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Tripping into a better future: can we use non-addictive psychedelic drugs against the downsides of ageing?

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Subash Chapagain
Subash Chapagain Oct 01, 2020
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How can psychedelic drugs be effectively used for a longer/happier life?

Once considered a stigmatized subject -thanks to the top-down War on Drugs post-1960s - psychedelic drugs have once again been revived as a domain of academic and medicinal interest after decades-long hiatus . In light of newer scientific evidence suggesting the capacity of certain psychedelic substances - mainly MDMA (called ecstasy or Molly), and Psilocybin (the psychoactive component of magic mushroom) and ayahuasca- to help relieve anxiety, depression, PTSD, addiction and the fear due to terminal disease, the cultural and institutional norms around these substances is changing for good . Even FDA has realised the promise of psychedelics and hence given Psilocybin a ‘breakthrough treatment designation .”

Psychedelic substances can have therapeutic value, especially in the conditions pertaining to psychological/emotional domains and conditions involving neural mechanisms. The functional neurological basis by which these drugs operate is yet to be fully explained, however, some insights have been already drawn by many investigative and clinical research. For instance, in a phase-I double-blinded, placebo-controlled, randomized study done by Eleusis, a clinical-stage life science company based in New York, it was demonstrated that micro-dosed lysergic acid diethylamide (LSD) [5,10,20 micrograms, six doses every 4 days] can have a significant effect for treating Alzheimer’s Disease. In this landmark research deemed to be the first modern clinical trial involving LSD, it was seen that the drug can activate the serotonin and dopamine receptors involved in control memory and cognition (and implicated in AD). Specifically, the drug was found to modulate its effects via the serotonin 5-HT2A receptor, the functional effect being anti-inflammatory potential and arrest of Alzheimer’s progression at its earliest detectable stage . This result seems to corroborate the previous findings from animal studies which discovered that 5-H2TA activation leads to increased cognitive functioning as well as associative learning capacity .

Another mechanism for the cognitive changes related to psychedelics that can potentially be applied for the older population is that these substances enhance neurogenesis and neuroplasticity. As diminished neurogenesis is considered as one of the key factor underlying cognitive declines in older adults , enhanced plasticity by the usage of psychedelics could act as compensatory responses in the ageing brain. Moreover, in vivo animal model studies have shown that psychedelics like LSD and DMT increased neuroplasticity and synaptogenesis , though the results are yet to be reproduced in human trials. Similarly, increased neurogenesis can also be effective against depression in which the prefrontal cortex neurons are said to undergo atrophy.

Apart from these direct effects on neurological features of the brain, psychedelics can be used to enhance the quality of life in the older age in various ways. For example:
  • psychedelics for enhancing convergent and divergent creativity
  • psychedelics against suicidality
  • psychedelics as tools to enhance the meaningful experience in life
  • psychedelics as stress-relievers in patients with chronic and terminal diseases
Given these amounting evidence, what other ways can you think that we can make safe and effective use of these non-addictive molecules for the betterment of human lives? What scientific and political homework is needed before unleashing them for clinical purposes?

[1]https://www.nytimes.com/2017/07/17/upshot/can-psychedelics-be-therapy-allow-research-to-find-out.html

[2]https://michaelpollan.com/articles-archive/the-new-science-of-psychedelics/

[3]Bauer, B. (2019). Psilocybin receives FDA breakthrough treatment designation. Psychedelic Science Review.Retrieved from https:// psychedelicreview.com/psilocybin-receives-fda-breakthroughtreatment- designation/.

[4]Family, N., Maillet, E. L., Williams, L. T. J., Krediet, E., Carhart-Harris, R. L., Williams, T. M., Nichols, C. D., Goble, D. J., & Raz, S. (2019). Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers. Psychopharmacology, 237(3), 841–853. https://doi.org/10.1007/s00213-019-05417-7

[5]Carhart-Harris, R. L., Kaelen, M., & Nutt, D. (2014). How do hallucinogens work on the brain? The Psychologist 662–665.

[6]Galvan, V., & Jin, K. (2007). Neurogenesis in the aging brain. Clinical Interventions in Aging, 2, 605–610

[7]Ly, C., Greb, A. C., Cameron, L. P.,Wong, J. M., Barragan, E. V.,Wilson, P. C., &…Duim,W. C. (2018). Psychedelics promote structural and functional neural plasticity. Cell Reports, 23, 3170–3182. https://doi.org/10.1016/j.celrep.2018.05.022.

