OPEN Foundation, Author at OPEN Foundation

NMDAR inhibition-independent antidepressant actions of ketamine metabolites

May 4, 2016 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / OPEN Foundation / G. Elmer, J. Fischell, K. Dossou, P. Georgiou, P. Morris, P. Zanos, R. Moaddel

Abstract

Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-d-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.

Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G. I., … & Dossou, K. S. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. http://dx.doi.org/10.1038/nature17998
Link to full text

NMDAR inhibition-independent antidepressant actions of ketamine metabolites Read More »

DMT: De trip voorbij, mogelijk een veelzijdig medicijn

May 2, 2016 / Uncategorized / OPEN Foundation

N,N-dimethyltryptamine, beter bekend als DMT, is een buitengewoon snelwerkend en krachtig psychedelicum. DMT kan worden genomen door het entheogene brouwsel ayahuasca te drinken, door het intraveneus of in de spieren te injecteren, of door het te inhaleren. Het wordt in verschillende planten en dieren van nature aangemaakt, inclusief in de mens. Zoals besproken in Jacobi en Presti (2005) heeft DMT, naast geest-veranderende effecten, ook een fysiologische werking. Zo zijn bijvoorbeeld anxiolytische en antidepressieve effecten aangetoond (Sanches et al, 2016).

DMT is niet alleen een agonist van serotonine 2A- en 2C-receptoren (5-HT_2A and 5-HT_2C); het bindt zich ook aan vermeende σ₁-receptoren en spoor-amine-receptoren (Vitale et al. 2011). Daarenboven kunnen zijn serotonergische analogen immunoregulatie beïnvloeden en mogelijk zelfs carcinogenese voorkomen (Frecska et al. 2012). De veelzijdige interacties van DMT laten zien dat de effecten ervan niet beperkt blijven tot het centrale zenuwstelsel, maar mogelijk nog een crucialere rol spelen in de cellulaire beschermingsmechanismen van het lichaam (Frecska et al. 2012).

Dr. Ede Frecska heeft meerdere papers gepubliceerd over de effecten van ayahuasca en DMT op creativiteit, weefselregeneratie, en de interhemisferische fusie in veranderde bewustzijnstoestanden (Frecska et al. 2016). Nu recentelijk is ontdekt dat DMT de σ₁-receptor – die een cruciale rol speelt bij de bescherming van het lichaam tegen oxidatieve stress – activeert, onderzoeken dr. Frecska en zijn team momenteel wat de rol van DMT is bij neurobescherming in de fase vóór de klinische dood (Frecska 2015).

σ₁-Receptoren spelen een sleutelrol in neurobescherming door zowel neuronale ontwikkeling als morfogenese te reguleren. Dit geschiedt door middel van regulatie en manipulatie van oxidatieve stress en mitochondriale functies (Tuerxun et al. 2010). Agonisten van σ₁-receptoren versterken neurobeschermende effecten door intracellulaire calcium-overbelasting tegen te houden en door de activering van pro-apoptopische genen te dwarsbomen, alsook door beschermende genen te activeren, zoals is aangetoond in beroertemodellen (Zhang et al. 2012). Dit leidt tot de afname van calciumneurotoxiciteit, voorkomt celdood door oxidatieve stress, en kan neuronale plasticiteit stimuleren (Kourrich et al. 2012). Een van de belangrijkste ontdekkingen is dat de voortdurende activatie van σ₁-receptoren tijdens ischemie leidt tot een reductie van de neurotoxiciteit (Katnik et al. 2006). Uiteindelijk suggereert dit onderzoek dat DMT een rol zou kunnen spelen in het doen afnemen van hypoxie/anoxie-schade zoals lokale anoxie (bv. een beroerte) of algemene hypoxie (zoals bij een hartstilstand) (Kourrich et al. 2012).

