At its most basic, ketamine is a mind-affecting drug that is commonly used as an anesthetic in medicine. It was first developed in the 1960s and has been federally approved for medical use in the United States since 1970.
As a psychotropic drug, it acts on the brain to create a dissociative state, during which a person may feel distant or detached from their body and the world around them. This dissociative quality makes patients less likely to register pain or associate it with a physical stimulus This is why it’s ideal as an anesthetic and even effective during major operations or after severe injuries.
When used as an anesthetic under professional medical supervision, ketamine is largely safe. The drug can cause respiratory depression, but these effects are generally less severe than those of other anesthesias, and it also leads to circulatory stimulation, which sets it apart from other anesthetic drugs. When taken in a medical setting, properly calibrated anesthetic doses are low risk, and they don’t cause physical dependence.
Ketamine has also been used illicitly, largely because of its psychoactive effects. Certain doses may lead to severe dissociation to the point of feeling entirely separated from one’s body, and some people may even experience hallucinations. Illicit ketamine is also administered differently from the clinical forms, which can lead to dangerous side effects.
What is the regulation status of ketamine?
Ketamine is listed as a Schedule III drug, which means it has recognized medical applications and a low risk of physical dependency. Schedule III drugs may still show a moderate risk for misuse.
The anesthetic form, known as racemic ketamine, has been in use for decades and currently has no safety restrictions. This form is administered as an injection in clinical settings.
American and European regulators approved S-ketamine, a therapeutic form with antidepressant qualities, in 2019. However, the FDA has had to release clarifications that this approval only covers the S-ketamine nasal spray, rather than a compounded formula that may be taken by other means. It also doesn’t cover off-label uses for racemic ketamine.
What is ketamine therapy?
In recent years, ketamine has also seen a surge in use as a depression treatment, especially in severe cases where other antidepressants have not helped and suicidal ideation is a major concern. Some studies suggest that ketamine-assisted therapy is effective at treating major depressive disorder due to its ability to quickly reduce depressive moods and suicidal ideation. These effects have even been shown to last for multiple days just from a single dose.
In 2019, the FDA approved Spravato®, a nasal spray containing S-ketamine for use in medically monitored situations to address treatment-resistant depression. However, because Spravato is still a sedative and anesthetic, ketamine-assisted therapy was originally intended to be undertaken only with direct medical supervision, and access to the drug was closely monitored.
This changed in 2020 when telehealth suddenly became the primary method of healthcare during the COVID-19 pandemic. The public health emergency required the federal government to extend the purview of telemedicine, and treatments like ketamine therapy, which could previously only be done in person, were allowed to happen remotely. Since then, the prescription of ketamine as a depression treatment has become more popular, despite the fact that only one form has been approved for such use.
As it stands right now, ketamine-assisted therapy is only verified to be effective when using S-ketamine in nasal spray form, and this treatment is only intended to address depression. The spray works because S-ketamine is an NMDA receptor antagonist, which means that it binds to NMDA receptors in the brain and prevents other substances from doing so. This causes an increase in a neurotransmitter called glutamate, which activates AMPA receptors in the brain and effectively increases the connectivity and efficiency of communication between neurons in the brain. This impacts moods and has been shown to decrease the symptoms of depression. It’s also possible that the drug helps with depression through other vectors, though they’re not yet well studied.
What’s the problem with off-label ketamine use?
It’s important to remember that the different forms of ketamine are not interchangeable. That means switching from therapeutic S-ketamine to anesthetic racemic ketamine can be dangerous. And compounded versions—which can have altered formulas and delivery methods—are completely unregulated, meaning they haven’t been studied or verified as safe and effective.
Even beyond these risks is the fact that off-label usage might not be properly supervised, putting patients at risk. If there’s no one available to monitor a patient for potential side effects, they’re at a greater risk for dangerously high blood pressure and depressed respiration. An altered formula can also increase the drug’s abuse potential and sedative and dissociative effects.
What about changing the delivery method? While compounded ketamine is available as a nasal spray, which can seem legitimate since Spravato is also a spray, it’s also available in tablet form. This means the drug is metabolized differently, which can lead to organ system problems, including urinary tract infections (UTIs). As with any tablet, it can also be crushed into powder and inhaled, which delivers the drug to the brain faster and speeds up the dissociative effects. This is why ketamine has become a popular party drug, nicknamed Special K.
When is ketamine therapy not recommended?
While ketamine-assisted therapy is promising and has shown positive results for many people, it isn’t without risks, and it’s not always the best option for every individual. In fact, many have begun questioning the therapy’s safety after one particular, high-profile case. Late in 2023, Matthew Perry, the actor perhaps best known for playing Chandler in Friends, was found unresponsive at his home and later declared deceased. The County of Los Angeles Medical Examiner has since declared that the cause of his death involved the “acute effects of ketamine,” as well as drowning, buprenorphine, and coronary artery disease. However there was no evidence that low levels of buprenorphine contributed to his death.
This has led some to question whether ketamine therapy, which Perry is known to have been undergoing, was to blame and if it’s in fact a safe treatment. Perry’s last ketamine treatment is said to have been over a week before his death, which means that the therapy was unlikely to have been the cause. Therefore, it’s more likely that the actor was undergoing further unknown ketamine treatment or using the drug illicitly. However, this doesn’t mean that his case doesn’t highlight an important message.
Perry was very open about his lifelong struggle with substance use disorder, including both extensive alcohol and opioid use. This left him with health problems, such as the coronary artery disease that contributed to his death, but it also indicated a risk of ketamine misuse. While medically supervised ketamine treatment is safe, additional use of the drug runs increased risks of deleterious and even fatal side effects. When considering whether ketamine-assisted therapy is right for an individual, their likelihood to misuse the drug should be taken into account. Additionally, ketamine has many potential physical side effects that need to be taken into consideration. Individuals with respiratory or circulatory issues may have an increased adverse reaction to the sedative properties of ketamine, and those with hypertension or bladder, kidney, or liver problems need to be extra careful taking ketamine.
What are the signs of ketamine misuse?
Despite its current medical applications and its promise of new applications in the future, it is still possible to misuse ketamine, and some individuals may experience addiction. The signs of misuse largely mirror those of other drugs, such as opioids and painkillers, though unlike many other drugs, ketamine leads only to psychological dependence and not physical dependence.
A person undergoing ketamine therapy may be misusing if they refuse to or struggle to stop or slow their use, develop an increasing tolerance to the drug and require higher doses, feel the compulsive need to take the drug, or become distressed when discontinuing use. Signs of addiction or overuse may include chronic bladder issues, including bloody urine, memory loss, or problems concentrating.
Sources
