- Our Thesis
- An Outdated Framework
- An Expanded Perspective
- Understanding Neuroplasticity
- Reshaping the Brain
- Mechanism of Action
- Miracle-Gro for the Brain
- The Default Mode Network
- The DMN and Mental Health
- Ketamine and the DMN
Wondermed's Scientific Approach
At Wondermed, we believe in every human’s innate potential to live a joyful and empowered life. Since our inception in 2020, we have committed to showing people a new way of healing and ultimately, a new way of being. As more and more people are failed by current approaches in mental healthcare, there has never been a more urgent time to shift the paradigm in our understanding and treatment of disorders like anxiety and depression. Wondermed believes that through education and the adoption of a more holistic approach to treatment, this shift can become a reality.
In order to create true change, we must transition from the oversimplified framework we’ve been using to talk about mental health, and embrace a more multidimensional and integrated model of understanding. Research has continued to demonstrate depression and anxiety are not simply caused by an imbalance or deficiency in neurotransmitters such as serotonin, and are instead influenced by a far more complex combination of factors. A more nuanced perspective is needed, one that considers not only the influence of anatomical small-scale systems such as neuron and dendrite growth, levels of certain proteins, and the regulation of signaling pathways, but higher level principles, such as how we can enhance our brain’s ability to adapt to change, modulate the relationship between our inner and outer worlds, and disrupt rigid thought patterns that keep us constrained to our past experiences.
As our scientific understanding of mental health evolves, it follows that our treatments must evolve as well. Benzodiazepines and SSRIs are based on a bottom-up approach, in hopes that modulating aspects of the brain at a chemical level will help solve more abstract intricate issues such as depression and anxiety. However, treating a byproduct rather than the root concern will never bring about sustained transformation.
Wondermed believes that psychedelic medicine, including ketamine therapy, holds the potential for true transformation in its ability to modulate higher up processes that allow us to see the world and ourselves through a different lens. Through mechanistic actions such as the upregulation of BDNF and mTOR signaling pathways, ketamine fertilizes the brain and increases plasticity of key regions involved in emotional processing and cognition. This increase in synaptogenesis and neurogenesis happens alongside the normalization of disruptions within and between larger brain networks, such as the Default Mode Network, responsible for our inner processing of abstract beliefs about the world and our place in it.
What does this all mean? Psychedelic therapy relaxes the rigidity around core beliefs that have solidified certain thought patterns in our brain we may not even know are there - thought patterns that color every experience and lead to negative loops that feel impossible to escape. It allows us to finally look at the core models that run our lives:
Do you believe the world is a safe place or a dangerous one?
Do you believe that people are trustworthy or to be feared?
Do you believe you are deserving of love?
This ability to see and question inner models is followed by a window of openness in the days and weeks following the experience, allowing the opportunity for new and more healthy thought patterns to take root.
Through the integration of these small and large scale processes, Wondermed believes ketamine and psychedelic therapy will pioneer a revolution in how we think about mental health and will serve as a catalyst in facilitating humans to learn how to access the power of their own brain in order to find true healing.
Our Thesis: The Power of the Brain
The human mind is incredibly powerful - constantly running subconscious programs influence how and what you think, the actions you take, and the emotions you feel – all together creating your unique experience of reality. When we’re fighting mental illnesses like anxiety or depression, these internal scripts often skew towards a negative view of ourselves and the world, leaving us to navigate our lives through the lens of this non-constructive system of core beliefs.
Wondermed believes in the innate power of the mind to restructure itself in a positive way. Our approach is about empowering you to harness the power of your mind to transform your life - leveraging psychedelic medicines, like ketamine therapy, alongside holistic healing modalities informed by cutting-edge neuroscience. It’s a model of mental health treatment that goes beyond just alleviating symptoms, striving to address depression and anxiety at the root. Wondermed’s philosophy is founded upon the view of the medicine as a catalyst for healing; a tool that lets you observe how your subconscious influences your reality, overcome the programming that’s been holding you back, and see the world in a whole new way. This revolutionary new perspective underlies a novel treatment approach, with a profound potential for transformational healing that’s supported by a growing body of science.
