1Affect regulation is a person’s ability to identify, initiate, or change the course of emotional experience. According to a study in Eating and Weight Disorders, body perception is informed by explicit and implicit images of the body and is constantly recalibrated based on multisensory sources, like tactile, auditory, vestibular, and visual information. Distortions in spatial cue integration can include a person’s inability to formulate an accurate interpretation of their body based on this data.

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Ketamine as an Emerging Treatment for Anxiety, Depression, Autism, and Other Conditions

July 21, 2022

A Molecule with Many Hands:

Ketamine as an Emerging Treatment for Anxiety, Depression, Autism, and Other Conditions

After it entered psychiatry, Ketamine sparked a paradigm shift in scientific perspectives on the biology of depression. While practitioners traditionally used Ketamine for anesthetic purposes in mainstream medicine, it also acts as a powerful antidepressant and anxiety-relieving medication, spurring its widespread adoption as an off-label treatment for a variety of mental health issues. 

This guide traces the current state of the research on Ketamine for anxiety, obsessive-compulsive disorders, and as a pharmacological agent to uncover insights related to poorly understood conditions, including autism and schizophrenia. 

Like other psychedelic treatments, Ketamine has the power to transform the individual and psychiatry at large, but it’s not a magic pill. In certain instances, Ketamine can create adverse or seemingly paradoxical reactions. Questions about the impacts of timing, dosing, and routes of administration are still under investigation. Still, Ketamine therapy offers a wealth of promise for conditions that have eluded psychiatric pharmacology for decades.  

How Ketamine Inspired a Generation of Psychiatric Research

Ketamine began receiving attention from mainstream psychiatry in the late 1990s. At this time, it was becoming clear that the monoamine hypothesis of depression wasn't sufficient to explain the biology of the condition. The monoamine hypothesis suggested that depression reflected depletions in neurotransmitters like serotonin, dopamine, and/or norepinephrine in the central nervous system. 

Yet this theory began to lose ground with studies showing that depletions in these neurotransmitters didn’t reliably induce or worsen pre-existing depression in people not taking medication, among other inconsistencies. 

Ketamine’s potential as a rapidly effective antidepressant became widely recognized in 2000 when research in Biological Psychiatry hypothesized Ketamine’s potential antidepressant effects based on animal models of glutamate dysfunction. 

In the first placebo-controlled double-blind trial of Ketamine’s antidepressant effects, researchers administered 0.5 mg/kg of intravenous (IV) Ketamine over 40 minutes to select subjects with major depressive disorder (MDD). Compared to placebo infusions with saline, subjects who received Ketamine had significant improvements in depressive symptoms in just 72 hours.  

After this initial success, research continued to point to Ketamine’s rapid actions against depression. Studies reported that just one 0.5 mg/kg dose of Ketamine could mitigate suicidal ideation among people with MDD, sometimes within just 40 minutes after an infusion. Since existing suicide interventions, such as hospitalization and psychotherapy, reduced the risk of suicide only on a long-term scale, Ketamine functioned as the first emergency anti-suicide drug. It proved capable of stabilizing individuals in acute states of distress. 

Potent, Yet Fleeting: Optimizing Ketamine’s Effects

After numerous studies reflected Ketamine’s powerful antidepressant effects, infusion clinics providing Ketamine as an off-label depression treatment multiplied. However, as research continued, it became clear that though Ketamine’s effects were rapid and robust, they were relatively short-lived, sometimes lasting only one to two weeks. 

As a result, the focus shifted from whether Ketamine reduced depression and suicidality to how to design dosing and timing protocols. The goal of this work has been to maximize and prolong the benefits while limiting the potential side effects that come with overly frequent use of any drug. While Ketamine is understood to be safe and well-tolerated, the consequences of long-term use are still under scrutiny. 

These protocols take the form of carefully timed dosing accompanied by therapeutic modalities designed to maximize the psychological “window of opportunity” Ketamine opens. 

Rewire Your Brain; Rewire Your Life: How Ketamine Works

Practitioners currently use the racemic form of Ketamine at infusion clinics as an off-label treatment for depression, anxiety, and other conditions. Janssen Pharmaceuticals patented a version of Ketamine, Spravato, which is available as a nasal spray for individuals with treatment-resistant depression. Other Ketamine enantiomers may feature in newly synthesized, more "functional" versions of Ketamine. These formulations will have fewer psychedelic, dopaminergic, and dissociative effects.