De medicinale eigenschappen van DMT blijven niet beperkt tot neurobescherming, maar reiken mogelijk ook tot immunobescherming. De 5-HT_2A– en ook de sigma-receptoren kunnen het immuunsysteem van het lichaam diepgaand beïnvloeden. Serotonine speelt een belangrijke rol in cellulaire immuunfuncties, en meer in het bijzonder in het onschadelijk maken van pathogenen en kankercellen (O’Connell et al. 2006). Agonisten van de σ₁-receptoren- kunnen niet alleen de productie van anti-inflammatoire cytokinen doen toenemen, maar ook pro-inflammatoire cytokinen doen afnemen. Beide processen zijn van belang bij het terugdringen van celschade in geval van verwondingen of ziekte (Frecska et al. 2012).

Of DMT ook vrijkomt tijdens bijna-doodervaringen blijft voorlopig nog speculatief, aangezien er maar weinige parallellen bestaan tussen deze ervaringen en DMT-visioenen (Strassman 2001). Echter, men zou op basis van de huidige – beperkte – kennis in dezen de hypothese kunnen maken dat DMT wordt geproduceerd in levensbedreigende situaties. McEwen en Sober (1967) hebben aangetoond dat konijnen die extreme omgevingsstress ondergaan aanzienlijke hoeveelheden DMT aanmaken in hun longen, die vervolgens worden afgegeven aan het bloed (McEwen & Sober 1967). De DMT wordt daarna doorheen de neurale membranen naar synaptische blaasjes getransporteerd en aan de hersenen afgeleverd. Rekening houdend met de relatie tussen DMT en σ₁-receptoren, wordt de hypothese gehanteerd dat DMT opgebouwde oxidatieve stress beperkt of omkeert. Dit fungeert als de basis van de hypothese van dr. Frecska, en als er bewijs wordt gevonden voor de rol van DMT in de neurobescherming van het menselijke brein in de fases voorafgaand aan klinische dood, dan zou DMT mogelijk gebruikt kunnen worden in de spoedeisende geneeskunde. Als dit slaagt, dan zou je je kunnen voorstellen dat ampullen DMT zullen worden gebuikt in ambulances, operatiekamers en rampgebieden. Klinisch onderzoek met mensen is nog wel nodig om te bepalen of dit wel of niet haalbaar is.

Ook al richt het onderzoek van dr. Frecska zich op preklinische studies met ratten, zijn onderzoek heeft verder gekeken dan de louter hallucinogene relevantie van DMT en heeft perspectieven geopend voor verder onderzoek naar de neurobeschermende rol van DMT. De mogelijke medische gevolgen hiervan zijn aanzienlijk. De toepassingen van DMT liggen misschien nog wel voorbij wat we ons kunnen voorstellen, en verdienen het zeker om systematisch te worden onderzocht.

Referenties

Frecska, E., 2015. What role does the ‘spirit molecule’ DMT play in the brain?. [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][Online] Available at: http://walacea.com/campaigns/dmt

Frecska, E., Bokor, P. & Winkelman, M., 2016. The Therapeutic Potentials of Ayahuasca: Possible Effects against Various Diseases of Civilization. Frontiers in Pharmacology, p. 10.3389.

Frecska, E. et al., 2012. A possibly sigma-1 receptor meditated dole of dimethyltryptamine in tissue protection, regeneration and immunity. Translational Neuroscience, pp. 1-18.

Jacob, M. & Presti, D., 2005. Endogenous psychoactive tryptamines reconsidered: an anxiolytic role for dimethyltryptamine.. Medical Hypotheses, 64(5), pp. 930-7.

Katnik, C. et al., 2006. Sigma-1 receptor activation prevents intracellular calcium dysregulation in cortical neurons during in vitro ischemia. Journal of Pharmacology and Experimental Therapeutics, Band 319, pp. 1355-1365.

Kourrich, S., Tsung-Ping, S., Fujimoto, M. & Bonci, A., 2012. The sigma-1 receptor: roles in neuronal plasticity and disease. Trends Neuroscience, 35(12), pp. 762-771.

