What Are The 3 Types Of Ketamine, And Which One Is Right For You?
When people talk about ketamine, they are speaking about the drug in a general way, as if there is only one type of ketamine. But in actual fact, there are three types of ketamine: R,S-ketamine, S-ketamine, and R-ketamine. These three different versions of ketamine have varying applications.
To better understand this compound — and its uses in medical and therapeutic contexts — it will be helpful to elucidate these three types of ketamine.
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What makes them different? Why are these differences relevant to their specific purposes? This will allow you to decide which one is right for you.
But before describing these three types of ketamine, it is worth explaining the chemistry behind the ketamine molecule, and how this can come in two different types. These two different types are the basis of the three types we will then detail.
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Types Of Ketamine: R And S Ketamine
As is true with many other synthetic drugs, ketamine is chiral, which means it exists in several isomeric forms. Isomers are molecules with the same bonded atoms, yet they differ in their three-dimensional orientation.
You can find ketamine as right- and left-handed mirror-image isomers known as R(+) and S(-) ketamine. These are enantiomer forms of ketamine. And they are non-superimposable, similar to when you place your right and left hand on top of each other. They don’t match up.
Because of their different spatial arrangements, R and S ketamine bind in the body and brain differently. This changes their pharmacological activity and how R and S ketamine are metabolized.
Nevertheless, all types of ketamine work in the brain by blocking, to varying degrees, a type of glutamate receptor called the N-methyl-D-aspartate (NMDA) receptor. By targeting this receptor, ketamine increases the amount of glutamate in the brain. Glutamate is an excitatory neurotransmitter, meaning it encourages cells to take action.
Through its effects on glutamate, ketamine can stimulate the creation of new neural connections. This is a process known as neuroplasticity, which research finds is disrupted in the brains of people suffering from clinical depression. By enhancing neuroplasticity, ketamine can help alleviate the symptoms of depression.
While R and S ketamine share many similarities, they are essentially two different drugs with their own properties. In light of these different properties, pharmaceutical companies have developed varying types of ketamine that have specific uses.
Types Of Ketamine: R,S-Ketamine
When manufacturers make ketamine in the lab, they create an equal 50/50 mixture of both R and S enantiomers. The generic form of racemic ketamine is R,S-ketamine. It gets sold under the brand name Ketalar. This type of ketamine has the longest track record of medical use, with over 50 years of use for anesthesia and pain relief in medical settings.
In 1970, the Food and Drug Administration (FDA) approved the use of ketamine (Ketalar) as an anesthetic. Following this FDA approval, Americans used the drug during the Vietnam War to treat wounded soldiers. Medics utilized ketamine in cases of amputees, gashes, and shock wounds.
As an anesthetic, ketamine for pain relief and amnesia was effective during medical treatment. It also helped to lessen the distress and fright that soldiers experienced when injured. Soldiers who were given a high, anesthetic dose of ketamine were much easier to load and transfer away from danger.
The anesthetic and analgesic effects of ketamine occur quickly after administration, which also made it useful on the battlefield.
Medical professionals also use ketamine in certain medical emergencies and procedures because it increases heart rate and blood pressure, which helps prevent blood loss. But it has this effect without lowering the breathing rate.
This differs from other anesthetics that lower heart rate, blood pressure, and breathing rate. Ketamine is, therefore, one of the safest anesthetics available.
Hospitals and medical settings still use R,S-ketamine as an anesthetic. This is despite ketamine becoming a Schedule III drug in the U.S. in 1999.
As well as being used medically, most recreational ketamine use involves the racemic form as a crystalline powder. People typically use the powder intranasally, although some users take it orally when the powder is pressed into tablets. A minority of users also inject the drug.
Medically, R,S-ketamine is available in a variety of forms, including oral, sublingual, nasal, rectal, subcutaneous, and intravenous (IV) and intramuscular (IM) injections.
Types Of Ketamine: S-Ketamine
S-ketamine (esketamine), sold under the brand name Spravato, is the S-enantiomer of ketamine. The FDA approved it, as a nasal spray, on March 5, 2019 for treatment-resistant depression (depression that has not responded to antidepressant medications).
The FDA recommended approval after reviewing four clinical trials looking at Spravato nasal spray for treatment-resistant depression. These were three short-term trials and one long-term one. One of the short-term trials showed statistically significant antidepressant effects compared to placebo.
In the longer-term trial, patients in stable remission following Spravato who continued treatment with Spravato and an antidepressant were free of depression for longer than patients who were given a placebo nasal spray plus the antidepressant.
On August 3, 2020, the FDA also approved Spravato for the treatment of major depressive disorder (MDD) with acute suicidal ideation or behavior.
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Janssen Pharmaceuticals, Inc., a subsidiary company of Johnson & Johnson, makes esketamine, selling it as a prescription under the brand name Spravato.
Due to restrictions, it is only available to patients in the presence of a healthcare provider in a medical setting. You cannot get a prescription to esketamine nasal spray, take it home with you, and administer the ketamine on your own.
