Alli Feduccia, Ph.D

Alli Feduccia, Ph.D

Alli Feduccia, Ph.D. is a Neuropharmacologist working as a Clinical Data Scientist at MAPS Public Benefit Corporation. She is also Co-Founder and Director of Psychedelic Support, an online platform to connect with mental health professionals.

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Alli Feduccia, Ph.D

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Clinical trials of MDMA, psilocybin, ketamine, and ayahuasca are offering a glimpse that the future may hold psychiatric treatments far different from daily drug prescriptions currently used for anxiety and addictive disorders. Research is only beginning to unravel how these experiences in altered states of consciousness produce large shifts in psychological functioning. Although a purely biochemical model is not inclusive of psycho-spiritual or transpersonal explanations, here I describe what scientific explorations are reveling about how the brain responds when exposed to mind-altering compounds and how consciousness is intrinsically related to sculpting of neural networks.     

Psychedelic substances being investigated for mental health disorders target different receptors in the brain and produce various subjective effects, yet all appear capable of producing durable changes in thoughts and behaviors. Is there a common underlying mechanism for the therapeutic benefits being shown in these studies? The latest findings are suggesting that neuroplasticity is likely one common denominator for the effectiveness of these drugs.

Networks Wired for Change

You’ve probably heard by now that the human brain can rewire itself. Neuroplasticity is the basis for learning that shapes our cognition, memories, and behaviors in response to experience (Sagi et al., 2012) Recovery of normal functioning after brain injuries, such as strokes, often involves a restructuring of neural networks to compensate for loss of neurons in affected brain regions. Similar reorganization can occur as a person overcomes an addictive disorder or long-term depression.

New synapses are formed and others deleted as sensory information is uploaded to the brain through our interactions with the world. Even mental events crafted by the imagination can impact this process (Askenasy & Lehmann, 2013). When we try something new, like learning to surf or riding a bike, repetition through practice or memorization strengthens the synaptic pathways necessary to perform the activity. In a similar way, re-exposure to stressful events trains the brain to respond in certain ways. Being able to react to different situations is what keeps us alive, but if the predominant pathway constantly activates fear and anxiety, then the learned response can become maladaptive. 

Psychedelic Neurochemical Soups

Antidepressant and anti-anxiety effects in clinical trials of ketamine, MDMA, and psilocybin last after the drugs have left the body, suggesting something in the brain has changed. What has been amended and the processes underlying positive gains isn’t fully understood, but various studies are converging on a persuasive pathway that may explain at least some of the therapeutic effects.

Psychedelics have been shown to alter biochemistry by means of neuroplasticity in prefrontal-limbic brain circuits that are involved in mood disorders. Classical psychedelics, such as psilocybin and LSD, bind to 5-HT2A receptors that subsequently promote release of glutamate (Vollenweider & Kometer, 2010), primarily by increasing activity in pyramidal neurons of the prefrontal cortex. Modification of networks possibly happens by glutamate-stimulated increase of receptor trafficking and elevation of brain derived neurotropic factor (BDNF) levels, a key regulator of a signaling pathway known to produce proteins needed to create new synapses. Fairly recent rodent experiments have provided the first evidence that the necessary molecules to induce plasticity are present when MDMA is administered during a fear extinction training paradigm (Young, Andero, Ressler & Howell, 2015). MDMA helped extinguish fear of a cue previously paired with a shock, and enhanced levels of BDNF in the amygdala, an important brain region for fear processing,  supporting the hypothesis that MDMA increases factors that can change a learned fear response.

A newly published paper tested many psychedelic substances (MDMA, ketamine, LSD, DOI, DMT, ibogaine) from different drug classes (tryptamine, amphetamine, and ergoline) in rodents and flies (Ly et al., 2018). All were found to promote functional and structural changes in cortical neurons, including increasing the number of dendritic spines and synapses. For the first time ever, psychedelics were found to converge on a common signaling pathway (BDNF – TrkB – mToR) that increases connections between neurons and supports critical communication in cognitive-emotional networks. Another study found that proteins involved in synaptic formation and maintenance were increased in “mini-brains” (cerebral organoids that model neural cells of developing brain) after exposure to 5-MeO-DMT, providing further evidence for neuroplastic-promoting effects of psychedelics (Dakic et al., 2017).

A long-standing question is whether the subjective experience of a psychedelic is important for therapeutic benefits or if activating a specific neural pathway without the altered state of consciousness could produce the same outcomes. To date, we haven’t had any straightforward ways to test this because the experience is integrally linked to the drug itself. But now that patents have been filed for non-hallucinogenic analogs for inducing neuroplasticity (Olson, & Regents of The University of California, 2017) it appears that researchers are seeking answers to this very question. Even if a drug can stimulate neuroplasticity, one might wonder what is actually being learned or changed if the environmental inputs and internal dialogue is the same.

Consciousness Drives Learning

It is intriguing to think about how psychotherapy may influence plasticity and if synergistic effects would transpire by adding a substance that regulates these processes. Psychedelics may open a window of opportunity to stimulate changes in neural pathways. But to solidify new neural states, reinforcement in normal consciousness, known as non-drug integration sessions in psychedelic clinical trials, is presumed important to modify behaviors and actualize the insights acquired during peak experiences. This is especially relevant for using psychedelics to treat mental health conditions, such as depression or addictive disorders.