McEwen, C. & Sober, A., 1967. Rabbit serum monoamine oxidase. The Journal of Biological Chemistry, Band 242, pp. 3068-3078.

O’Connell, P. et al., 2006. A novel form of immune signaling revealed by transmission of the inflammatory mediator serotnin between dendritic cells and T cells. Blood, Band 107, pp. 1010-1017.

Sanches, R. F. et al., 2016. Antidepressant Effects of a Single Dose of Ayahuasca in Patients With Recurrent Depression: A SPECT Study. Journal of Clinical Psychopharmacology, 36(1), pp. 77-81.

Strassman, R., 2001. DMT: The Spirit Molecule. First Hrsg. Rochester: Park Street Press.

Strassman, R. & Qualis, C., 1994. Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects. Archives of General Psychiatry, pp. 85-97.

Tuerxun, T. et al., 2010. SA4503, a sigma-1 receptor agonist, prevents cultured cortical neurons from oxidative stress-induced cell death via suppression of MAPK pathway activation and glutamate receptor expression. Neuroscience Letters, Band 469, pp. 303-308.

Zhang, Y. et al., 2012. Sigma-1 receptor agonists provide neuroprotection against gp12- via a change in bel-2 expression in mouse neuronal cultures. Brain Research, Band 1431, pp. 13-22.

[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]

DMT: De trip voorbij, mogelijk een veelzijdig medicijn Read More »

LSD alters eyes-closed functional connectivity within the early visual cortex in a retinotopic fashion

April 29, 2016 / LSD, Neuroscience, Papers, Publications / OPEN Foundation / C. Orban, J. McGonigle, L. Roseman, M. Kaelen, M. Sereno, R. Carhart-Harris, R. Leech

Abstract

The question of how spatially organized activity in the visual cortex behaves during eyes-closed, lysergic acid diethylamide (LSD)-induced “psychedelic imagery” (e.g., visions of geometric patterns and more complex phenomena) has never been empirically addressed, although it has been proposed that under psychedelics, with eyes-closed, the brain may function “as if” there is visual input when there is none. In this work, resting-state functional connectivity (RSFC) data was analyzed from 10 healthy subjects under the influence of LSD and, separately, placebo. It was suspected that eyes-closed psychedelic imagery might involve transient local retinotopic activation, of the sort typically associated with visual stimulation. To test this, it was hypothesized that, under LSD, patches of the visual cortex with congruent retinotopic representations would show greater RSFC than incongruent patches. Using a retinotopic localizer performed during a nondrug baseline condition, nonadjacent patches of V1 and V3 that represent the vertical or the horizontal meridians of the visual field were identified. Subsequently, RSFC between V1 and V3 was measured with respect to these a priori identified patches. Consistent with our prior hypothesis, the difference between RSFC of patches with congruent retinotopic specificity (horizontal-horizontal and vertical-vertical) and those with incongruent specificity (horizontal-vertical and vertical-horizontal) increased significantly under LSD relative to placebo, suggesting that activity within the visual cortex becomes more dependent on its intrinsic retinotopic organization in the drug condition. This result may indicate that under LSD, with eyes-closed, the early visual system behaves as if it were seeing spatially localized visual inputs.

Roseman, L., Sereno, M. I., Leech, R., Kaelen, M., Orban, C., McGonigle, J., … & Carhart‐Harris, R. L. (2016). LSD alters eyes‐closed functional connectivity within the early visual cortex in a retinotopic fashion. Human Brain Mapping. http://dx.doi.org/10.1002/hbm.23224

Link to full text

LSD alters eyes-closed functional connectivity within the early visual cortex in a retinotopic fashion Read More »

DMT: Beyond the trip, a potential multifaceted medicine

April 26, 2016 / DMT, Publications / OPEN Foundation

N,N-dimethyltryptamine, more commonly known as DMT, is an exceptionally fast-acting and powerful psychedelic. DMT can be ingested by drinking the entheogenic brew ayahuasca, injected intravenously, intramuscularly or through inhalation. It is produced endogenously in a variety of plants and animals, including in humans. DMT exerts physiological effects that go beyond its mind-altering effects, as discussed in Jacob and Presti (2005). For example, DMT has been shown to induce anxiolytic and antidepressant effects (Sanches et al. 2016).