[8]Kuypers, K. P. C., Riba, J., de la Fuente Revenga, M., Barker, S., Theunissen, E. L., & Ramaekers, J. G. (2016). Ayahuasca enhances creative divergent thinking while decreasing conventional convergent thinking. Psychopharmacology, 233, 3395–3403. https://doi. org/10.1007/s00213-016-4377-8.

[9]Hendricks, P. S., Thorne, C. B., Clark, C. B., Coombs, D.W., & Johnson, M. W. (2015). Classic psychedelic use is associated with reduced psychological distress and suicidality in the United States adult population. Journal of Psychopharmacology, 29, 280–288. https://doi. org/10.1177/0269881114565653.

[10]Griffiths, R. R., Richards, W. A., McCann, U., & Jesse, R. (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology, 187, 268–283. https://doi.org/10.1007/ s00213-006-0457-5.

[11]Kelmendi, B., Corlett, P., Ranganathan,M., D’Souza, C., & Krystal, J. H. (2016). The role of psychedelics in palliative care reconsidered: A case for psilocybin. Journal of Psychopharmacology, 30, 1212– 1214. https://doi.org/10.1177/0269881116675781

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Psychedelics as promising agents against autoimmune diseases: a thorough look

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Subash Chapagain
Subash Chapagain Nov 27, 2020
Autoimmune diseases (AiDs) are the results of the immune system’s failure of tolerating self-antigens in which the system attacks its own healthy tissues in an individual. The causes of AiDs can be specific or multifactorial, depending on the disorder type . Some prominent causes of AiDs are genetic predispositions, psychological stress and environmental triggers . inflammation and infections, Hypothalamic-pituitary-adrenal (HPA) axis dysregulation, mitochondrial dysfunction and microbiome dysbiosis .

The current treatment practices for AiDs are heavily in the realm of bioactive drugs. But the immunosuppressive and biologic medications that are designed to resemble antibodies, receptors and other immunological factors can cause immunocompromised state thereby increasing the risks of infections and immune-related illnesses in the affected population. Such increased risks include malignancy and cardiovascular conditions, suggesting that there is a need to explore other approaches to treat AiDs . This is where both classical and non-classical psychedelic drugs come into the picture. They have been regarded as promising agents to treat autoimmune disorders.

But first, let’s start with a bit of connecting threads.

There's a link between AiD and psychological disorders

Various neurobiological studies pertaining to psychiatric disorders in recent decades have revealed that there is a significantly strong co-occurrence of autoimmune conditions and mental and mood disorders. Anxiety, schizophrenia, and bipolar disorders are some of these psychological disorders . Studies have also suggested that depression and anxiety symptoms are probably the results of autoimmune mechanisms that are caused due to inflammation occurring in the nervous system, or via the dysregulated inflammatory loops of cytokines between peripheral and brain-resident immune cells .

How might psychedelics work as immunomodulatory agents?

The role of psychedelics as potent agents against AiDs come potentially from their immunomodulatory activity through the mobilization of cell-intrinsic neuroprotective mechanisms. Even though this research area that explores the usage of psychedelics for clinical purposes against AiDs is still infancy, the preliminary data is strongly indicative of these compounds having anti-inflammatory and immunomodulating effects . The classical psychedelic, lysergic acid-N,N-diethylamide (LSD) has the capacity to suppress proliferation of B-lymphocytes and pro-inflammatory cytokines IL-2, IL-4 and IL-6 in vitro spleen lymphocytes that were derived from female B6C3F1 rats at the concentration range of 1-100 μM .. In the same research, it was seen that 0.001-0.1 uM range of LSD increased NK cells number while 100uM suppressed NK cells; suggesting a dose-specific pattern of immunomodulation.

In a different investigation, the substituted amphetamine 2,5-Dimethoxy-4-iodoamphetamine (DOI) was found to lower TNF-α levels in 10 week old male mice via 5-HT2A receptor agonism . Note that The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family. The same group in another recent study reported similar anti-inflammatory effects of 5-HT2A agonism in rat model of lung inflammation . Given the role of the 5-HT system in immune-modulation and inflammatory properties, it is highly likely that there are undiscovered immune and inflammatory effects from exposure to psychedelic compounds due to their serotonergic activity.

In a human study where ayahuasca was taken by healthy volunteers, the levels of lymphocytes recorded showed that CD4 and CD3 cells decreased and NK cells increased after administration . A significant decrease in C-reactive protein (CRP) levels in the blood were reported in a more recent human study in both healthy and depressed volunteers, but without any reduction in IL-6 levels . In a different human intramuscular ketamine study, levels of Il-6 and TNF-α were found to be drastically reduced between 40-240 min post-infusion. The reductions were directly correlated with depression scores except on 3 and 7 days post-infection .

