Since the 1960s, ketamine has proved to be an essential medicine, providing anesthesia, sedation, and analgesia in psychedelic clinics and hospitals around the world. More recently, ketamine has been shown to provide rapid relief from severe depression. This discovery led to FDA approval of the first ketamine-related drug in 2019. For decades, depression has been thought to arise from chemical imbalances in monoamine neurotransmitter systems like serotonin and norepinephrine. As a result, traditional antidepressants are used to increase the function of these systems, usually with limited efficacy over a long time frame.
In contrast, ketamine treatments quickly alleviate severe depression and suicidal ideation by modulating different neurotransmitter systems. While ketamine’s antidepressant action is still not fully understood, its unique mechanism of action and effectiveness represents a paradigm shift in psychiatry’s understanding of treatment-resistant depression. The extent of these effects varies, however, depending on the types of ketamine.
Different Types of Ketamine
Before we dive into the three types of ketamine, let’s take a look at the chemistry behind the molecule. Like many synthetic drugs, ketamine is chiral, meaning it exists in several isomeric forms. Isomers are molecules with the same bonded atoms, but which differ in their three-dimensional orientation. Ketamine is available as a pair of right- and left-handed mirror-image isomers known as R(+) and S(-) ketamine. These enantiomers are non-superimposable, similar to our right and left hand when they are placed on top of each other.
Due to their different spatial arrangements, the enantiomeric forms of ketamine bind in the body and brain differently. In turn, this alters both their pharmacological activity, and how the enantiomeric forms metabolize. However, all forms of ketamine work in the brain by blocking, to varying extents, a type of glutamate channel called the N-methyl-D-aspartate receptor. By targeting this receptor, ketamine increases the excitatory neurotransmitter glutamate in the brain. This mechanism activates downstream targets that stimulate the creation of new neural connections. This process is known as neuroplasticity, which is known to be disrupted in the brains of those with depression.
Although sharing many similarities, R and S ketamine are effectively two different drugs with their own properties. Recently, pharmaceutical companies have taken interest in purifying and patenting single-enantiomer (enantiopure) ketamine drugs.
R,S-ketamine
When producers make ketamine in the lab, they curate it as an equal 50/50 mixture of both R and S enantiomers. This generic form of racemic ketamine is R,S-ketamine, selling under the brand name Ketalar. It has the longest track record of use medically, with over 50 years of use for anesthesia and pain relief in medical settings.
In addition to its medical use, most recreational ketamine is in the racemic form as a crystalline powder. People use it intranasally, or sometimes orally when pressed into tablets. Medically, it is available in a wide variety of other forms, including oral, sublingual, nasal, rectal, subcutaneous, and intramuscular injections.
S-ketamine (Esketamine)
Esketamine is the S-enantiomer of ketamine. The FDA approved it in March of 2019 for treatment-resistant depression, when used in conjunction with an oral antidepressant (SSRI). The FDA recommended approval after reviewing five Phase III trials, of which two showed significant positive effects with moderate efficacy. Individuals recognize the substance for its rapid action in reducing depression and suicidal ideation. This relief becomes visible within four to 72 hours, and lasts up to several weeks.
Esketamine is made by Janssen Pharmaceuticals, Inc., a subsidiary company of Johnson & Johnson. It is currently selling as a prescription medication under the brand name Spravato. Due to a restriction distribution system, it is only available to patients in the presence of a healthcare provider in a medical setting.
Compared to its enantiomer, Arketamine, esketamine is a more potent psychedelic drug. It possesses greater dissociative effects and dopaminergic activity. Its affinity for the NMDA receptor and anesthetic potency is ~4 times larger. Studies have also shown the body removes it more quickly than R-ketamine or racemic ketamine.
R-ketamine (Arketamine)
Unlike the S enantiometer, the FDA has not given approval to Arketamine as an antidepressant–yet. However, there are both promising preclinical research and open-label trials showing Arketamine may be superior for severe depression. Arketamine shows weaker activity at the NMDA and sigma receptors. As a result, it produces fewer hallucinogenic and dissociative effects than esketamine.