More than a Chemical Imbalance: An Outdated Framework
While steadily progressing research has significantly advanced our knowledge of the science behind depression and anxiety, our understanding of the factors underlying these disorders is far from complete.
For the last five decades, the prevailing theory for the origins and development of depression and anxiety has pointed to low levels of certain neurotransmitters in the brain as the culprit.6 Consequently, targeting these key neurotransmitters – such as serotonin, norepinephrine, dopamine, and GABA – became a major focus in the development of treatments for these disorders.
As a result, medications thought to help correct this “chemical imbalance” — such as SSRIs and benzodiazepines — have dominated psychiatry for decades. While these medications have long been the gold standard of treatment, they’ve garnered considerable criticism for their unsatisfactory rates of effectiveness, long delays before patients feel a positive impact, and unpleasant side effects.14
Studies report that between 30 and 50% of patients with depression treated with traditional antidepressants experience no improvement in their symptoms, while only about 50% of patients with anxiety respond to conventional treatments.1, 12 So while these medications have offered relief for countless people, they’ve failed to do the same for innumerable others, leaving millions without adequate treatment for their mental illnesses. Furthermore, the popular “chemical imbalance” hypothesis upon which these treatments are based has recently been called into question, with critics pointing out its lack of substantial scientific backing, while new discoveries continue to reveal that the pathophysiological underpinnings of disorders is far more complex than was previously known.8
In other words: Our current model for managing disorders like depression and anxiety remains based on an outdated and oversimplified understanding of these conditions. Wondermed is committed to developing improved treatments for these conditions that are informed by new scientific discoveries that have helped us better understand the pathologies of these complex disorders.
An Expanded Perspective
Research has established that the factors underlying disorders like depression and anxiety are far more nuanced than the previous cut-and-dried presumption of a deficiency in serotonin or norepinephrine. A growing number of scientists are endorsing a broader view that points to abnormalities in higher-level neuron circuit functioning, connections between neurons, and neuron growth.14
This view is supported by the finding that both depression and anxiety disorders are marked by a loss of neurons and a reduction in connectivity within particular regions of the brain, such as the prefrontal cortex and the hippocampus.5 These powerful higher brain centers coordinate a range of fundamental cognitive processes, regulating our thoughts, moods, and emotions.
A loss of connections in these regions, as is seen in conditions like depression and anxiety, interferes with the ability of these structures to function properly, leading to impaired cognition and disruptions in normal mood and emotional control.5
The association between depression and anxiety disorders and these structural abnormalities has spurred a surge of interest in finding treatments that could potentially reverse this damage, such as through supporting the generation of new neurons and the growth and strengthening of connections between nerve cells and circuits.7
Those processes fall under the umbrella of a phenomenon known as neuroplasticity, which refers to the brain’s remarkable ability to change, adapt, and reorganize itself throughout life. Neuroplasticity is a crucial function of a healthy brain, and includes processes like neurogenesis (the formation of new neurons), synaptogenesis (the formation of new connections between neurons), and the strengthening – or weakening – of existing connections between neurons and neural circuits.8 Wondermed believes that the brain’s ability to rewire and reprogram itself is its innate superpower, one that lies within all of us – and that this superpower may be the key to creating lasting positive change and sustained healing.
