Magi™ nootropics are made with natural β-Carbolines, unique neuromodulators that have been shown to exhibit anti-inflammatory activity in the brain and promote neurogenesis. β-Carbolines have been shown to engage with the brain’s imidazoline, serotonin, noradrenaline, and dopamine systems affecting mood, energy, sensation, perception, and pain. We have formulated some Magi nootropics that are lightly perceptive to provide these benefits, but even with those formulations that are sub-perceptive, Magi nootropics provide unique brain health benefits that go beyond what the mind can perceive.
Although applicable to any psycho*active substance, the term “microdosing” has become rooted in psychedelics as a contrast to the practice of “macrodosing”: taking a fully perceptive dose of a psychedelic / hallucinogenic / deliriant / dissociative compound that significantly alters sensory perception, precipitates a non-ordinary state of consciousness, and triggers a subjective view of self-identity. Microdosing, whether with a psychedelic or psycho*active compound, is performed with a dose that is so low as to be either sub-perceptive or only slightly perceptive such that normal functioning is not impaired and the participant retains full agency of physical and psychological control.
For example with magic mushrooms (psilocybin), a macrodose is considered as 2-5g of mushrooms (10-25mg of psilocybin) while a microdose is 0.075-0.2 g of mushrooms (0.5-1.0 μg of psilocybin).
Across the Middle East, the ancestral plant Espand has long been used as a medicinal remedy for ailments ranging from kidney stones to asthma to epilepsy. As a rich source of β-Carbolines, we now understand their myriad health benefits, including for the central nervous system .
Microglia are nervous system-specific immune cells that reside in the brain and are responsible for injury repair, immune response to pathogens, and waste removal. Excessive microglial activation has been shown to promote the release of pro-inflammatory cytokines (signaling proteins) that are implicated in neurodegenerative diseases as well as mood disorders. Research has shown that harmaline, an Espand-derived beta-Carboline which is also found in Banisteriopsis Caapi (an ingredient of Ayahuasca), significantly reduces the release of pro-inflammatory cytokines in microglia – an anti-inflammatory effect for these neurological immune cells .
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) is a signaling protein that plays a key role in regulating immune response to infection in the nervous system by promoting inflammatory cytokines. Over activation of NF-kB has been shown to be involved in many cancers and inflammatory diseases . Harmine, another Espand-derived β-Carboline that is also found in Banisteriopsis Caapi, has been shown to significantly inhibit pro-inflammatory activity of infected NF-kB cells – anti-infection and anti-inflammatory effects for these immune cells .
β-Carbolines, such as harmine and harmaline, have also been shown to function as antioxidants with demonstrated antimutagenic and antigenotoxic properties . On account of these neuroprotective properties, these compounds have been evaluated for treatment of neurodeg*enerative disorders .
β-Carbolines have been shown to inhibit a number of enzymes (called regulatory kinases) that are implicated in neurodegenerative diseases. The most studied is dual-specificity tyrosine phosphorylation-regulated kinase 1-A (DYRK1a), which is regulated by a gene that is overexpressed in Down Syndrome and is believed to play a significant role in brain defects associated with aging .
DYRK1a is found in regions of the brain involved in cognition and memory, and is a regulator of numerous neurodevelopmental mechanisms including:
– tau proteins that maintain the stability of neurons in proximity to the blood brain barrier 
– beta-amyloid production, that plays a role in neural growth and repair
Overexpression of DYRK1a leads to an excessive breakdown of tau proteins, compromising neural connectivity, as well as beta-amyloid overproduction, which leads to buildup of amyloid plaques in the brain that are often seen in patients suffering from Alzheimer’s disease . Harmine is one of the most effective inhibitors of DYRK1a .
Harmine is also an inhibitor of acetylcholinesterase (AChE) , the enzyme that breaks down the neurotransmitter acetylcholine (ACh, the “learning hormone”) and is often used as a biomarker for cognitive impairment. Reduction of ACHE levels in the cortex and hippocampus (involved in cognition and episodic memory) have been shown to prevent neurodegeneration .
