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How Long Does Ketamine Last? Maintenance and Integration in Ketamine Therapy

August 26, 2022

How Long Does Ketamine Last? Maintenance and Integration in Ketamine Therapy 

Thanks to its rapid onset and robust effects, many consider Ketamine therapy to be the first innovation in depression treatment in decades. But Ketamine’s therapeutic benefits are notoriously transient if not supported with ongoing maintenance dosing, psychotherapy, or a combination of the two. As a result, the question, "How long does Ketamine last?" has guided recent research.

Currently, there are many unanswered questions about how to offer Ketamine as a long-term treatment in the safest and most effective way possible. Researchers are collecting insights to inform protocols designed to sustain Ketamine's therapeutic effects while mitigating the risks associated with its use on a longer timescale. 

This article outlines the factors influencing Ketamine's short-term therapeutic benefits. It also dives into the two strategies under investigation for prolonging Ketamine's depression- and anxiety-relieving properties over time: maintenance treatment and psychedelic integration therapy.

How Long Does Ketamine Last in the Short Term? 

A single dose of Ketamine can bring relief from conditions like depression in minutes or hours. Its therapeutic effects typically peak at 24 hours and last for about a week

Ketamine’s route of administration (ROA) most profoundly influences the nature and onset of its effects, though body weight, age, and other individual factors also play important roles in the quality of the experience. The main difference between ROAs is their level of bioavailability, or how much of the medication they enable the body to use.

No single ROA is ideal or best for every person. While they can have different subjective effects, the level of invasiveness of a given ROA can also influence the character of the experience. For example, intravenous (IV) Ketamine is the most bioavailable, but it can also feel medical and procedural, which can be alienating for people focusing on inner reflection. 

Ketamine’s Effects Across Routes of Administration 

Ketamine practitioners have documented success using a variety of ROAs. The most commonly used include intravenous (IV), intramuscular (IM), intranasal (IN), oral, or sublingual.

This is how Ketamine's onset, duration, and effects shift across ROAs: 

Intravenous (IV): IV Ketamine is 100% bioavailable, meaning that the body can use all of the medicine administered. Its onset occurs within 30 seconds, and practitioners typically deliver the infusions over 40 minutes, with a recovery period lasting about an hour. The precise control practitioners have over the medicine’s drip rate makes the onset, plateau, and after effects of IV Ketamine more gentle and gradual. 

Intramuscular (IM): Given via a syringe injected into the thigh or shoulder, IM Ketamine also has a rapid onset of about two to five minutes, peaking at between 20 and 40, and lasting between one and three hours, depending on the dose. Being a direct injection into the bloodstream, IM Ketamine also has a high bioavailability at about 93-95%. Because IM causes an immediate upstroke in blood levels right after injection, followed by a similarly large downstroke, IM Ketamine has a much sharper onset, plateau, and comedown than IV. 

Intranasal (IN): IN Ketamine comes in two forms: S-Ketamine (esketamine), available as the nasal spray, Spravato, and R-Ketamine (arketamine), which is under investigation as a less dopaminergic and dissociative alternative. When used nasally, esketamine enters the bloodstream through small blood vessels in the sinuses. It has a much lower bioavailability at about 25-35%. making the onset slower, occurring within five to 10 minutes, with effects lasting between one and three hours. 

Sublingual (tablets and troches): Sublingual Ketamine (as rapidly dissolving tablets or troches) is held in the mouth for maximum absorption and removed before swallowing. This approach allows it to bypass the gastrointestinal tract and avoid liver metabolism, lengthening the experience and heightening its effects. This is critical, since its bioavailability is also relatively low, at about 15-25%. Sublingual Ketamine sets in within 5 to 10 minutes and lasts between one and three hours. Depending on a person’s reaction, practitioners may provide a second or third dose to maximize its duration and effectiveness. 

Oral (lozenges): Oral Ketamine takes about 20 minutes to take effect, so it’s the ROA with the slowest onset and longest duration, lasting about four to six hours. Orally delivered Ketamine also has the lowest bioavailability, at 10%. Given its ease of administration, at-home Ketamine sessions typically involve lozenges, sublingual tablets, or troches.

Widening a Window of Opportunity: Ketamine as a Long-Term Treatment

As many different studies documented Ketamine therapy’s powerful yet short-lived properties, researchers committed to a more intensive treatment approach, one focusing on "stacking" multiple sessions within a short timeframe, usually, six sessions delivered over two weeks. 