DMT is not only an agonist of serotonin 2A and 2C receptors (5-HT_2A and 5-HT_2C); it also binds to σ₁putative receptors and trace amine receptors (Vitale et al. 2011). In addition, its serotonergic analogues can influence immunoregulation, and may even prevent carcinogenesis (Frecska et al. 2012). DMT’s multifaceted interactions show that its effects are not limited to the central nervous system but may play a more crucial role in the body’s cellular protective mechanisms (Frecska et al. 2012).

Dr. Ede Frecska has published multiple papers on the effects of ayahuasca and DMT on creativity, tissue regeneration, and the interhemispheric fusion in altered states of consciousness (Frecska et al. 2016). With the recent discovery of DMT’s activation of the σ1 receptor , which plays a crucial role in protecting the body from undergoing oxidative stress, Dr. Frecska and his team are currently investigating DMT’s role in neuroprotection prior to clinical death (Frecska 2015).

σ₁receptors play a key role in neuroprotection by regulating both neuronal development and morphogenesis. This is done through the regulation and manipulation of oxidative stress and mitochondrial functions (Tuerxun et al. 2010). Agonists of σ₁ receptors exacerbate neuroprotective effects by inhibiting intracellular calcium overload and by thwarting the activation of pro-apoptopic genes, as well as activating protective genes, as shown in stroke models (Zhang et al. 2012). This leads to the reduction of calcium neurotoxicity, prevents oxidative stress-induced cell death, and can stimulate neuronal plasticity (Kourrich et al. 2012). Most importantly, the constant activation of σ₁ receptors during ischemia leads to a reduction of neurotoxicity (Katnik et al. 2006). Ultimately, this research suggests that DMT may have a role in reducing the hypoxic-anoxic damages such as local anoxia (e.g. stroke) or general hypoxia (e.g. cardiac arrest) (Kourrich et al. 2012).

DMT’s medicinal properties are not limited to neuroprotection, but can extend to immunoprotection as well. The 5HT_2A receptors, as well as the sigma receptors, can profoundly influence the body’s immune system. Serotonin plays an important role in cellular immune functions, and more specifically in the elimination of pathogens and cancer cells (O’Connell et al. 2006). σ₁ receptor agonists can increase the production of anti-inflammatory cytokines as well as reduce pro-inflammatory cytokines. Both these processes are important in reducing the cellular damage in case of injury or disease (Frecska et al. 2012).

Currently, there is only speculation that DMT is produced during near-death experiences, as there are few parallels between near-death experiences and DMT visions (Strassman 2001). However, based on limited information, one may conjecture the production of DMT during life-threatening situations. McEwen and Sober (1967) have demonstrated that when undergoing extreme environmental stress, rabbits produce vast quantities of DMT in the lungs, which are then released into the blood (McEwen & Sober 1967). DMT is then transported through the neural membranes within synaptic vesicles and delivered to the brain. Knowing the relationship between DMT and the σ₁ receptors, it is hypothesised that DMT limits or reverses the accumulated oxidative stress. This serves as the foundation of Dr. Frecska’s hypothesis, and if evidence is found of DMT’s role in the neuroprotection of the human brain in the stages leading up to clinical death, then DMT would have the potential to be used as an emergency medicine. If successful, one could envision the use of DMT ampoules to be used intravenously in ambulances, operating rooms and in disaster zones. Clinical studies with humans are still necessary in order to define whether it is feasible or not.

Although Dr. Frescka’s studies focus on rats (pre-clinical studies), his studies have looked beyond DMT’s mere hallucinogenic relevance and have opened avenues into further studying DMT’s neuroprotective role. The potential medical ramifications are vast. The applications of DMT may be beyond what we can imagine, and certainly deserve to be systematically studied.

References