Outside of the realm of the central nervous system, Sphingosine Kinase-1 (SphK1) is a different regulatory kinase which promotes cell promotion and survival in pulmonary tissue, and when overexpressed, is linked with cancer progression. Harmaline has been shown to be a potent SphK1 inhibitor . Angiotensin converting enzyme (ACE) regulates the volume of fluid in the body’s circulatory system and is one of the leading targets for anti-hypertensive drugs . Harmaline has also been shown to be a potent ACE inhibitor, demonstrating its anti-hypertensive effects .
In addition to neuroprotection, beta-Carbolines have been shown to promote neurogenesis: the growth of new brain cells.
Brain-derived neurotrophic factor (BDNF) is a protein that regulates neurogenesis and is found in regions of the brain involved in learning, memory, and higher level thought that is critical to healthy neurological development . Decreased levels of BDNF are associated with many debilitating neurodegenerative diseases . Research has shown that harmine promotes BDNF expression in the hippocampus of healthy rodents, providing antidepressant like effects , as well as impaired rodents, helping to ameliorate learning and memory impairment and attenuating cognitive dysfunction (i.e. brain fog) .
Human neural progenitor cells (hNPCs) are precursors from which CNS neural cells are formed (i.e. brain stem cells) . Neurogenesis from hNPCs has been shown to be negatively affected by stress, depression, and neurodegenerative disease. In-vitro studies have shown that treatment with harmine increased proliferation of hNPCs by 71.5% with no toxicity nor DNA damage.
Ancestral Supplement for The Good Mind: MAGI
Sleep & Brain Health
“Wakefulness is low level brain damage, while sleep is neurological sanitation.” – Matthew Walker 
Sleep may be the most critical thing we can do for our emotional, physical, and mental health. Sleep is critical for:
– Learning as the brain state where new neural connections are formed (neuroplasticity)
– Consolidation of memories and integration of emotional response 
– Brain detoxification: your glymphatic system flushes and detoxifies the brain of toxins such as amyloid plaques 
– Stress management: your body’s sympathetic nervous system activity decreases and cortisol levels drop 
– Immune health: your body’s immune system releases anti-inflammatory cytokines 
– Bodily repair: your pituitary gland releases growth hormone 
– Weight loss: given the impact of sleep on metabolism 
– Physical attractiveness 
Sleep is divided into four stages that cycle throughout the night :
– Awake: The drowsy stage of consciousness in between the onset of sleep and wakefulness. Heartrate and breathing begin to slow down.
– Light: Heartrate and breathing begin to slow even further and you enter a deeper stage of relaxation as your body’s sympathetic nervous system begins to disengage. Dreams are short and trivial. Your brain produces high theta brainwaves with the occasional sleep spindle .
– Deep: Heartrate and breathing at their slowest rate, and body is in deepest state of relaxation. Your endocrine system secretes hormones in support of organ, tissue, and cell regeneration and growth, your immune system secretes anti-inflammatory cytokines, and your brain’s glymphatic system flushes out toxins. Dreams are more vivid and expansive. Your brain produces high delta brainwaves, though it has been shown that patients suffering from depression and pain are more likely to demonstrate high alpha brain waves during deep sleep (Alpha-Delta Sleep disorder) .
– REM: Heartrate and breathing increase, and brain activity increases, characterized by high frequency beta and gamma brainwaves (brain activity is similar to waking state). Dreams are deeply immersive and interactive. Rapid eye movement and limb muscles become temporarily paralyzed to prevent acting out dreams.
While all stages of sleep are important, deep sleep, which decreases as we age, is particularly critical to waking up feeling refreshed. β-Carbolines are believed to play a role in the sleep cycle of dreams, as they are similar structurally to melatonin and serotonin, and are also produced endogenously in the pineal gland . Magi Lucid Dream Aid is formulated with a precise dose of select β-Carbolines to help enhance the REM stage of sleep, while Magi Deep Sleep Aid is formulated with a precise dose of different β-Carbolines to help enhance delta brainwaves during the deep stage of sleep.
