Ketamine Treatment Methods Guide: Every Route of Administration Explained

Ketamine Treatment Methods Compared

This ketamine treatment methods guide compares the routes providers actually use to deliver ketamine, including intravenous (IV) infusion, intramuscular (IM) injection, intranasal spray, oral and sublingual tablets, and rectal administration. Ketamine is a dissociative anesthetic, originally developed for surgical use, that is now prescribed off-label for depression and certain pain conditions, and in one FDA-approved nasal spray form for treatment-resistant depression. Each route has a different bioavailability, meaning the percentage of a dose that actually reaches the bloodstream, along with its own onset speed, cost, and monitoring requirement. There is no single best method for every patient. The right choice depends on the condition being treated, how quickly symptom relief is needed, insurance coverage, and how much medical supervision a patient wants or needs.

Understanding Bioavailability

Bioavailability is the fraction of an administered drug dose that reaches systemic circulation in active form, expressed as a percentage. IV administration is defined as 100% bioavailability because the entire dose enters the bloodstream directly. Every other route loses some percentage of the dose to metabolism or incomplete absorption before it reaches circulation. See our bioavailability glossary entry for more on how this concept applies across medications.

These differences matter because they change how a dose is written. A 50 mg sublingual dose delivers roughly 12.5 to 15 mg to the bloodstream, while a 50 mg IV dose delivers the full 50 mg. Providers adjust nominal doses upward for lower-bioavailability routes to reach comparable blood levels.

Intravenous (IV) Infusion

How It Works

IV infusion delivers ketamine dissolved in saline directly into the bloodstream through a peripheral catheter, usually placed in the arm or hand. An infusion pump controls the delivery rate, allowing precise dosing over a set period.

Standard Psychiatric Protocol

The most widely studied protocol for depression uses a dose of 0.5 mg per kilogram of body weight, infused over 40 minutes, two to three times per week. A typical initial series runs six infusions over two to three weeks, followed by individualized maintenance infusions every two to six weeks. Some clinics adjust the dose, infusion length, or scheduling based on clinical experience and emerging research.

Pain Protocol

Pain-focused IV protocols usually differ from psychiatric ones. Doses often run 0.5-1.0 mg per kilogram per hour, sometimes higher, over sessions lasting 2-4 hours, or as multi-day continuous infusions for conditions such as complex regional pain syndrome (CRPS), a chronic pain condition, usually affecting a limb, involving prolonged and disproportionate pain following an injury. Some centers offer prolonged continuous infusions in inpatient settings for these cases.

Who It Is Best For

IV infusion tends to fit patients seeking the most evidence-based option, those with treatment-resistant depression who need rapid symptom relief, patients with complex chronic pain conditions, and people who prefer the reassurance of full medical monitoring during treatment.

Intranasal Administration

FDA-Approved Esketamine (Spravato)

Spravato is a nasal spray containing esketamine, the S-enantiomer of ketamine, a single mirror-image molecule isolated from the racemic (mixed) ketamine compound. According to the FDA, Spravato was approved in March 2019 for treatment-resistant depression and was later expanded to cover major depressive disorder with suicidal ideation. It remains the only ketamine-based treatment with FDA approval for a psychiatric indication. See our racemic ketamine vs. esketamine comparison for how the two forms differ.

Dosing Protocol

Induction, during weeks one through four, typically uses 56 mg or 84 mg twice weekly. Maintenance, from weeks five through eight, usually drops to 56 mg or 84 mg once weekly. Extended maintenance from week nine onward continues at 56 mg or 84 mg, once weekly or every two weeks. Each dose is self-administered with a nasal spray device under direct supervision.

Administration Procedure

The patient arrives at a REMS-certified facility, where REMS stands for Risk Evaluation and Mitigation Strategy, an FDA-mandated safety program that restricts how certain medications can be dispensed and monitored. Staff record baseline vital signs, the patient self-administers the spray under observation, and a two-hour post-dose monitoring period follows with periodic vital sign checks. Patients cannot drive for the remainder of the day.

