Ketamine: Benefits and Risks for Depression, PTSD & Neuroplasticity

The episode opens by framing ketamine as a compound with two very different public lives. It is used clinically to treat depression, suicidality and PTSD, and it is also used recreationally, with what the episode calls a high potential for abuse. The stated plan is to cover the clinical research and the risks together: how ketamine produces dissociative states, what a so-called K hole is in scientific terms, dosages, delivery routes, and the potential harms of using it outside an appropriate clinical context.

A central claim is that the immediate effects felt while under the influence are only part of the story. Ketamine is described as changing neural circuitry, and that applies both to its use in treating depression, suicidality and PTSD and to recreational use, where long-term brain changes also occur. This is why the episode also covers neuroplasticity, meaning the nervous system's ability to change in response to experience, and brain-derived neurotrophic factor (BDNF), described as a critical molecule for all forms of learning, memory and change in the nervous system.

The episode points out something it says most people do not realize: ketamine is very similar to phencyclidine (PCP), known on the street as angel dust or sherm. The two broadly share a mode of action in the brain, since both are dissociative anesthetics, although the episode says it is not talking about the specifics. PCP was taught in drug education and shown on television as a drug that removed pain perception and made people violent, with stories of users breaking their hands on light poles or fighting off eight or 10 police officers. The episode explicitly does not vouch for these stories ("I don't know whether or not any of that is true or not") and notes that PCP was grouped with drugs like cocaine and methamphetamine.

Public discussion of ketamine now focuses mostly on its benefits, and the episode accepts that these benefits are real, but only under specific conditions and not for everyone:

In the appropriate clinical context, at the appropriate dosages, and given at the appropriate frequency, ketamine has proven to be a miraculous drug for some people, not all people, for the treatment of depression, suicidality, and PTSD.

The same drug also shows up at parties, where people talk about entering K holes, a state the episode links to taking too much ketamine, whether a little too much or a lot. The episode identifies a newer overlap between medical and recreational use. Some people obtain ketamine legally to treat depression but take it outside the clinic, which the episode stresses is very different from the conditions in most of the studies on ketamine and depression. It also argues that wider access to any drug with abuse potential tends to bring more recreational use, and that some users do become addicted. Addiction here is described as feeling compelled to use ketamine even as it degrades work, school, relationships and finances.

On history, the episode mentions some early cases in the 1970s of ketamine being used to treat PTSD, mainly in soldiers in Vietnam or people returning from it. It says clinical use for depression, suicidality and PTSD has really taken off only in the last five to 10 years. Ten or 20 years ago, the drug was grouped closely with PCP and seen mainly as a drug of abuse.

To explain how a drug once viewed as a street drug came to be widely prescribed, the episode reviews how thinking about depression has changed. The monoamine hypothesis dates from about 1950 and gained ground in the early 1980s and '90s. It holds that depression comes from deficiencies in monoamines such as serotonin, dopamine and norepinephrine. These are neuromodulators made from amino acids, and they can raise or lower activity in neural circuits across the brain and body. The episode notes, for example, that the gut has and needs serotonin.

The episode then draws a sharp line between the theory and the drugs it produced:

Now, in reality, there is very little, if any, evidence that there is a deficiency of monoamines in any form of depression.

Even so, drugs that raise monoamines can often relieve some symptoms of depression in some people. The examples given are Prozac and Zoloft, which increase serotonin, and bupropion (brand name Wellbutrin), which increases dopamine and norepinephrine. The episode cites two main limits learned over the last 30 or 40 years:

Effectiveness: these drugs are said to work in only about 40% of depressed people who take them, so about 60% do not respond at all. Side effects: even people who get relief often face dry mouth, more commonly drops or rises in appetite, large drops in libido, or changes in sleep. These can make the drugs impossible, or at least very uncomfortable, to keep taking. Some people do find a dose that gives relief without side effects they can't tolerate.

The episode balances this by saying SSRIs and Wellbutrin have helped a tremendous number of people and in many cases have warded off suicidality. The gap it describes is the need for compounds without similar side effects that could ideally help everyone with depression, not just 40%. This is where ketamine comes in. The episode says that before the 1990s, ketamine-type compounds were studied mainly in neuroscience and pharmacology labs for their abuse and anesthetic properties.

Ketamine is a dissociative anesthetic, and the episode says it is often, though not always, used to induce some forms of anesthesia for surgery. It explains that anesthesiologists rarely give just one drug. Typically one drug reduces anxiety and sometimes some pain, another takes the patient into a deeper plane of anesthesia, and modern methods monitor that plane and can bring a patient out if it becomes too deep. The episode suggests that surgical patients might ask which drugs are used to put them under, keep them under and bring them out.

"Plane of anesthesia" is defined as a spectrum. It runs from full wakefulness, to reduced anxiety, to falling asleep, to a depth at which even a really intense pinch would not wake a person. Ketamine blocks the response to pain and can produce deep anesthesia at certain doses. At lower doses it produces transition points between being awake and being deeply anesthetized. The episode calls this transition the dissociative state, a liminal state that can feel somewhat like dreaming. That state is what has most often been sought for treating depression, suicidality and PTSD.

This framing supports one of the episode's warnings about recreational use. It is not clear what plane of anesthesia or dissociation recreational users are actually seeking. Effects vary a great deal with dose, and individuals vary tremendously in how they respond. Delivery route also matters. The routes listed are oral pills, sublingual troches that dissolve under the tongue, and injection into a vein or a muscle, and each can produce very different speeds of onset and effects. The episode presents this variability as the reason some recreational experiences are desirable while others are unpleasant, very unpleasant or dangerous.