Understanding Neuroplasticity: The Key to Sustained Healing
To understand the concept of neuroplasticity, it’s important to understand the basic structure and function of the brain. The fundamental units that make up the brain are neurons, specialized cells that function to rapidly transmit information across the vast and complex networks of the nervous system. Neurons communicate with one another using chemical messengers known as neurotransmitters, which are released by one cell into a space called the synapse, which serves as a junction that connects one neuron to another. Neurotransmitters travel across the synapse to pass along their message to an intricate web of branched spines, known as dendrites, which extend from the body of the receiving neuron. Neurons are continually forming, eliminating, and modulating connections in response to the constant flow of information taken in by the brain on a daily basis.8
Throughout life, the brain is constantly forming new synaptic connections in response to different stimuli and experiences, a process that plays an important role in memory and learning. Existing connections between neurons are also modified throughout life: They can either be strengthened by repeated use or weakened when they aren’t used. The formation of new connections between neurons, also known as synaptogenesis, and the strengthening or weakening of existing connections, reflect two mechanisms through which the brain changes and “rewires” itself – neuroplasticity. Neuroplasticity also includes neurogenesis (the generation of new neurons) and dendritogenesis (changes in the number, shape, and density of dendritic spines).8
The brain enables you to perform a variety of complex functions – from multiplying two numbers together, to thinking about what to get a friend for their birthday, to playing a song on the piano. These actions, thoughts, and emotions are made possible by neural “circuits,” organized pathways of neurons that work together to perform a specific function. The more you “run” a neural circuit in your brain – for example, when practicing that song on the piano – the stronger the circuit becomes. This is summarized by an old saying in neuroscience, “neurons that fire together, wire together” – the behaviors and thought patterns you practice and perform on a daily basis get stronger. Our innate ability to reinforce and strengthen neural circuits just by repeatedly using them means that if we feel badly on a daily basis, these negative thoughts can become even stronger and more persistent. But it also means we have the ability to weaken these negative emotional and cognitive patterns and replace them with more positive ones - a process that lies at the core of Wondermed’s treatment approach.
Reshaping the Brain: “The Master Neurotransmitter”
The newfound attention garnered by neuroplasticity has sparked interest in a neurotransmitter known as glutamate, the major excitatory neurotransmitter in the central nervous system. Glutamate is the primary neurotransmitter involved in neuroplastic processes and has been called “the master neurotransmitter responsible for shaping the entire brain.”11 This role as a key regulator of processes related to neuroplasticity have implicated the promising potential of treatments that target glutamate, such as ketamine.
Ketamine’s Mechanism of Action: The Nitty Gritty Details
So what exactly happens when ketamine enters the body? While ketamine interacts with a variety of receptors in the brain, one of its most notable targets is a type of receptor for the neurotransmitter glutamate, known as an N-methyl-D-aspartate (NMDA) receptor. Ketamine is what we call a “non-competitive antagonist” for this receptor type, which is essentially a fancy way of saying that when ketamine binds to an NMDA receptor, it prevents the receptor from being activated.15
Ketamine has a high affinity for NMDA receptors located on a specific type of neuron, known as GABAergic interneurons. When activated, GABAergic interneurons release a neurotransmitter known as GABA into the synapse. GABA is an inhibitory neurotransmitter, meaning it restrains the propagation of chemical messages throughout the brain by making it harder for the target neuron to release glutamate.
When ketamine binds to NMDA receptors on these interneurons, it prevents them from being activated and releasing GABA. And without GABA inhibiting the target cell from unleashing its stores of glutamate, the release of this neurotransmitter surges, resulting in a spike in extracellular glutamate concentration.15
As a result of these heightened glutamate levels induced by ketamine, the odds that a molecule of glutamate will end up binding to and activating other compatible receptors increases. One important receptor that is affected by this increased availability of glutamate is a receptor subtype known as AMPA receptors (AMPA is short for 𝛼-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid).15
The resulting increase in AMPA receptor action triggers downstream mechanisms which ultimately enhance neuroplasticity, namely via two main processes: the upregulation of BDNF and mTOR.15
“Miracle-Gro for the Brain”
The first important event resulting from ketamine’s binding is an increase in levels of a protein called brain-derived neurotrophic factor (BDNF), referred to as “Miracle-Gro for the brain” by Dr. John J. Ratey, a Harvard Medical School psychiatry professor. BDNF is an important growth factor involved in healthy neuron function, synapse formation, and synaptic plasticity. By increasing levels of BDNF, ketamine facilitates the formation of new, healthy neural connections and supports overall neural health and synaptic connectivity.15
The second event is an increased activation of the mammalian target of rapamycin (mTOR) signaling pathway. mTOR is involved in a variety of processes related to neuroplasticity, from stimulating the expression of proteins associated with synaptogenesis to regulating dendritic spine growth.15
Ketamine preferentially upregulates these processes in the PFC and the hippocampus, effectively repairing the damage to these regions characteristic of depression and anxiety disorders.5
In addition to repairing neuronal damage associated with anxiety disorders, ketamine’s ability to enrich neuroplasticity also leads to an increase in flexibility in the brain, making it easier to change negative patterns of thoughts and behaviors and replace them with more positive ones.
