Ketamine: The Chemistry, Effects, and Brain Science

By Tessa Eskin

Ketamine is rapidly emerging as an incredibly effective and fast-acting mental health medicine. The drug first emerged after the synthesis of phencyclidine in 1956, an anesthetic for monkeys. Testing on humans, however, resulted in cases of acute ‘emergence delirium’, lasting hours after surgery. Dr. Calvin Lee Stevens, while searching for a short-acting derivate, stumbled onto the compound C1-581—today known as ketamine.

August of 1964 saw the first human trial of intravenous ketamine, resulting in minimal emergence delirium. Subjects reported dissociative effects—a floating feeling with disconnection from their bodies and environment, and numbness in the limbs. From the 1970s, the anesthetic was a staple for surgeries on wounded soldiers during the Vietnam War.

Since the 1990s, ketamine has been a common treatment for chronic pain. But this anesthetic is fast proving to have immense and near-miraculous physiological benefits, most notably for depression. The research reveals a deeper understanding of the brain, giving new hope to hope to patients and clinicians alike.

Floating in Space

Medically, ketamine is administered as a clear liquid. On the street, it appears as a grainy white or brown crystalline powder or tablets. Administered nasally, ketamine takes about 15 minutes to hit, entering the bloodstream quickly. Orally, it takes about 20 minutes.

The intoxicating effects can last from 20 minutes to a couple of hours, inducing a dreamlike, detached, and relaxed state. Ketamine can alter perceptions of time and space, and sometimes causes hallucinations. In fact, the feeling is comparable to ‘floating in space’, prompting the recreational use of ‘Special K’ as a party drug.  

Ketamine is at once sedating and stimulating, with mild psychedelic effects on the mind. It can often cause euphoria,  feelings of ‘looseness’, and depersonalization. But beneath the surface of these experiences, a flurry of chemical changes are taking place within the brain. Scientists still can’t fully explain how it works, but have several leading theories resulting from research on ketamine as an antidepressant.

Ketamine & Depression

Research has recently confirmed ketamine treatment as among the biggest breakthroughs in depression in over 50 years. Studies on patients with treatment-resistant depression show both short-term relief and long-term benefits. Amazingly, long after the intoxicating effects of ketamine wore off, subjects with depression reported feeling lighter, more relaxed, and clearer. The next day some even said they felt like they were back to themselves. No antidepressant has ever alleviated depression so quickly.

Unlike traditional antidepressants, ketamine appears to rapidly reverse symptoms of depression in a matter of hours, with long-lasting effects. Ketamine appears to repair damaged brain circuits, which researchers believe are a leading cause of depression.

Stress, Depression and Synapses

Depression likely results from certain misconnections of synapses, often caused by chronic stress. Ketamine implements a two-step program to resolve this. First, it detaches the improper synapses—allowing them to regrow and reattach. Then, over time, synapses regenerate, connecting cells and allowing the brain to communicate more effectively as a network.

The suspected cause for depression is the effect of stress, which depletes synapses in the prefrontal cortex and limbic system. Studies show that ketamine assists with the regrowth of these damaged synapses.

Ketamine binds to NMDA receptors in the brain, increasing the amount of glutamine between receptors. Glutamine is the most common excitatory neurotransmitter in the brain, regulating large parts of the nervous system. plays a vital role in the changes synapses undergo in response to experiences that underlie learning and memory. Glutamine then activates connections in the AMPA receptor.

The blockade of NMDA receptors and simultaneous activation of AMPA receptors cause a release of molecules that assist communication between neurons. This creates neural highways that allow better control over negative emotions. Depressive symptoms are relieved almost immediately, with positive behavioral effects maintained over time.

There may be an additional benefit, as depression is linked to chronic inflammation, and ketamine happens to be a powerful anti-inflammatory medication. It’s likely a combination of these effects that give such quick and long-lasting relief for treatment-resistant depression.

In March 2019, the FDA approved esketamine, a ketamine-derived treatment for depression. The drug will be administered as a nasal spray, released by Janssen Pharmaceuticals of Johnson & Johnson. This and other advances in ketamine treatments will offer relief to countless patients suffering from depression, hopefully helping combat the current global mental health crisis.