top of page


Why you shouldn't be fooled AND Why Spravato is not equivalent to the original ketamine.

ketamine, esketamine, nasal spray, spravato, janssen
Why you shouldn't be fooled AND Why Spravato is not equivalent to the original ketamine.

Spravato is the creation of Janssen Pharmaceuticals a subsidiary of Johnson & Johnson. The Spravato (esketamine) was approved by the FDA in March of 2019 and the only FDA approved use for Spravato is for treatment resistant depression. The diagnosis of treatment-resistant depression is commonly made when a patient has been treated with at least 2 traditional antidepressant medications that have failed to provide adequate improvement in depression symptoms. Spravato has not been FDA approved for anxiety, post-traumatic stress disorder (PTSD), bipolar disorder or any other mental health conditions. It is also not approved for the treatment or relief of any acute or chronic pain disorders. Spravato is classified as a schedule III controlled substance according to the Drug Enforcement Agency (DEA) and is therefore a highly regulated medication.

Let’s discuss chemistry for a moment, when you're talking about a typical drug, many are comprised of two molecules that are mirror images of each other, these are called enantiomers. Think of enantiomers like your hands, they look the same, but you can't overlap them one-over-the-other, without one being “backwards.” When both enantiomers are included in a final pharmaceutical product, the product is called a “racemic” compound. The original generic ketamine is a racemic compound. Another example of a racemic medication is racemic epinephrine, which is commonly given as a nebulizer treatment.

Spravato (esketamine) is a nasal spray that essentially consists of one of the two mirror image molecules that is found in the original generic ketamine product. Specifically, Spravato is the S-enantiomer filtered out of the original racemic ketamine product, therefore Spravato contains only one of the two enantiomers that make up the original racemic ketamine.

Oftentimes, when it comes to pharmacology, many drugs have one enantiomer that tends to produce the majority of the medical benefits, while the other enantiomer produces much of the side effects.

What Janssen was trying to accomplish by creating Spravato (esketamine), was isolate the S-enantiomer from the original ketamine product that they believed was responsible for most of the medical benefits, while eliminating the R-enantiomer that they postulated was responsible for the “negative” side effects like dissociation. The problem with their idea is that most ketamine practitioners actually believe dissociation is a very important part of ketamine’s mechanism of action and the dissociative effect is not at all “negative side effect.” As a result of only containing a part of the original ketamine product, the effectiveness of Spravato didn't play out as well as Janssen had planned. In fact, it failed to produce the desired results in multiple studies including 2 of the Phase III clinical trials.

The original generic ketamine, is the version of ketamine that consists of both enantiomers. It is this original version of ketamine that produces the maximum level of efficacy. For this reason the original version of ketamine has been heralded as the most effective anti-depressant ever discovered. I do applaud Janssen’s attempt to create a version of this original ketamine product that could be patented. Unfortunately for them, their product is far less effective that the original generic ketamine that has been administered for decades.

Let’s dig a bit deeper into why a company like Janssen would try to make a slight change to the already effective generic ketamine molecule. Since ketamine’s original patent has expired it can now be bought, sold, and produced as a generic medication. Pharmaceutical companies cannot make a large profit on a generic medication because anyone can produce and sell a generic medication, which increases competition and ultimately drives down prices for generic medications.

From a pharmaceutical company’s perspective the proverbial gold-mine is found in patented medications. A pharma company MUST be able to patent a drug in order to protect their financial investment and guarantee that they have the exclusive rights to produce their drug. When a company has exclusive rights to produce a drug, they control the market, when they control the market, they get to set the prices as high as they choose. So, with a patent in place, the pharmaceutical companies can ensure that they are able to recoup the hundreds of millions of dollars it takes to get FDA approval for a new medication. Janssen essentially took half of the already effective original ketamine product to create Spravato (esketamine). They did this because it allowed them to patent their “new” drug. By having a patent, Janssen was able to ensure that they could make massive profits from their “new” drug so long as it received FDA approval. Unfortunately, their drug turned out to be far less effective than the commonly available, extremely low cost, generic ketamine that had been available for years.