Ketamine opens a "window of opportunity" characterized by relaxed defenses, flexible attitudes, and the ability to explore challenging emotions without high degrees of reactivity. As a result, stacking Ketamine sessions can not only lead to more pronounced benefits but also lengthen their window of effectiveness.

When delivered as a series, Ketamine brings a longer timeline of relief across many different diagnoses, including (but not limited to) treatment-resistant depression (TRD), anxiety disorders, and PTSD. Compared to a single treatment, which lasts about a week, multi-dose protocols can bring relief that lasts for weeks or months. 

For example, this study evaluated the impact of six 0.5 kg/mg doses of Ketamine given over two weeks to participants with severe depression. The participants found relief from their anxiety and depression symptoms that endured six weeks after their final infusion. 

Similarly, a 2019 clinical trial became the first direct comparison of responses to single and repeated Ketamine infusions within the same individual. The researchers found the participants’ antidepressant response rates doubled with repeated infusions. They also noted that repeated Ketamine infusion sessions had cumulative effects, with depression severity steadily reducing with each session.

The downside is that though infusion series offer antidepressant and anxiety-relieving properties that endure for much longer than a single treatment, their effects can also be transient if not delivered consistently. Researchers have noted the average time for relapse after a Ketamine infusion series is 18 days after the final infusion. 

Extending Ketamine’s Effects Neurochemically: Maintenance Dosing

Given the many indications that Ketamine’s effects are best prolonged through ongoing dosing, research has focused on treatment algorithm optimization. One leading question centers on the degree to which Ketamine treatment frequency can be reduced without interfering with benefits. In the clinical trial mentioned above, researchers discovered that once-weekly infusions sustained Ketamine's antidepressant properties as long as participants continued to receive them. However, mirroring the results of a single infusion series, participants relapsed about three weeks after the maintenance infusions ended.

As an array of studies point to the value of multi-dose protocols, practitioners have settled into a treatment algorithm with a gradually descending administration frequency. A typical administration approach for IN Ketamine, for instance, consists of twice weekly treatments for four weeks, a step down to a single treatment per week, ending with maintenance treatments every other week based on individual response. Researchers publishing in Therapy and Practice note they found success using a similar strategy for IV Ketamine, though the guidance for this is currently more individualized. 

Investigators have also documented the effects of maintenance treatment using Ketamine alone and along with antidepressants. For example, a case series in the Journal of Psychiatric Practice noted the possible synergy between Lamotrigine and Ketamine after a participant achieved a seven-month-long remission from treatment-resistant bipolar depression while using the two medications together. 

The researchers also reported that a person with unipolar TRD achieved functional remission with maintenance Ketamine infusion treatments continuing over five years. 

Ongoing research about maintenance treatments center on the comparative effectiveness of different Ketamine formulations, the optimal number, intervals, and duration of treatments, and similar questions. These investigations center on optimizing responsiveness and sustaining Ketamine’s long-term benefits but also its safety.  

Like any new treatment, there are unanswered questions about the consequences of using Ketamine on a longer timescale, particularly because of risks like bladder cystitis, neurotoxicity, and addiction. While these effects are largely understood to be products of overuse, the safety profile of long-term Ketamine therapy hasn’t yet been completely established.

Despite the uncertainties, most researchers agree that its benefits outweigh its risks among certain subsets of patients. Investigators in the Journal of Clinical Psychopharmacology even describe it as unethical to discontinue an effective treatment for people with severe depression and similar conditions who can't find relief from other available medications.

With these concerns in mind, maintenance treatment is currently given on a case-by-case basis, with careful monitoring and guidance depending on the severity of the person's conditions, their (lack of) responses to other treatments, etc. 

In the future, advanced computational models may help determine whether specific biomarkers predict clinical outcomes with Ketamine, and these insights may guide maintenance approaches. 

Extending Ketamine's Effects Psychologically: Ketamine-Assisted Psychotherapy

The transitory yet potent nature of Ketamine's effects also spurred interest in its potential synergistic actions with psychotherapy.

Ketamine-assisted psychotherapy (KAP) harnesses the emotional openness and clarity brought about by Ketamine to accelerate and deepen rapport between the therapist and client. Liberation from ordinary levels of fear, defensiveness, and self-consciousness drives emotional reframing, invites new ways of seeing old problems, and at higher doses, causes ego death or profound changes in felt bodily form. 