Additionally, arketamine shows less dopaminergic activity than its mirror image molecule, which may translate to lower abuse potential. Arketamine is also able to stimulate the formation of new neural connections (synaptogenesis), which may also underlie its potent antidepressant action. All in all, Arketamine may be a more potent and longer-lasting antidepressant, with fewer side effects than esketamine.
It’s important to note that findings in animal models of depression don’t seamlessly map onto the complexities of human depression. However, this research has sparked the interest of biopharmaceutical companies, spurring them to further assess the therapeutic potential of Arketamine. ATAI’s Perception Neuroscience, the same company developing psilocybin as a treatment for depression, recently embarked on a Phase I trial evaluating its tolerability and pharmacokinetics in patients with treatment-resistant depression.
Ketamine: Common Routes of Administration
Although people have been using ketamine in a variety of forms for over 50 years , the intranasal and intravenous routes are the principal ways professionals administer ketamine for depression.
Intranasal
Ketamine consumers often do the intranasal route in both in recreational and medical settings for racemic ketamine and Spravato, respectively. Recreationally, powdered ketamine is insufflated at a common dose of ketamine ranging from 30–75 mg. On the other hand, individuals administer Spravato as a nasal spray in medical settings in a fixed dosage of either 54 or 84 mg. This corresponds to two or three insufflations, given intermittently in two-hour visits, one to two times per week.
Intravenous Infusion
The most common consumption method of racemic ketamine is often off-label as an intravenous infusion in the treatment of severe depression. It produces potent antidepressant effects within hours, which can endure for several weeks. For depression, health practitioners typically administer racemic ketamine intravenously at a dose of 0.5mg/kg over approximately 45 minutes. Typically, IV ketamine therapy consists of six ketamine infusions, spaced out over two to three weeks.
How to Determine the Right Type of Ketamine for You
Ketamine’s success rate is almost double that of traditional antidepressants, and so for some, it might be an easy choice when traditional treatments fail. Yet, choosing which type of ketamine is a more nuanced matter. This is because the best treatment choice depends not only on the type of ketamine, but also on each person’s unique needs and familiarity with the drug.
After the first placebo-controlled study finding potent antidepressant effects in 2000, individuals have been using racemic ketamine as off-label at sub-anesthetic doses to treat severe depression. It still remains a popular off-label option for major depression, typically used when other antidepressant treatments fail to produce a response. People also successfully use it for a range of other mental health disorders, including PTSD, OCD, anxiety disorders, and neuropathic pain. Currently, the government has only endorsed esketamine strictly for major depressive disorder.
Which Form of Ketamine is More Effective?
Despite Spravato’s FDA approval, it may not be superior to the racemic form under some metrics. The bioavailability of IV ketamine is 100%, meaning the full dose of the substance is available have an effect in the brain. Therefore, healthcare providers know exactly how much dose should be given over the treatment time period.
In addition, the dosage can be titrated optimally depending on where the patient is in his or her treatment timeline: the first dose will be much different than the last dose in the treatment course. On the other hand, the intranasal bioavailability of Spravato is 43%, with absorption rates varying from person to person. For non-responders, it can be difficult to discern whether or not the problem is a matter of absorption or the drug itself.
Spravato is also significantly more expensive, with a price tag of US$590–885 per dose for the patient or insurance. The cost of ketamine infusion therapy depends on the patient’s treatment plan but can generally range from $400–1200 per infusion. These infusion sessions are typically quicker than the clinic visit for Spravato, lasting approximately half as long as a Spravato treatment visit.
As for Arketamine, significant clinical data and potential FDA approval for medical use are years away. But based on the available literature, it may be a superior antidepressant to esketamine. It may also be safer and have fewer side effects. Until more research emerges, racemic ketamine is the best option until researchers find one enantiomer to be significantly safer; and to have fewer side effects.
RS CONTRIBUTING AUTHOR: DYLAN BEARD
Dylan Beard is a freelance science writer and editor based in the beautiful Pacific Northwest. After finishing his physics degree and dabbling in neuroscience research at UC Santa Barbara in 2017, he returned to his first love: writing. As a long-term fan of the human brain, he loves exploring the latest research on psychedelics. Among other studies such as nootropics, psychology, consciousness, meditation, and more. When not writing, you can probably find him on hiking trails around Oregon and Washington or listening to podcasts. Feel free to follow him on Insta @dylancb88.