Most patients and many providers have gotten caught up in the Spravato hype and the fancy marketing by Janssen, but most haven’t actually looked into the studies or the efficacy data. Both of which are very disappointing compared to the results that have been obtained by the generic ketamine.

The fact that Spravato (esketamine) is intended to be taken alongside a traditional antidepressant, is also a fact that is not well known among ketamine providers. Every study that Janssen conducted involved patients that had received nasal esketamine AND who were also prescribed a traditional antidepressant to take along side the esketamine.

When talking about side effects side effects of Spravato, we can see that many are very similar to the generic ketamine. The Spravato package insert states some of the following.

Side Effects:

Sleepiness & Sedation - Clinical trials show that 49% to 61% of patients develop some level of sedation. 0.3% of Spravato patients lost consciousness after administration



Spinning sensation


Just like IV ketamine the patient may still have some amount of dissociation. This manifests as feelings of being disconnected from themselves, disconnected from thoughts, feelings, or space-time. No adverse effects of Spravato nasal spray on cognitive function were observed in the longer one year study conducted by Janssen.

When it comes to other unwanted side effects associated with Spravato, in clinical studies, there was a higher rate of lower urinary tract symptoms (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis) in Spravato-treated patients than in placebo-treated patients. No cases of esketamine related interstitial cystitis were observed in any of the studies, which involved treatment for up to a year.

Other notable side effects consist of nausea, vomiting and other side effects that are similar to generic ketamine. Increased blood pressure is another known side effect of Spravato. This is a side effect that we also see with IV ketamine infusions.

Shockingly, Janssen reports an increase in blood pressure that was much higher for Spravato, than most IV ketamine clinicians might have expected. Janssen reported that 8% to 17% of patients experienced an increase of more than 40mmHg in their systolic blood pressure and or 25mmHg in their diastolic pressure within the first one and a half hours of administration. One possible explanation for this substantial blood pressure increase, an increase that appears to be more severe than the blood pressure increase from IV ketamine, is that the Spravato nasal spray device delivers the dose much faster compared to the slower IV infusion of ketamine. IV ketamine infusions are typically administered over 40-60 minutes. Janssen’s studies indicate that the blood pressure peak is something that happens about 40 minutes after the administration of Spravato and can last up to four hours.

Some of the contraindications that are listed on the package insert are related to the rapid and sometimes steep increases in blood pressure. Contraindications listed on the Spravato package insert include vascular aneurysms, abdominal aneurysms, hemorrhagic brain bleeds and any AV malformations. As you can see the side effects are still extremely similar to the original IV ketamine and so there is no additional benefit to patients from a side effect perspective.

The REMS program: After a medication receives FDA approval, pharmaceutical companies are allowed to market and sell the newly approved drug, but they need to continue collecting data for studies. Janssen has set up a Risk Evaluation & Mitigation Strategy (REMS) to continue gathering data related to the use of their product. For a healthcare setting, pharmacy or a patient to receive Spravato, they must enroll in the REMS program.

According to the FDA approval, Spravato must be administered in a supervised office setting and the patient needs to remain supervised for a minimum of two hours after administration. Just like after an IV infusions of the original ketamine, the patient cannot drive themselves home. Therefore, Spravato offers little in the way of added convenience for the patients, the only benefit here is that the patient can avoid an IV insertion.

On the day of Spravato treatment the patient should not have eaten solid foods within 2 hours and should not have consumed clear liquids for 30 minutes prior to the administration. Again this is a somewhat similar practice to what many IV ketamine practitioners recommend for NPO status, although the majority of IV ketamine clinicians tend to require longer periods of NPO status. So Spravato seems to have a slight advantage when it comes to less stringent NPO requirements.

Spravato must be administered in a healthcare setting and according to the FDA, patients are not allowed to be directly dispensed Spravato, or to take Spravato with them for self-administration outside the healthcare setting. In other words, the medication is required to be administered in the supervised healthcare setting, but it can not leave the healthcare setting.