-  Li, Shuping, et al. “A review on traditional uses, phytochemistry, pharmacology, pharmacokinetics and toxicology of the genus Peganum.” Journal of Ethnopharmacology, vol. 203, May 2017, pp. 127-162. doi: 10.1016/j.jep.2017.03.049
-  Lopes Santos, Beatriz Werneck, et al. “Components of Banisteriopsis caapi, a Plant Used in the Preparation of the Psychoactive Ayahuasca, Induce Anti-Inflammatory Effects in Microglial Cells.” Molecules, 2022 Apr 13;27(8):2500. doi: 10.3390/molecules27082500
-  Liu, Ting, et al. “NF-κB signaling in inflammation.” Signal Transduction and Targeted Therapy, 17023 (2017). https://doi.org/10.1038/sigtrans.2017.23
-  Liu, Xin, et al. “Harmine is an inflammatory inhibitor through the suppression of NF-κB signaling.” Biochemical and Biophysical Research Communications, Jul 2017, pp. 489(3):332-338. doi: 10.1016/j.bbrc.2017.05.126
-  Moura, Dinara Jaqueline, et al. “Antioxidant properties of b-carboline alkaloids are related to their antimutagenic and antigenotoxic activities.” Mutagenesis, vol. 22, no. 4, Jun 2007, pp. 293-302. doi:10.1093/mutage/gem016
-  Samoylenko, Volodymyr, et al. “Banisteriopsis caapi, a unique combination of MAO inhibitory and antioxidative constituents for the activities relevant to neurodegenerative disorders and Parkinson’s disease.” Journal of Ethnopharmacology, vol. 127, no. 2, Feb 2010, pp. 357-367. https://doi.org/10.1016/j.jep.2009.10.030
-  Wegiel, Jerzy, et al. “The role of DYRK1A in neurodegenerative diseases.” The FEBS Journal, vol. 278, no. 2, Jan 2011, pp. 236-245. https://doi.org/10.1111/j.1742-4658.2010.07955.x
-  Kaplan, Luke, et al. “Neuronal regulation of the blood–brain barrier and neurovascular coupling.” Nature Reviews Neuroscience, vol. 21, 416–432 (2020). https://doi.org/10.1038/s41583-020-0322-2
-  Kimura, Ryo, et al. “The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease.” Human Molecular Genetics, 2007 Jan 1;16(1):15-23. doi: 10.1093/hmg/ddl437
-  Göckler, Nora, et al. “Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation.” The FEBS Journal, 2009 Nov;276(21):6324-37. doi: 10.1111/j.1742-4658.2009.07346.x
-  He, Dandan, et al. “Effects of harmine, an acetylcholinesterase inhibitor, on spatial learning and memory of APP/PS1 transgenic mice and scopolamine-induced memory impairment mice.” European Journal of Pharmacology, 2015 Dec 5;768:96-107. doi: 10.1016/j.ejphar.2015.10.037
-  Muthuraju, Sangu, et al. “Acetylcholinesterase inhibitors enhance cognitive functions in rats following hypobaric hypoxia.” Behavioral Brain Research, 2009 Oct 12;203(1):1-14. doi: 10.1016/j.bbr.2009.03.026
-  Roy, Sonam, et al. “Discovery of Harmaline as a Potent Inhibitor of Sphingosine Kinase-1: A Chemopreventive Role in Lung Cancer.” ACS Omega, 2020 Sep 1; 5(34): 21550–21560. doi: 10.1021/acsomega.0c02165
-  Wong, Marty K.S. “Angiotensin Converting Enzymes.” Handbook of Hormones, 2016: 263–e29D-4. doi: 10.1016/B978-0-12-801028-0.00254-3
-  Hivrale, Vandana K. “Angiotensin-Converting Enzyme Inhibitory Potential of Harmaline Isolated from Peganum Harmala L. Seeds.” Journal of Herbs, Spices, & Medicinal Plants, vol. 19, no. 1, Jan 2013, pp. 48-53. https://doi.org/10.1080/10496475.2012.736925