Compared to R-ketamine (which we will explore next), esketamine is a more potent psychoactive drug. It induces greater dissociative effects and dopaminergic activity. This means taking this drug is more likely to lead to effects like feeling detached from your body, your surroundings, and your sense of self.
Its affinity for the NMDA receptor and anesthetic potency is four times greater. In addition, the body removes S-ketamine more quickly than racemic ketamine or R-ketamine.
Types Of Ketamine: R-Ketamine
Unlike S-ketamine, the FDA has not yet approved R-ketamine (arketamine) as an antidepressant.
However, pre-clinical research and open-label trials indicate that R-ketamine may be superior to S-ketamine in the treatment of severe depression. Arketamine shows weaker activity at the NMDA and sigma receptors. As a result, this type of ketamine produces fewer hallucinogenic and dissociative effects than esketamine.
This makes arketamine an attractive depression treatment for many, especially since the psychoactive effects of ketamine can be off-putting to many patients. Studies have illustrated that greater mystical-type effects of ketamine lead to better therapeutic outcomes (such as in quitting an addiction).
Nonetheless, if a type of ketamine can still benefit patients without inducing intense subjective effects, this option could appeal to those struggling with depression and addiction who are hesitant about altering their minds.
Moreover, arketamine shows less dopaminergic activity than esketamine. This may therefore translate to lower abuse potential.
Ketamine Has Addictive Properties
Many drugs, including ketamine, can be addictive due to them increasing dopamine levels in the brain. Dopamine is a chemical of reward or motivation. When it is released, following a certain activity or the ingestion of a drug, we are motivated to seek out that behavior again.
Repeated infusions of low doses of ketamine may have addictive properties. For this reason, if arketamine does have less addictive potential, it could prove useful for patients who need repeated infusions.
Arketamine is also able to stimulate the formation of new neural connections (known as synaptogenesis), which may contribute to its antidepressant effect.
To summarize, arketamine may be a less potent and longer-lasting antidepressant, with fewer side effects than esketamine. However, we should note here that many of the findings on using arketamine to treat depression come from animal models, which don’t map seamlessly onto the complexities of human depression.
Which Ketamine Is Right For You?
Now that we have distinguished the types of ketamine, let’s discuss how to decide which one is right for you.
Racemic ketamine, at subanesthetic doses, is a popular off-label option for people suffering from major depression, typically used in cases of treatment-resistant depression. People also use this type of ketamine for other mental disorders, including post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), anxiety disorders, and addictions.
When visiting a ketamine clinic, the ketamine you receive via IV injection will be the racemic variety. Currently, the U.S. government has only endorsed esketamine for MDD.
But this endorsement from the government doesn’t mean that Spravato is necessarily superior. The bioavailability of IV racemic ketamine is 100 percent. This means the full dose of the substance is available to have an effect on the brain. This allows healthcare providers to know precisely what dosage to give.
In contrast, the intranasal bioavailability of Spravato is approximately 48 percent. And absorption rates differ from person to person. This can be due to factors like nasal passage conditions, such as mucus and congestion. It also depends on whether or not the individual properly self-administers the intranasal spray.
For those who don’t respond to Spravato, it’s hard to know if this is an issue of absorption or the drug itself.
What Is The Cost Of Ketamine?
Spravato is also significantly more expensive. It has a price tag of $590-885 per dose, which adds up when taking regular doses. The recommended frequency of dosing with Spravato is twice per week for four weeks.
On the other hand, the cost of ketamine therapy ranges from $400-800 per infusion. Typically, it consists of six infusions spread out over two to three weeks. Another benefit of ketamine infusions is that they involve a quicker visit to the clinic than with Spravato.
We will need more research on arketamine before we can fairly compare its advantages and disadvantages to those of racemic ketamine and esketamine. Yet according to the available literature, it may be a superior antidepressant to esketamine, with a reduced risk of addiction and fewer side effects.
Arketamine isn’t yet available as a treatment option, so the choice really comes down to esketamine and racemic ketamine. They are both effective at treating depression, although because of the differences related to bioavailability and absorption mentioned above, the racemic version could be the more reliable option.
Does Insurance Cover Any Types Of Ketamine?
However, ketamine infusions aren’t covered by insurance because it’s experimental and not FDA-approved. So you’ll have to pay out of pocket for it.
Esketamine, meanwhile, is almost always covered by insurance, including Medicare, as it’s FDA approved. To be eligible for insurance coverage for esketamine, you need to have tried at least two other antidepressants without benefit.
From a cost perspective, esketamine may be the preferable option. But, according to one study, IV racemic ketamine is much more effective than intranasal esketamine.
Researchers found that the former had a longer antidepressant effect for patients with depression. Additionally, it has lower drop-outs due to adverse events. Therefore, if you’re looking for the most effective treatment, with minimal adverse effects, racemic could be the best option.