Reflection through integration practices, for example, therapy sessions and journaling, could be a way for the brain to receive feedback to incorporate the novel experiences encountered in altered states within the framework of everyday “normal” cognition. Conscious attention and motivation brought about through integration practices likely strengthen the lessons learned through journeys in altered states. A person’s will and intention can not only motivate them to engage in novel activities but may also drive attachment of emotional information to experiences, making it more likely that information will be noticed, imprinted, and transcribed into long-standing memories and habits. Meditation and mindfulness practices, for example, have demonstrated that directing one’s attention to observe thoughts can alter a range of physiological and psychological processes (Raffone & Srinivasan, 2010). Through thought and actions, the brain is able to alter structure and function.

More research is needed to validate these hypotheses, but combining a drug that facilitates neuroplastic modifications required for behavioral changes with therapy is a rational approach to test for treatment of mood disorders.

Our Brains Grow: Are Psychoactive Plants the Fertilizers?

The term “neuroplasticity” extends beyond functional adaptations and formation of new synaptic connections to describe anatomical changes. New neurons are born every day in the adult brain, specifically in the hippocampus, a region important for memory (Deng, Aimone & Gage, 2010). Although many don’t survive, several integrate into nearby brain tissue to become functional in neural circuits. This process referred to as adult neurogenesis plays a role in memory and learning, with increased neurogenesis associated with gains in cognition and memory capacity. On the other hand, decreased neurogenesis is implicated in several disorders, including Alzheimer’s disease, schizophrenia, stress-related disorders, and depression (Zhao, Deng, & Gage, 2008).

Drugs that regulate the serotonin system impact neurogenesis, and therapeutic benefits of antidepressants for treating depression is associated with increased birth of new neurons Eliwa, Belzung, & Surget, 2017). Research is underway to understand if psychedelic compounds may trigger neurogenesis.

Animal studies and two recent clinical trials of depressed patients demonstrated that ayahuasca has rapid antidepressant effects. When alkaloids (harmine, harmaline, and tetrahydroharmine) prevalent in ayahuasca were added to a petri dish with hippocampal stem cells, more cells migrated and matured into adult neurons (Morales-García, et al., 2017). Taken together, this suggests that ayahuasca may stimulate adult neurogenesis which may underlie its potent antidepressant effects.

Trailblazing a New Discipline of Neuroscience Research

While neuroscience research has proven that the brain is malleable through functional changes at the synaptic level and by birthing new neurons to rebuild circuits, we have only just embarked in research to understand how altered states of consciousness generated from psychedelics influence these biochemical processes. By mapping the neurological mechanisms, we may be able to optimize the therapeutic and transformative potential of these experiences. Research on psychedelic-assisted therapies and integration practices will further illuminate what is most effective and how best to implement for individualized care.

References

Askenasy, J. M., & Lehmann, J. (2013). Consciousness, brain, neuroplasticity. Frontiers in Psychology, 412. DOI: 10.3389/fpsyg.2013.00412

Dakic, V., Nascimento, J. M., Costa Sartore, R., Moraes Maciel, R., Araujo, D. B., Ribeiro, S. … Rehen, S. K. (2017). Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Scientific Reports, 7(1), 12863.

Deng, W., Aimone, J. B., & Gage, F. H. (2010). New neurons and new memories: How does adult hippocampal neurogenesis affect learning and memory? Nature Reviews Neuroscience, 11(5), 339–50.

Eliwa, H., Belzung, C. & Surget, A. (2017). Adult hippocampal neurogenesis: Is it the alpha and omega of antidepressant action? Biochemical pharmacology, 141, 86–99.

Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C. … David Olson, D. (2018).  psychedelics promote structural and functional neural plasticity. Cell Reports, 23(11), 3170–3182.

Morales-García, J. A., Fuente Revenga, F., Alonso-Gil, S., Rodríguez-Franco, M. I., Feilding, A., Perez-Castillo, A., & Riba, J. (2017). The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen ayahuasca, stimulate adult neurogenesis in vitro. Scientific Reports, 7(1), 5309.

Olson, D. E & Regents of The University of California. (2017). Compounds (non-hallucinogenic analogs) for increasing neural plasticity. [Patent application WO2018064465]. Retrieved from https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=82BAEA12447CCAC62BA8161E7682D3A9.wapp2nA?docId=WO2018064465&recNum=5&office=&queryString=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22G01N%22%26fq%3DPAF_M%3A%22THE+REGENTS+OF+THE+UNIVERSITY+OF+CALIFORNIA%22&sortOption=Pub+Date+Desc&maxRec=557

Raffone, A., & Srinivasan, N. (2010). The exploration of meditation in neuroscience of attention and consciousness. Cognitive Processing, 11(1), 1–7

Sagi, Y., Tavor, I., Hofstetter, S., Tzur-Moryosef, S., Blumenfeld-Katzir, T, & Assaf, Y. (2012). Learning in the fast lane: New insights into neuroplasticity. Neuron, 73(6), 1195–1203.

Vollenweider, X., & Kometer, M. (2010). The neurobiology of psychedelic drugs: Implications for the treatment of mood disorders. Nature Reviews Neuroscience, 11(9), 642.

Young, M. B., Andero, R., Ressler, K. J., & Howell, L. L. (2015).  3, 4-Methylenedioxymethamphetamine facilitates fear extinction learning. Translational Psychiatry, 5(9), e634.

Zhao, C., Deng, W., & Gage, F. H. (2008). Mechanisms and functional implications of adult neurogenesis. Cell,132(4) 645–660.