Ketamine-Assisted Psychotherapy:

A Practical Guide for Medical Providers

L. Alison McInnes, MD, MS Jessica Yu, NP, MA, MS

Private Practice Psychiatrist Psychiatric and Family Nurse Practitioner,
San Francisco, California Kaiser Permanente
Adjunct Clinical Associate Professor San Francisco, California
University of California, San Francisco
 Ketamine-Assisted Psychotherapy
A Practical Guide for Medical Providers

• L. Alison McInnes MD, MS: Founded regional ketamine therapy

program at Kaiser Permanente San Francisco in 2015 and
pioneered group dosing of oral ketamine in 2016. Subsequently
continued to provide IV and oral ketamine therapy in private
practice both solo and in collaboration with other psychiatrists.

• Jessica Yu, NP, MA, MS: Ketamine-assisted psychotherapy;

Psychedelic-Assisted Therapies and Research trainee.
 Faculty Disclosure
• Dr. McInnes: Consultant—Clexio Biosciences Ltd.; Medical Advisor—
Osmind.

• Ms. Yu has no financial relationships to disclose relating to the subject matter

of this presentation.
 Disclosure
• The faculty have been informed of their responsibility to disclose to the
audience if they will be discussing off-label or investigational use(s) of drugs,
products, and/or devices (any use not approved by the US Food and Drug
Administration).
– The off-label use of ketamine for the treatment of treatment-resistant depression
will be discussed.

• Applicable CME staff have no relationships to disclose relating to the subject

matter of this activity.

• This activity has been independently reviewed for balance.

• Brand names are included in this presentation for participant clarification

purposes only. No product promotion should be inferred.
 Learning Objectives

• Describe the scientific and theoretical basis for the use of

ketamine-assisted psychotherapy in treatment-resistant
depression

• Select suitable candidates for ketamine-assisted psychotherapy

• List both acute and long-term risks and benefits of ketamine-

assisted psychotherapy
 Major Depressive Disorder

• MDD is a significant cause of disability worldwide, increases the risk of

suicide, and can worsen other chronic medical conditions

• Effective pharmacologic treatments are available yet there are

limitations to these treatments including the delayed onset of action for
traditional ADs, lack of response, or incomplete response to treatment

• TRD usually refers to an inadequate response to at least 2 ADs or

augmentation strategies of adequate dose and duration

• The need for more effective and rapid-acting agents is apparent

AD = antidepressant; MDD = major depressive disorder; TRD = treatment-resistant depression.

Shin C, et al. Psychiatry Investig. 2020;17(3):181-192. Gaynes BN, et al. Depress Anxiety. 2020;37(2):134-145.
 A Brief History of Ketamine

• Ketamine hydrochloride was invented in 1962 by an American

chemist and developed by the Parke-Davis pharmaceutical
company in an effort to find a safer and more predictable
anesthetic than its predecessor phencyclidine

• Ketamine has a known side effect of dissociation. Dissociation is

defined as a floating sensation or a sensation of disconnection
from one’s body

• Consequently “dissociative anesthetic” is used to describe

ketamine and the entire class of arylcyclohexylamine anesthetics

Domino EF. Anesthesiology. 2010;113(3):678-684.

 Esketamine and Arketamine

Ketamine is a racemic mixture of both molecules

 Ketamine is an NMDA Receptor Channel Blocker

• Ketamine binds to the PCP site

within the ionotropic channel
pore in a use dependent fashion

• Uncompetitive high-affinity
NMDAR antagonist

NMDA = N-methy-D-aspartate.
Duman RS. F1000Res. 2018;7.
 Medical Use of Ketamine
• In 1970, the FDA approved ketamine for anesthesia in children,
adults, and the elderly

• Ketamine has a broad range of medical applications because of

its rapid onset, short duration of action, relative hemodynamic
safety, and respiratory safety

• Used in Vietnam because of these properties – escalation to club

drug

• Ketamine can be administered orally, sublingually, intranasally,

rectally, intramuscularly, intravenously, and subcutaneously
Kolp E, et al. Ketamine psychedelic psychotherapy: Focus on its pharmacology, phenomenology, and clinical applications. International
Journal of Transpersonal Studies. 2014;33(2):84-140.
 Psychiatric Use of Ketamine

• Eugene Krupitsky was using ketamine for alcoholism in the 70s

• John Lilly was also exploring psychological aspects of ketamine

• IV ketamine for depression was first pioneered by Krystal and Charney

at Yale in the 1990s

• Since the early 2000s there have been 7 RCTs of single-dose IV

ketamine for MDD and bipolar depression totaling ~ 148 participants
and many more open-label studies, and the NIMH protocol of 0.5
mg/kg over 40 minutes was widely adopted

RCT = randomized controlled trial.