The initial Spravato treatment consists of Spravato (esketamine) administration 2x a week for the first 4 weeks then once every 1-2 weeks thereafter. The recommended starting dose is a 56 milligrams dose. So, day one, the dose starts low at 56 milligrams. On subsequent doses the dose can be increased up to 84 milligrams. Spravato comes packaged in a nasal spray administering device, each device will deliver two doses that total 28 milligrams. A typical patient will require 2-3 Spravato devices per visit.

Now that you have a basic understanding of Spravato and its administration, let’s review its performance in various studies. The most important takeaway is that 2 out of 5 Phase III clinical studies failed to demonstrate with statistical significance any improvements over placebo. These poor study results are not only disappointing, but they were somewhat shocking. Remember that in all the studies by Janssen, Spravato was administered and studied in combination with another antidepressant. So essentially Spravato was bolstered by the addition of a traditional antidepressant and yet it repeatedly still failed to deliver the results that Janssen had hoped for.

Although a direct comparison of generic ketamine and Spravato (esketamine) has not been conducted, It is safe to conclude that Spravato (esketamine) is substantially less effective than the generic ketamine that has been administered to patients for quite some time.

A limitation of Spravato that may be contributing to its low efficacy rate is its lower bioavailability. Janssen documents state that Spravato has a low 48% bioavailability. Generic ketamine given via different routes of administration have different levels of bioavailability, for example intravenous (IV) ketamine has 100% bioavailability, intramuscular 90% to 93%, and oral bioavailability of ketamine is around 16 to 30%. Given that esketamine is essentially half of the generic ketamine molecule and has less than half the bioavailability of IV ketamine, it is fairly easy to see why Spravato produces very poor results.

Another problem exists with Spravato and is a result of inconsistent absorption that is inherently a challenge with the nasal route of administration. The most obvious cause of poor absorption during nasal administration is that the administration requires squeezing the dose into the patient’s nose, the problem with this route is that a substantial amount of the medication can be swallowed, some of it can potentially be sneezed out, some of it can drip out, all leading to the patient receiving a smaller than intended dose. Other patient specific conditions that can adversely affect Spravato absorption include allergies, nasal congestion, inflammation, and colds. All of these can result in a massive decrease in the amount of medication that is absorbed into the body.

Overall, Spravato is half of the original the ketamine product and will likely play out to be half as effective as the original racemic ketamine that has been available for years.

Not everything is a negative for Spravato though, first the FDA approval of this partial ketamine molecule has allowed for a massive increase in public awareness. Immediately following the FDA approval and for several weeks after, esketamine was highlighted on nearly every national news outlet as a viable FDA approved treatment option for depression. This massive increase in public awareness is certainly beneficial for existing ketamine practices.

Additionally, the FDA approval of Spravato may potentially open the door for patients to receive esketamine that may be covered by their health insurance plans. Although Spravato is far less effective than IV ketamine, insurance coverage will allow patients who otherwise can’t afford the more effective IV ketamine to at least gain access to the less effective Spravato (esketamine). It is still too early to know if insurance companies will provide coverage for Spravato or even if the amount they reimburse the providers will be worth it. But, if everything falls into place and reimbursement is good, lower income patients could potentially get access to a product that falls within their budgets. Even though Spravato (esketamine) is less effective there is a chance this it can still help some patients obtain symptom relief and maybe even save lives. Overall most ketamine therapy providers view the Spravato approval as a plus for patients and ketamine therapy practices because of the massive increase in public awareness and the possibility of potentially being able to treat patients who ketamine therapy would previously have been out of financial reach.

An important note for patients who may be reading this post:

If you are a patient who has tried Spravato (esketamine) and it didn’t work for you, do not be disheartened there is still a good chance the original IV ketamine could help you obtain relief. Patients who have not obtained results from Spravato should consider seeking a ketamine provider who treats patients with generic IV ketamine because studies have shown the generic ketamine is the version that can deliver the absolute best chance for symptom relief.

Live your best life.



bottom of page