Compounded Intranasal Ketamine

Some practitioners prescribe compounded racemic ketamine nasal spray from compounding pharmacies. This is an off-label use and is not subject to Spravato's REMS requirements. Compounded formulations are usually less expensive but lack the standardized dosing and manufacturing consistency of the FDA-approved product.

Who It Is Best For

Intranasal ketamine, particularly Spravato, tends to fit patients whose insurance covers it, those who want an FDA-approved treatment, patients who want to avoid IV access, and people who value the regulatory safeguards built into the REMS program.

Oral and Sublingual Administration

How They Work

Oral ketamine formulations are usually prepared by compounding pharmacies as tablets, troches (lozenges), or liquid solutions. Sublingual dosing places the tablet or troche under the tongue, where it dissolves and absorbs through the oral mucosa directly into the bloodstream; after a 10-15 minute hold time, any remaining liquid is spit out or swallowed. Swallowed oral dosing is absorbed through the gastrointestinal tract and passes through first-pass liver metabolism before reaching circulation, which lowers its bioavailability.

Typical Dosing

Because bioavailability is lower, oral and sublingual doses run higher in absolute milligrams than IV doses to reach comparable blood levels. Sublingual troches typically range from 100-400 mg, held under the tongue for 10-15 minutes. Oral tablets or liquid typically run 0.5-2.0 mg per kilogram, adjusted by response. Frequency varies widely, from daily to two or three times per week during acute treatment, tapering to a maintenance schedule.

At-Home Protocols

Oral and sublingual ketamine are the forms most commonly prescribed for at-home use. A typical at-home protocol includes an initial assessment, possibly with in-office sessions first, a prescription for a compounded formulation with specific dosing instructions, telehealth or in-person follow-up to assess response, safety guidelines such as having a sitter present and not driving afterward, and regular check-ins with the prescribing clinician. Some providers add monitoring apps, symptom surveys, or video-observed dosing sessions.

Who It Is Best For

Oral and sublingual formulations tend to fit maintenance therapy after an initial response to IV or in-office treatment, patients without a nearby ketamine clinic, cost-sensitive patients, those with stable conditions who don't need intensive monitoring, and people who prefer the convenience and privacy of at-home treatment.

Intramuscular (IM) Injection

How It Works

IM injection delivers ketamine directly into muscle tissue, typically the deltoid (upper arm) or gluteal (buttock) muscle, where the rich blood supply allows rapid absorption into the bloodstream.

Dosing

A typical psychiatric dose runs 0.5-1.0 mg per kilogram. Onset begins 3-5 minutes after injection, peak effects occur at 15-30 minutes, and acute effects last 45-90 minutes.

Administration Setting

IM ketamine is given in ketamine therapy clinics, psychiatric offices, ketamine-assisted psychotherapy (KAP) sessions, and occasionally in emergency departments for acute suicidal ideation.

Who It Is Best For

IM injection tends to fit patients who want high bioavailability without IV access, those in KAP sessions where a defined onset and peak can complement the therapeutic process, patients who find IV placement uncomfortable or have difficult veins, and clinical settings without infusion equipment.

Rectal Administration and Extended Infusion Protocols

Rectal Administration

Rectal ketamine is less commonly discussed but is sometimes used in specific clinical situations, particularly pediatric procedural sedation. Its bioavailability runs approximately 25-30%, similar to sublingual dosing. It is rarely used for psychiatric treatment in adults, though it may occasionally be considered for patients who cannot tolerate oral medication or other routes of administration.