The Sig1R receptor is another target that psychedelics like DMT and 5-MeO-DMT bind with high affinity. This receptor plays a crucial role in regulating different cellular mechanisms like mitochondrial apoptosis, proliferation and neuroprotection . Sig1R also modulates immune and inflammatory response by activation of transcription factors nF-kB and mitogen-activated protein kinases (MAPKs). Both NF-kB and MAPKs are pivotal molecules involved in immune responses as well as inflammatory cytokine production.

In one study, harmine, a major component of the ayahuasca vine, suppressed pro-inflammatory NF-kB production at doses of 25 and 50mg/kg in response to treatment with LPS in male Kunming mice in which kidney injuries were induced . Harmine also inhibited tumour necrosis factor-alpha (TNF-α) and LPS-induced TNF-α transactivity and nuclear translocation in mouse macrophage, another study showed .

In another separate in vitro and animal in vivo study, DMT and 5-MeO-DMT showed anti-inflammatory IL-10 increase while pro-inflammatory Il-1B, IL-6, TNF-α and chemokine CXCL8/IL-8 levels were decreased in human monocyte-derived dendritic cells . Salivary IL-6 levels were also found to decrease after inhalation of 5-MeO-DMT in a relatively small group of human subjects .

All of these reported results are suggestive of the possibility that serotonergic psychedelics can very soon emerge as potential candidates in the AiD treatment. Pharma grade DMT and other tryptamine analogs are already available or are in the verge of market release for human clinical trials, and the future looks promising for these drugs.

Some psychedelics might work against glutamate excitotoxicity

The cytotoxic effects of the excessive (uncontrolled) release and binding of post-synaptic neurons is known as glutamate excitotoxicity; and it is seemingly implicated in brain-related diseases including multiple sclerosis, depression, addiction and neurodegenerative diseases .

Though not a classical psychedelic, the dissociative anaesthetic compound ketamine is shown to have the ability to protect against glutamate-mediated excitotoxicity via non-competitive blocking of the NMDA glutamate recepto r. Ayahuasca component Harmine has been also reported to increase Excitatory Amino Acid Transporter 2 (EAAT2) glutamate pump expression in the CNS, suggesting the possibility that it may reduce glutamate toxicity in vivo .


All of these examples and possible mechanisms cited above present a robust promise for using psychedelics in the treatment of AiDs which are more likely to complicate as individual ages. Psychedelics might hence be really useful in this rather under-realised realm of therapeutic application via their immunomodulatory actions.

[1]J.-M. Anaya, C. Ramirez-Santana, M.A. Alzate, N. Molano-Gonzalez Rojas-villarraga a. The autoimmune ecology Front. Immunol., 7 (2016), 10.3389/fimmu.2016.00139

[2] M.M. Kosiewicz, A.L. Zirnheld, P. Alard Gut microbiota, immunity, and disease: a complex relationship Front Microbio, 2 (2011), 10.3389/fmicb.2011.00180

[3]B.E. Phillips, Y. Garciafigueroa, M. Trucco, N. Giannoukakis Clinical tolerogenic dendritic cells: exploring therapeutic impact on human autoimmune diseaseFront. Immunol., 8 (2017), 10.3389/fimmu.2017.01279

[4]L. Abdelhamid, X.M. Luo Retinoic acid, Leaky Gut, and autoimmune diseases Nutrients, 10 (2018), 10.3390/nu10081016

[5]C. Kaegi, B. Wuest, J. Schreiner, U.C. Steiner, A. Vultaggio, A. Matucci, et al. Systematic review of safety and efficacy of rituximab in treating immune-mediated disorders Front. Immunol., 10 (2019), p. 1990, 10.3389/fimmu.2019.01990

[6]G. Moroncini, G. Calogera, D. Benfaremo, A. Gabrielli Biologics in inflammatory immune-mediated systemic diseases CPB, 18 (2018), pp. 1008-1016, 10.2174/1389201019666171226152448

[7]E.G. Severance, F.B. Dickerson, R.H. Yolken Autoimmune phenotypes in schizophrenia reveal novel treatment targets Pharmacol. Ther., 189 (2018), pp. 184-198, 10.1016/j.pharmthera.2018.05.005

[8]E.-M. Siegmann, H.H.O. Müller, C. Luecke, A. Philipsen, J. Kornhuber, T.W. Grömer Association of depression and anxiety disorders with autoimmune thyroiditis: a systematic review and meta-analysis JAMA Psychiatry, 75 (2018), p. 577, 10.1001/jamapsychiatry.2018.0190