People with depression and anxiety commonly exhibit rigid patterns of thinking that keep them trapped in a cycle of persistent worry, dread, and hopelessness. These negative thought loops are often all-consuming and self-reinforcing – meaning the more time spent running these scripts, the stronger and more automatic the neural pathways associated with these scripts become. By enhancing neuroplasticity, ketamine effectively facilitates a rewiring of the brain, providing an opportunity for new, positive patterns of thinking to take root.
The Default Mode Network
In addition to impacting the brain’s organization through local changes to neural pathways and circuits, ketamine also impacts the connectivity of the brain at the macro level by altering the functioning of higher-order cognitive networks. One such network is an extensive system of interconnected brain regions known as the default mode network, or the DMN.
In older perspectives of neuroscience, the brain was thought to remain relatively idle when we are at rest, becoming increasingly active when we engage in more demanding cognitive tasks and goal-directed behaviors. However, newer brain imaging studies have revealed that this is far from the case – with findings that show the activity of the brain is no less bustling and dynamic during passive tasks than it is during tasks that require more focused effort.4
We’ve come to understand that this high level of activity observed in the brain during idle periods is a product of what we now call the default mode network.4 We can think of the DMN as our internal dialogue – it becomes active when we think about ourselves or about others or about the world, when we reflect on the past or imagine the future, and when we engage in activities like contemplation, reflection, daydreaming, and emotional processing.
The DMN is most active when the brain is not focused on the external world and is instead engaged in introspective thought, but this network never fully “turns off.” It remains active in the background of all we do, consciously or unconsciously, in our daily lives.13
The DMN and Mental Health
The ongoing activity of the DMN forms what can quite literally be described as our brain’s “default mode” of function, profoundly influencing how we perceive our reality and how we operate within the world. Abnormal patterns of DMN activity are a well-established feature of both depression and anxiety disorders, a finding that is unsurprising considering the significant role this network plays in shaping how we experience and navigate the world.13
Individuals with these disorders often exhibit a prevailing inner monologue dominated by negative self-talk, maladaptive rumination, worrying, and an inclination towards rigid, detrimental patterns of thought. As the architect of our inner monologue, the DMN has been implicated in constructing these aberrant patterns of thought.
Studies have found that individuals with depression or anxiety show increased activity in certain regions of the DMN, as well as a failure to downregulate the automatic, spontaneous activity of this network at times when it is appropriate and constructive to do so, such as when focusing on a task.4 These dysfunctional alterations are thought to underlie many of the maladaptive cognitive patterns typical of these disorders, resulting in an inability to escape from an incessant cycle of negative thoughts.
Ketamine and the DMN
Wondermed has leveraged this knowledge to inform treatment of depression and anxiety. We know from studies imaging the brains of meditation practitioners that mindfulness and other forms of meditation have been shown to reduce DMN activity. We also know that the same seems to be true for psychedelics, which regulate the connectivity between the DMN and areas of the brain active in task behavior, while also decreasing within network DMN activity.