Extended IV Infusions for Pain

For certain chronic pain conditions, particularly CRPS, some specialized centers offer extended continuous ketamine infusions lasting from several hours to multiple days, conducted in inpatient or intensive outpatient settings with comprehensive monitoring. Protocol variations include multi-hour outpatient infusions of 2-6 hours at moderate doses, multi-day inpatient infusions of 3-5 days with carefully escalated, higher cumulative doses, and, in select international centers, extremely high-dose protocols that induce a medically managed coma for severe refractory pain conditions. These extended protocols require specialized medical expertise, intensive monitoring, and careful patient selection.

Ketamine-Assisted Psychotherapy (KAP)

KAP is not a separate route of administration but a treatment framework that pairs ketamine dosing with structured psychotherapy. It can use any of the delivery methods above, though sublingual, IM, and IV routes are most common in KAP settings. For a full walkthrough of what a session involves, see our ketamine-assisted psychotherapy guide.

The KAP Model

A typical KAP protocol has three phases. Preparation sessions are psychotherapy sessions held before dosing, used to set therapeutic goals, build rapport, and discuss what to expect. Medicine sessions involve ketamine administration with a therapist present, using the altered state of consciousness as a therapeutic tool, sometimes with guided meditation, music, or gentle dialogue. Integration sessions are follow-up psychotherapy that helps process and apply the insights from the medicine session to everyday life.

Theoretical Rationale

The rationale behind KAP is that ketamine opens a window of enhanced neuroplasticity and psychological openness, during which defensive barriers may temporarily lower, emotional material that's otherwise hard to reach may become more accessible, the dissociative state may create distance from trauma that allows new perspectives, and heightened neuroplasticity may help therapeutic insights translate into lasting change.

Current Evidence

Research on KAP is growing but remains earlier-stage than research on ketamine alone. Several clinical trials have reported encouraging results, particularly for alcohol use disorder and PTSD. Whether adding structured psychotherapy produces more durable results than ketamine alone is still an open question. Early evidence points that direction, but larger controlled trials are needed.

Comparing Methods: A Practical Decision Framework

Clinical Urgency

For patients in acute psychiatric crisis, such as active suicidal ideation or severe treatment-resistant depression, IV infusion or IM injection tend to be preferred for their high bioavailability and rapid onset, since they offer the most predictable, fast response.

Evidence Base

IV infusion has the strongest clinical evidence for psychiatric use, followed by intranasal esketamine. Oral, sublingual, and IM routes have growing evidence bases but fewer large randomized controlled trials so far.

Cost and Insurance

Spravato is the most likely to be covered by insurance; see our insurance coverage guide for details. IV infusion is typically out-of-pocket, and our ketamine cost guide breaks down typical pricing by method. Oral and sublingual formulations are generally the least expensive option, with IM injection falling in between.

Convenience and Access

Oral and sublingual formulations offer the most convenience, especially through telehealth prescribers. IV and IM routes require clinic visits, and Spravato requires visits to a REMS-certified facility.

Medical Monitoring Needs

Patients with cardiovascular concerns, complex medical histories, or no prior ketamine experience may do better with the intensive monitoring available during IV infusion. Stable patients on maintenance therapy may be well suited to at-home oral or sublingual protocols; see our ketamine safety guide for a broader look at monitoring and risk factors.

Treatment Phase

Many patients follow a phased approach: an acute phase using IV infusion or in-office treatment for initial relief, a transition phase shifting toward a more sustainable method, and a maintenance phase using oral, sublingual, or periodic booster infusions as needed.

Emerging Delivery Methods

Several delivery methods remain in earlier stages of development and are not yet standard options at most clinics. Extended-release oral formulations are being developed to provide steadier blood levels with less frequent dosing, which could improve both consistency and convenience. Transdermal patches, which deliver medication through the skin, are under investigation as a way to maintain steady drug levels without the variability of oral dosing or the inconvenience of repeated injections. Inhaled ketamine, delivered by nebulizer or inhaler rather than nasal spray, is also being explored as a route that could combine faster onset with better standardization than compounded nasal sprays. None of these are currently established treatment options; they represent areas of ongoing research rather than available choices.