Ketamine exerts its antidepressant effects through a series of events related to glutamate, an excitatory neurotransmitter common to all vertebrates. Glutamate is central to learning, memory, and the delivery of thoughts and feelings. Ketamine increases glutamate by blocking the NMDA receptors, interfering with the signals that ordinarily pass between the brain and spinal column.

The compound’s changes to glutamate transmission levels then enhance activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, leading to the production and release of brain-derived neurotrophic factor (BDNF). Promoted during activities like exercise, BDNF supports neurogenesis or the growth of new neurons. 

It also stimulates neuroplasticity, the brain’s ability to adjust its structure and function to accommodate incoming information. While BDNF can factor into therapeutic responses to traditional antidepressants, they may not appear for many weeks, whereas Ketamine’s effects on brain plasticity manifest in a matter of hours.  

Like classic psychedelics, these neurochemical events reduce activity in the self-referential default mode network (DMN). The DMN is the hub of self-focused processing associated with rumination: worry about the past, anticipation for the future, etc. Mental health conditions like anxiety, depression, and PTSD tend to co-occur with heightened activity in the DMN.

From a subjective standpoint, Ketamine’s effects help people disidentify from long-held thought and behavior patterns, generating the psychological conditions for lasting change. Since rigid, fear- or worry-based assumptions drive so many emotional imbalances, Ketamine can help people open the door to new, more expansive ways of interpreting their inner lives and outer circumstances.

Ketamine for Anxiety: GAD, SAD, and PTSD

Because Ketamine has such a multi-faceted and complex pharmacological profile, investigators are exploring its potential as a treatment for people who can’t find relief from existing medications. A non-exhaustive list includes generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorders, and post-traumatic stress disorder (PTSD). 

Traditional SSRIs are known to cause emotional blunting, or a restricted range of both positive and negative emotions. As a result, not only do they fail to address the root cause of a person’s distress, but they may even interfere with their levels of motivation and empathy. They also can induce other significant, life-disrupting symptoms, such as headaches, insomnia, and sexual dysfunction. 

At the same time, when people take SSRIs or SNRIs for anxiety, they may not find relief for as long as two to four weeks. During this time, antidepressants can cause jitteriness and otherwise heighten anxiety levels, leading people to stop taking medication before they notice any benefit from it. 

By contrast, Ketamine can increase synaptic connections and relieve anxiety symptoms after just 24 hours. Researchers are exploring Ketamine’s potential for treating the following anxiety-centric conditions.

Generalized Anxiety Disorder and Social Anxiety Disorder 

A large body of work points to Ketamine’s role in anxiety disorders. To focus on just one, a 2020 study in the International Journal of Neuropsychopharmacology compared EEGs of 12 individuals with diagnoses of SAD or GAD. 

Looking at the effects of ascending levels of Ketamine against the benzodiazepine midazolam, the researchers found that Ketamine dose-dependently improved scores on a fear questionnaire. The study’s EEG results also suggested that its effects on theta brain wave frequencies in the right frontal side of the brain resembled the effects of conventional anxiety drugs. 

Post-Traumatic Stress Disorder (PTSD)

Since the publication of landmark books like Dr. Bessel van der Kolk’s The Body Keeps the Score, PTSD has received a great deal of attention within the somatic and other holistic therapy communities. 

Given the side effects and slow onset of commonly prescribed SSRIs for PTSD, researchers view Ketamine and other psychedelics as resources to address the “PTSD psychopharmacotherapy crisis," born of the fact that existing treatments help people achieve remission in only about 30 percent of cases.

After evidence suggested that the glutamatergic system played a key role in PTSD, researchers explored whether NMDA receptor agonists, like Ketamine, could alleviate PTSD symptoms. 

Authors in Neurochemistry International reviewed several studies showing dose-dependent, rapid, and persistent effects of Ketamine for PTSD and comorbid disorders. In particular, the authors cite evidence from a randomized double-blind crossover trial demonstrating that just one subanesthetic intravenous (IV) dose of Ketamine rapidly reduced the core symptoms of PTSD, outpacing the effects of the placebo and midazolam. 