[9]C.R. Pryce, A. Fontana Depression in autoimmune diseases R. Dantzer, L. Capuron (Eds.), Inflammation-Associated Depression: Evidence, Mechanisms and Implications, vol. 31, Springer International Publishing, Cham (2016), pp. 139-154, 10.1007/7854_2016_7

[10]R. Dantzer, J.C. O’Connor, G.G. Freund, R.W. Johnson, K.W. Kelley From inflammation to sickness and depression: when the immune system subjugates the brain Nat. Rev. Neurosci., 9 (2008), pp. 46-56, 10.1038/nrn2297

[11]A. Szabo Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities Front. Immunol., 6 (2015), 10.3389/fimmu.2015.00358

[12]R.V. House, P.T. Thomas, H.N. Bhargava Immunological consequences of in vitro exposure to lysergic acid diethylamide (LSD) Immunopharmacol. Immunotoxicol., 16 (1994), pp. 23-40, 10.3109/08923979409029898

[13]D.E. Nichols Psychedelics Pharmacol. Rev., 68 (2016), pp. 264-355, 10.1124/pr.115.011478

[14]F. Nau, J. Miller, J. Saravia, T. Ahlert, B. Yu, K.I. Happel, et al. Serotonin 5-HT 2 receptor activation prevents allergic asthma in a mouse model American Journal of Physiology-Lung Cellular and Molecular Physiology, 308 (2015), pp. 191-198, 10.1152/ajplung.00138.2013

[15]R.G. dos Santos, M. Valle, J.C. Bouso, J.F. Nomdedéu, J. Rodríguez-Espinosa, E.H. McIlhenny, et al. Autonomic, neuroendocrine, and immunological effects of Ayahuasca: a comparative study with d-Amphetamine J. Clin. Psychopharmacol., 31 (2011), pp. 717-726, 10.1097/JCP.0b013e31823607f6

[16]N.L. Galvão-Coelho, A.C. de Menezes Galvão, R.N. de Almeida, F. Palhano-Fontes, I. Campos Braga, B. Lobão Soares, et al. Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca J. Psychopharmacol. (Oxford) (2020), 10.1177/0269881120936486

[17]M.-H. Chen, C.-T. Li, W.-C. Lin, C.-J. Hong, P.-C. Tu, Y.-M. Bai, et al. Rapid inflammation modulation and antidepressant efficacy of a low-dose ketamine infusion in treatment-resistant depression: A randomized, double-blind control study Psychiatry Res., 269 (2018), pp. 207-211, 10.1016/j.psychres.2018.08.078

[18]A. Szabo, A. Kovacs, E. Frecska, E. Rajnavolgyi Psychedelic N,N-Dimethyltryptamine and 5-Methoxy-N,N-Dimethyltryptamine Modulate Innate and Adaptive Inflammatory Responses through the Sigma-1 Receptor of Human Monocyte-Derived Dendritic Cells PLoS One, 9 (2014), 10.1371/journal.pone.0106533

[19]In one study, harmine, a major component of the ayahuasca vine, suppressed pro-inflammatory NF-kB production at doses of 25 and 50mg/kg in response to treatment with LPS in male Kunming mice in which kidney injuries were induced.

[20]X. Liu, M. Li, S. Tan, C. Wang, S. Fan, C. Huang Harmine is an inflammatory inhibitor through the suppression of NF-κB signaling Biochem. Biophys. Res. Commun., 489 (2017), pp. 332-338, 10.1016/j.bbrc.2017.05.126

[21]M.V. Uthaug, R. Lancelotta, A. Szabo, A.K. Davis, J. Riba, J.G. Ramaekers Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment Psychopharmacology, 237 (2020), pp. 773-785, 10.1007/s00213-019-05414-w

[22]M. Kostic, N. Zivkovic, A. Cvetanovic, I. Stojanovic, M. Colic IL-17 signalling in astrocytes promotes glutamate excitotoxicity: indications for the link between inflammatory and neurodegenerative events in multiple sclerosis Mult. Scler. Relat. Disord., 11 (2017), pp. 12-17,

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[24]C.G. Abdallah, T.G. Adams, B. Kelmendi, I. Esterlis, G. Sanacora, J.H. Krystal Ketamine’s mechanism of action: a path to rapid-acting antidepressants Depress. Anxiety, 33 (2016), pp. 689-697,

[25]Y. Li, R. Sattler, E.J. Yang, A. Nunes, Y. Ayukawa, S. Akhtar, et al. Harmine, a natural beta-carboline alkaloid, upregulates astroglial glutamate transporter expressionNeuropharmacology, 60 (2011), pp. 1168-1175,

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