Ketamine specifically has been shown to modulate the functional connectivity and activity of the DMN, allowing for regulation of previously dysfunctional processes involved in depression and anxiety. During a ketamine session, connectivity within the frontal regions of the DMN decreases, essentially “turning down the volume” on our default thought patterns and providing space to reflect on these repetitive scripts with renewed perspective.
We all experience our realities through a system of core, personal beliefs about who we are and how the world works. When we’re depressed or anxious, we’re more likely to see ourselves and the world in a negative light, and this fundamental system of beliefs and assumptions can keep us trapped in limiting negative patterns.
Ketamine and psychedelics effectively disrupt these rigid belief systems, initiating a window of increased openness to change in the days and weeks following treatment and creating an optimal state for positive cognitive restructuring and behavioral change. Wondermed aims to take advantage of this window of neuroplasticity, emphasizing the importance of purposeful behavioral change, integration work, and lifestyle modifications in order to generate lasting positive transformations and sustained healing.
- Ansara, E. D. (2020). Management of treatment-resistant generalized anxiety disorder. The mental health clinician, 10(6), 326–334.
- Arnsten A. F. (2009). Stress signaling pathways that impair prefrontal cortex structure and function. Nature reviews. Neuroscience, 10(6), 410–422.
- Calder, A. E., & Hasler, G. (2023). Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 48(1), 104–112.
- Coutinho, J. F., Fernandesl, S. V., Soares, J. M., Maia, L., Gonçalves, Ó. F., & Sampaio, A. (2016). Default mode network dissociation in depressive and anxiety states. Brain imaging and behavior, 10(1), 147–157.
- Duman R. S. (2014). Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections. Dialogues in clinical neuroscience, 16(1), 11–27.
- Eske, J., & Moawad, H. (2019, September 26). Chemical imbalance in the brain: Myths and facts. Medical News Today.
- Krystal, J. H., Tolin, D. F., Sanacora, G., Castner, S. A., Williams, G. V., Aikins, D. E., Hoffman, R. E., & D'Souza, D. C. (2009). Neuroplasticity as a target for the pharmacotherapy of anxiety disorders, mood disorders, and schizophrenia. Drug discovery today, 14(13-14), 690–697.
- Liu, B., Liu, J., Wang, M., Zhang, Y., & Li, L. (2017). From Serotonin to Neuroplasticity: Evolvement of Theories for Major Depressive Disorder. Frontiers in cellular neuroscience, 11, 305.
- Liu, W., Ge, T., Leng, Y., Pan, Z., Fan, J., Yang, W., & Cui, R. (2017). The Role of Neural Plasticity in Depression: From Hippocampus to Prefrontal Cortex. Neural plasticity, 2017, 6871089.
- Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., Burbach, K. F., Soltanzadeh Zarandi, S., Sood, A., Paddy, M. R., Duim, W. C., Dennis, M. Y., McAllister, A. K., Ori-McKenney, K. M., Gray, J. A., & Olson, D. E. (2018). Psychedelics Promote Structural and Functional Neural Plasticity. Cell reports, 23(11), 3170–3182.
- Pal M. M. (2021). Glutamate: The Master Neurotransmitter and Its Implications in Chronic Stress and Mood Disorders. Frontiers in human neuroscience, 15, 722323.
- Ruelaz, A. R. (2006, October 1). Treatment-Resistant Depression: Strategies for Management. Psychiatric Times.
- van Oort, J., Kohn, N., Vrijsen, J. N., Collard, R., Duyser, F. A., Brolsma, S. C. A., Fernández, G., Schene, A. H., Tendolkar, I., & van Eijndhoven, P. F. (2020). Absence of default mode downregulation in response to a mild psychological stressor marks stress-vulnerability across diverse psychiatric disorders. NeuroImage. Clinical, 25, 102176.
- Yale School of Medicine. (2021, June 17). How Depression Affects the Brain. Yale Medicine News.
- Yang, C., Yang, J., Luo, A., & Hashimoto, K. (2019). Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites. Translational psychiatry, 9(1), 280.