Interestingly, Ketamine’s effects on PTSD are dose-dependent. Other studies show that Ketamine can promote the development of PTSD when it’s given shortly after a traumatic event. Ongoing research will focus on the specific window of time within PTSD to optimize its therapeutic effects while mitigating its potential risks. 

Ketamine and Obsessive-Compulsive Disorders

Authors in Brain Science categorize eating and substance abuse disorders within the larger umbrella of obsessive-compulsive disorders (OCD). These conditions share traits like obsessive thoughts, compulsive behaviors, and anxiety, yet they’re channeled through different preoccupations. 

Many studies over the last decade have pointed to Ketamine’s role in treating OCD spectrum disorders. Here's what we know: 

OCD 

Glutamate dysfunction plays a central role in the brain circuitry of OCD, making Ketamine a potentially useful treatment. One study looked at the effects of Ketamine on OCD when combined with exposure-based cognitive-behavioral therapy (CBT). For eight out of 10 test subjects, OCD symptoms didn’t persist or progress even after Ketamine’s acute effects faded. 

Yet despite these and other promising results, Ketamine’s role in OCD treatment hasn’t yet been definitively proven. Researchers note that it’s not clear whether abnormalities in the glutamate system fundamentally drive OCD or whether they are downstream effects of other processes more directly involved in its origins. 

Eating Disorders (EDs)

Eating disorders aren’t completely understood, but research focuses on drawing connections between ED symptoms and structural changes in the brain. Scientists point to correlations between disordered eating patterns and abnormalities in brain regions associated with affect regulation and social and spatial cue integration. These impairments compel restrictions in cognition and behaviors that further reinforce body image distortions. 

Researchers first studied Ketamine combined with oral nalmefene for individuals with anorexia nervosa (AN) in 1998. A clinical trial by Mills et al. reported significant reductions in symptoms for nine out of 15 individuals that lasted seven to 24 months after follow-up. The responders had significantly fewer symptoms of obsessive neurosis, along with greater weight acceptance and restoration. 

More recently, a 2021 case series in Clinical Case Reports evaluated individuals with severe AN and treatment-resistant depression who didn't respond to antidepressants. The subjects received intramuscular (IM) or IV Ketamine at 0.5mg/kg at four to six-week intervals over 12 months. This treatment led to meaningful changes in depression and suicidality, with moderate changes in anxiety and disordered eating. In this case, it wasn’t clear whether their improvements in ED symptoms were due to reduced mood symptoms or if the treatment independently affected their EDs.  

Researchers have also investigated Ketamine for EDs in conjunction with a modality called Emotion-Focused Family Therapy (EFFT). The intent behind EFFT is to help clients accept and process emotions that drive maladaptive eating behaviors and develop a capacity for self-soothing that is rooted in allowing, rather than trying to fight or change, their emotional experience. 

On the Psychedelic Therapy Podcast, clinical psychologist and EFFT creator Dr. Adele Lafrance described the results of a small study involving the administration of Emotion-Focused Ketamine-Assisted Psychotherapy for women with AN. 

After three IM Ketamine sessions followed by EFFT, Dr. Lafrance and her colleagues had the participants complete a scale called the Emotional Breakthrough Inventory, which measures emotional insights after psychedelic therapy. The results suggested that the intervention was as powerful as a clinical dose of psilocybin. Given its potency, pairing Ketamine with a person-centered, emotion-focused therapy modality helps make the most of the brain state the compound induces.

While research on Ketamine for EDs has focused primarily on AN, investigators note that Ketamine may help treat other EDs by normalizing glutamate dysfunction. Ketamine would also simultaneously promote the creation of new synapses and neuroplasticity in the weeks following use. Future research will explore and establish the optimal dose, duration, and frequency of Ketamine administration.  

1Affect regulation is a person’s ability to identify, initiate, or change the course of emotional experience. According to a study in Eating and Weight Disorders, body perception is informed by explicit and implicit images of the body and is constantly recalibrated based on multisensory sources, like tactile, auditory, vestibular, and visual information. Distortions in spatial cue integration can include a person’s inability to formulate an accurate interpretation of their body based on this data.

Alcohol Use Disorder (AUD)

Ketamine’s ability to drive neuroplasticity and new synaptic connections point to its utility in AUD. Research in Neuroscience and Biobehavioral Reviews describes the tendency of alcohol to interfere with synaptic plasticity neurogenesis in the hippocampus. 

