Ketamine’s clinical journey spans more than six decades, evolving from a battlefield anesthetic to a groundbreaking therapeutic tool in mental health. Its history reflects a convergence of neurobiological discovery, clinical intuition, and unmet therapeutic needs, leading to its current role in the treatment of depression, addiction, and treatment-resistant conditions. This article explores the key milestones that have shaped ketamine’s evolution and its relevance in contemporary psychiatric practice.

Depression, anxiety and chronic stress are associated with the loss and retraction of dendritic spines, disrupting communication between key brain regions involved in emotion, memory and decision-making. This disconnection reduces cognitive flexibility and promotes rumination and rigid negative patterns. Ketamine and other psychedelics have been shown to rapidly enhance neuroplasticity by increasing the formation and stabilization of dendritic spines, reopening critical learning periods. When combined with psychotherapy and supportive habits, this window of plasticity can facilitate lasting emotional and behavioral change.

This article explains the key differences and similarities between ketamine and esketamine in the treatment of resistant depression. It reviews their shared glutamatergic mechanisms, distinct stereoisomeric forms, routes of administration and side effect profiles. Evidence from preclinical and clinical studies suggests racemic ketamine and R-ketamine may offer longer lasting antidepressant effects and fewer adverse reactions than S-ketamine. The text also addresses subjective experiences, dissociative effects, cost, regulatory issues and why many clinics prioritize racemic ketamine in personalized, evidence based care.

Ketamine-assisted psychotherapy can use several routes of administration, each with different pharmacokinetic profiles. This article explains bioavailability and half-life, and compares intramuscular, intranasal and oral ketamine. Intramuscular administration offers very high bioavailability, rapid onset and longer half-life, while intranasal delivery has moderate bioavailability and shorter duration, and oral use shows slower onset and lower absorption. Based on these factors, the clinic prioritizes intramuscular injection as a balanced option combining efficacy, predictability, patient comfort and clinical safety in routine ketamine-assisted psychotherapy settings.

Prolonged or complicated grief affects around 10% of bereaved people and is marked by persistent longing, intense emotional distress, and functional impairment. Current evidence shows only moderate benefits from psychotherapy and no proven efficacy of medication alone. Recent research highlights psychedelic-assisted therapies as promising alternatives. Ketamine-assisted therapy may support grief treatment through two complementary mechanisms: a neurobiological window of enhanced neuroplasticity that increases psychological flexibility, and meaningful altered-state experiences that facilitate acceptance, emotional processing, and the reconstruction of personal narratives around loss.

Chronic neuropathic pain is often severe, persistent, and poorly responsive to conventional treatments such as anti-inflammatories or opioids. Ketamine has emerged as a promising option by modulating NMDA receptors involved in pain perception and memory. Clinical studies show that ketamine can significantly reduce pain for weeks, particularly in complex neuropathic conditions. Beyond analgesia, ketamine may also improve comorbid depression and PTSD, which frequently accompany chronic pain. When combined with psychotherapy, ketamine offers an integrative approach addressing both physical suffering and psychological distress.

Chronic pain is a complex condition lasting more than three months that affects millions of people and severely impacts quality of life. It includes multiple forms such as neuropathic, musculoskeletal, cancer-related and post-surgical pain, often without a clearly identifiable cause. Conventional treatments like anti-inflammatories and opioids show limited efficacy or significant risks. Growing evidence supports ketamine as a safe and effective option, offering sustained pain reduction and enabling multidisciplinary approaches that combine medical, psychological and rehabilitative interventions for long-term functional improvement.

Suicidal ideation represents a major public health concern and requires rapid, effective intervention. Conventional treatments such as antidepressants and psychotherapy often act too slowly for high-risk patients. Recent clinical evidence shows that ketamine can significantly reduce suicidal ideation within hours or days, particularly in individuals with bipolar disorder. Randomized controlled studies demonstrate higher remission rates compared to placebo, without worsening symptoms. Although further long-term research is needed, ketamine emerges as a valuable tool for suicide prevention in acute and high-risk clinical situations.

Ketamine is a dissociative anesthetic synthesized in 1962 that has become a key compound in modern mental health research. Acting primarily as a non-competitive NMDA receptor antagonist, ketamine increases glutamate signaling, promotes synaptogenesis, and enhances neuroplasticity. It also interacts with opioid, serotonergic, muscarinic, and adrenergic receptors, and increases BDNF expression. These combined mechanisms help explain its rapid antidepressant effects, while ongoing research continues to clarify why some patients respond and others do not, and how dosage and context influence therapeutic outcomes.

Posttraumatic stress disorder (PTSD) involves intrusive memories, hyperarousal, dissociation, avoidance, and high comorbidity with depression, anxiety, and substance use. Standard treatments combine psychotherapy and antidepressants, yet remission rates remain low. Ketamine-assisted psychotherapy is emerging as a promising adjunct, targeting glutamatergic dysfunction, enhancing neural connectivity, and enabling therapeutic processing of traumatic memories from altered states of consciousness. Clinical studies show rapid symptom reduction after ketamine infusions, though effects may be transient and protocols require optimization. Careful screening is essential, as recent trauma may represent a contraindication.

The “Talk Openly about Mental Health” project brings mental health conversations into the public space of Gràcia, Barcelona, giving voice to lived experiences and professional perspectives. In the edition focused on mental health and drugs, Estefanía Moreno represented Clínica Synaptica with a talk on ketamine-assisted psychotherapy. The event combined clinical insights, community dialogue, and artistic expression, fostering openness, reflection, and a shared commitment to reducing stigma around mental health.