(2): p. 135-41.

14. Pfeffer, M., H.W. Korf, and H. Wicht, Synchronizing effects of melatonin on diurnal and circadian rhythms. Gen Comp Endocrinol, 2018. 258: p. 215-221.

15. Borjigin, J., L.S. Zhang, and A.A. Calinescu, Circadian regulation of pineal gland rhythmicity. Mol Cell Endocrinol, 2012. 349(1): p. 13-9.

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