-  Miranda, Magdalena, et al. “Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain.” Frontiers in Cellular Neuroscience, Aug 2019. https://doi.org/10.3389/fncel.2019.00363
-  Palasz, Ewelina, et al. “BDNF as a Promising Therapeutic Agent in Parkinson’s Disease.” International Journal of Molecular Sciences, 2020 Feb; 21(3): 1170. doi: 10.3390/ijms21031170
-  Fortunato, Jucélia, et al. “Acute harmine administration induces antidepressive-like effects and increases BDNF levels in the rat hippocampus.” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 33, no. 8, Nov 2009, pp. 1425-1430. https://doi.org/10.1016/j.pnpbp.2009.07.021
-  Liu, Peifang, et al. “Harmine Ameliorates Cognitive Impairment by Inhibiting NLRP3 Inflammasome Activation and Enhancing the BDNF/TrkB Signaling Pathway in STZ-Induced Diabetic Rats.” Frontiers in Pharmacology, 2020; 11: 535. doi: 10.3389/fphar.2020.00535
-  Martínez-Cerdeño, Verónica, and Stephen C. Noctor. “In Vitro Expansion of a Multipotent Population of Human Neural Progenitor Cells.” Frontiers in Neuroanatomy, 2018; 12: 104. doi: 10.3389/fnana.2018.00104
-  Walker, Matthew. “Why We Sleep.” 1st ed. Simon & Schuster, 2017.
-  Maquet, Pierre. “The role of sleep in learning and memory.” Science, vol. 294, no. 5544, Nov 2001, pp. 1048-1052. DOI: 10.1126/science.1062856
-  Reddy, Oliver Cameron, and Ysbrand D. van der Werf. “The Sleeping Brain: Harnessing the Power of the Glymphatic System through Lifestyle Choices.” Brain Science, 2020 Nov; 10(11): 868. doi: 10.3390/brainsci10110868
-  Seravalle, Gino, et al. “Sympathetic Nervous System, Sleep, and Hypertension.” Current Hypertension Reports, 20: 74 (2018). https://doi.org/10.1007/s11906-018-0874-y
-  Krueger, James M., et al. “The role of cytokines in physiological sleep regulation.” Annals of the New York Academy of Sciences, vol. 933, no. 1, Mar 2001, pp. 211-221. https://doi.org/10.1111/j.1749-6632.2001.tb05826.x
-  Takahashi, Y., et al. “Growth hormone secretion during sleep.” The Journal of Clinical Investigation, Sep 1968. doi: 10.1172/JCI105893
-  Leproult R., and E. Van Cauter. “Role of Sleep and Sleep Loss in Hormonal Release and Metabolism.” Pediatric Neuroendocrinology, vol. 17, 2010, pp. 11-21. https://doi.org/10.1159/000262524
-  Sundelin, Tina, et al. “Negative effects of restricted sleep on facial appearance and social appeal.” Royal Society Open Science, 2017 May; 4(5): 160918. doi: 10.1098/rsos.160918
-  Patel, Aakash K., et al. “Physiology, Sleep Stages.” StatPearls, Jan 2022. https://www.ncbi.nlm.nih.gov/books/NBK526132/
-  Fernandez, Laura M.J., and Anita Lüthi. “Sleep Spindles: Mechanisms and Functions.” Physiological Reviews of the American Physiological Society, vol. 100, no. 2, Apr 2020, pp. 805-868. https://doi.org/10.1152/physrev.00042.2018
-  Jaimchariyatam, Nattapong, et al. “Prevalence and Correlates of Alpha-Delta Sleep in Major Depressive Disorders.” Innovations in Clinical Neuroscience, 2011 Jul; 8(7): 35–49. PMID: 21860844; PMCID: PMC3159543.
-  Callaway, J.C. “A proposed mechanism for the visions of dream sleep.” Medical Hypotheses, 1988 Jun;26(2):119-24. doi: 10.1016/0306-9877(88)90064-3