These maladaptive changes promote cycles of craving and dependence. Researchers are thus investigating whether Ketamine could reverse these effects by driving connectivity in neural networks, contributing to synaptic plasticity and neurogenesis. 

Through these mechanisms, Ketamine may reduce maladaptive learning associated with AUD by generating new neural pathways that lend themselves to different behaviors. 

Ketamine for Autism Spectrum Disorder (ASD)

Studies have explored Ketamine for autism in both experimental and theoretical contexts. In 1991, research exploring whether Ketamine and other NMDA receptor agonists could help treat autism and other developmental disorders led to noteworthy results. 

Researchers gave children with autism 40 mg of Ketamine intramuscularly, followed by a 200 mg IV over two hours. The treatment led to enhanced alertness, calmness, and in one case, language generation, with changes lasting five to 12 days after administration.

In 2020, research in Cerebral Cortex showed for the first time that Ketamine restored brain dysfunctions that result from a genetic deletion seen in conditions like autism and Tourette syndrome. Autism has many genetic, environmental, and other roots, so while researchers don't frame Ketamine as a cure for autism, it could be part of an overarching autism therapy protocol. 

Ketamine may play a role in autism treatment because its mechanisms of action mimic the theoretical view of autism as a disorder of synaptic function and neural network connectivity. 

Progress in Neuro-Psychopharmacology and Biological Psychiatry gave Ketamine to mice shortly after their birth to gain insight into the mechanisms that drive ASD origins. 

The investigation worked to untangle the mechanisms behind the condition's origins and progression, aiming to highlight new targets for future drug treatments.

Ketamine for Schizophrenia

As with depression, studies about NMDA receptor antagonists, such as Ketamine, led to pronounced shifts in the understanding of schizophrenia. When evidence suggested that Ketamine could induce a schizophrenia-like state, pharmacological models began viewing the condition as a form of NMDA hypofunction, rather than dopaminergic dysfunction. 

This paradigm shift stimulated a body of research examining whether Ketamine could be used as a model to develop medications aimed at treating schizophrenia. While most of the research focuses on using Ketamine’s effects to understand the mechanisms behind schizophrenia, researchers have also looked at the drug’s impacts on individuals with the condition. 

For example, scientists in European Neuropsychopharmacology studied the consequences of 0.3 mg/kg of S-Ketamine for a person with schizophrenia and severe post-psychotic depression. After a protocol with three weekly Ketamine infusions over three weeks, the subject had reductions in depression and suicidality without psychotic or dissociative effects. 

Given how much remains mysterious about the condition, the authors urge more investigation into the effects of higher doses and other routes of administration. 

Ketamine Transformed Earlier Conceptions of Mental Illness, But Can It Change Psychiatry at Scale? 

As with other psychedelics, the many uses of Ketamine speak to its potential to transform psychiatry at a systemic level. 

Traditional psychiatric treatment centers on daily, sometimes lifelong medication. Ketamine therapy can unburden people from the psychological effects of this type of dependence. With treatments occurring a few times a year rather than every day, Ketamine is part of a new paradigm centered on therapeutic experiences whose effects extend well into the future.

Ketamine therapy also brings a greater coherence between the pharmacological and the psychological. Conventionally, practitioners use talk therapy and SSRIs in conjunction with each other. Yet traditional SSRIs and talk therapy don’t synergize or heighten each other’s effects to nearly the same extent as psychedelics. 

Since Ketamine accelerates rapport and bonding between client and therapist, therapy modalities that synergize with the subjective effects of psychedelic compounds are vital to psychedelic therapy’s trajectory. Along with EFFT, practitioners have pointed to Eye Movement Desensitization and Reprocessing (EMDR) therapy and Internal Family Systems (IFS), among others, as modalities capable of extending and broadening the neurological window of opportunity Ketamine induces. 

Investigations related to Ketamine’s accessibility, how to optimize dosing and maintenance schedules, and ideal routes of administration are urgent and ongoing. Yet given the growing ubiquity of “diseases of despair,” Ketamine may be a safer and more robust option for people who haven’t found relief from conventional therapies. It may simultaneously allow psychiatry to help people in ways that had long been only marginally possible.

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