Though KAP also tends to involve repeated dosing, it can also be understood as a more explicitly biopsychosocial approach to Ketamine treatment (different from the biomedically minded Ketamine infusion therapy). 

Researchers and clinicians disagree about precisely how Ketamine facilitates psychotherapy, but the prevailing theories point to its capacity to enhance neuroplasticity, which accelerates emotional learning and the rapid extinction of memories previously paired with pain, to name just two hypotheses.

KAP practitioners use therapeutic modalities like cognitive-behavioral therapy (CBT), motivational interviewing, Internal Family Systems (IFS) (and many others) to help clients move through and integrate their experiences with the medication. 

Like infusion therapy, individuals often start with six treatments spread over two or three weeks, sometimes repeating this approach until they achieve remission. As noted by KAP practitioners in the Journal of Psychoactive Drugs, the standard protocol is to create treatment plans that include various frequency and dosing strategies adapted to an individual’s specific diagnoses and needs.

KAP protocols have maximized and prolonged Ketamine’s therapeutic effects across many different conditions. For example, an open-label trial published in Psychotherapy and Psychosomatics documented the synergy between CBT and Ketamine infusions for treatment-resistant depression. The researchers gave participants four infusions over two weeks, along with 12 sessions of CBT. Of the eight participants who responded to the treatment, seven achieved a remission lasting an average of three months after their last infusion.  

Another study combined Ketamine infusions with prolonged exposure therapy for veterans with post-traumatic stress disorder (PTSD). At a four-month follow-up, the veterans' PTSD symptoms remained significantly reduced compared to their baselines.

Other investigations have documented KAP's role in treating generalized anxiety disorder, chronic pain, opioid tapering, and several other conditions. As noted in a recent systematic review of the literature on KAP, factors like higher doses of Ketamine, more frequent sessions, and longer durations of psychotherapy are known to significantly improve the effectiveness and durability of Ketamine treatment across conditions.

Future research will further illuminate how to optimize responsiveness to KAP, and this research will inform maintenance protocols. 

Is Ketamine Treatment Complete without Integration Therapy?

Of course, there’s polarization in the field about whether integration therapy is fundamental to the treatment’s success, or a useful but negotiable addition to it.

KAP practitioners view the presence of a skilled therapist capable of maintaining a therapeutic container before, during, and after the therapy to be critical to the treatment’s success.

They also usually regard diet and lifestyle practices, like meditation, exercise, and journaling, as essential aspects of their treatment and maintenance protocols. KAP practitioners’ focus on integration differs from the view of many infusion specialists. 

In line with the biomedical system’s preoccupation with depression as a biomechanical problem (rather than a biopsychosocial one), infusion specialists consider precise administration and dosing protocols to be central to prolonging Ketamine’s therapeutic effects, pointing to the large body of research documenting Ketamine’s antidepressant and anxiety-relieving properties without the help of psychotherapy. 

Although KAP practitioners and infusion specialists part ways on many crucial questions, they both agree that Ketamine provides individuals with new, healing baselines that allow them to make constructive changes in their lives. Like any pharmacological treatment, Ketamine is a tool and a source of support for a transformative process primarily made possible by the individual, not a medication. 

Maya’s Role in the Future of Ketamine Therapy

As with all psychedelics, Ketamine therapy opens the door to a radically new approach to mental health treatment.

Yet with its great promise comes the responsibility of wise and careful stewardship. Ketamine can provide relief from negativity, awe-inspiring transpersonal experiences, and more, but it can also cause a range of unintended consequences.

In the pursuit of standardized protocols to ensure the safety, efficacy, and longevity of Ketamine therapy, research into maintenance dosing and KAP serve as antidotes to the risks that are inevitable with any novel treatment, but especially one as paradoxical, fast-acting, and potent as Ketamine. 

As the first practice management software designed specifically for psychedelic practitioners, Maya also supports the future of long-term Ketamine therapy. 

Maya bridges the gap between research and practice, allowing researchers, providers, and participants to work together to chart real-world outcomes and directly contribute to the psychedelic research literature. 

Maya also makes it possible to track treatment outcomes and trends across time. These trends can then inform strategies for personalizing and optimizing Ketamine therapy and other psychedelic treatments. 

If you’re interested, we'd love for you to join our researcher or provider community, so you can connect with our network of psychedelic professionals around the world and learn more about how Maya can help you optimize and extend the impact of your work.

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