Berman RM, et al. Biol Psychiatry. 2000;47(4):351-354. Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966.
 Psychiatric Use of Ketamine (cont’d)

• The first set of APA guidelines for IV ketamine were published in

2017 using the NIMH protocol

• The American Society of Ketamine Physicians (ASKP3) was

formed to represent the rapidly growing number of ketamine
providers with annual meetings to provide some consensus
around ketamine practice

Sanacora G, et al.; American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments. JAMA
Psychiatry. 2017;74(4):399-405.
 Psychiatric Use of Ketamine
Esketamine (Spravato®)
• In March 2019 the FDA approved intranasal esketamine in
conjunction with an oral AD for TRD. Esketamine is the S-
enantiomer of generic ketamine and is available in a device of 28
mgs to achieve target doses of 56 mg or 84 mg

• The FDA requires both clinician and patient registration in Risk

Evaluation and Mitigation Strategies (REMS) to administer
esketamine under protocol

• A recent study indicates esketamine plus a new AD demonstrated

favorable safety and tolerability in up to 1 year of patients with
TRD
Wajs E, et al. J Clin Psychiatry. 2020;81(3):19m12891.
 Ketamine Mechanism of Action: Pharmacology

• Inhibition of GABAergic interneurons results in a surge of glutamate

release
• Increase in glutamatergic AMPA receptor activity and blockade of extra-
synaptic glutamatergic NMDA receptors
• Stimulation of BDNF and mTORC1 results in increased synaptogenesis
and synaptic potentiation – the cellular basis of learning
• Ketamine administration also leads to rapidly restored ensemble activity of
neurons in brain regions relevant to mood and this enhanced functional
connectivity is correlated with amelioration of depressive behaviors in
rodents
BDNF = brain-derived neurotrophic factor; GABA = gamma-aminobutyric acid; mTORC1 = mammalian target of rapamycin complex 1.
Moda-Sava RN, et al. Science. 2019;364(6436):eaat8078.
 Proposed Antidepressant Mechanism of Action
of Ketamine

“GO” pathway

“Stop” pathway

Murrough JW, et al. Nat Rev Drug Discov. 2017;16(7):472-486.

 Variable Dosing Strategies

• The most common methods of administration currently include

intravenous, intramuscular, and sublingual or oral

• Most methods of ketamine administration involve an induction

period of more frequent dosing followed by a maintenance dosing
at a reduced frequency

• Range of dosing is variable and differs between methods of

administration; however the data suggest that lower doses may
be more effective
 Ketamine Dosing
U-shaped Response Curve

Fava M, et al. Mol Psychiatry. 2018 Oct 3:10.1038/s41380-018-0256-5.

 Monteggia Lab Dosing Data in Rodents
• Ketamine is often used at 2.5–10 mg/kg to examine
antidepressant effects and 20–50 mg/kg to model schizophrenia
in rodents

• The authors compared effects at a range of doses and found that

low-dose (5 mg/kg) ketamine produced rapid antidepressant
effects, not observed at higher doses

• At 5 mg/kg ketamine significantly increased the level of BDNF,

while higher doses of ketamine did not alter BDNF levels in the
hippocampus

Kim JW, et al. Behav Brain Res. 2020;380:112378.

 Monteggia Lab Dosing Data in Rodents (cont’d)

• Low concentration ketamine also evoked the highest synaptic

potentiation in the hippocampal CA1 region, while higher
concentrations significantly decreased the synaptic effects

• Conclusion: Low-dose ketamine produces antidepressant effects

and has independent behavioral and synaptic effects compared to
higher doses of ketamine

Kim JW, et al. Behav Brain Res. 2020;380:112378.

 Ketamine Behavioral and Therapeutic Effects

• All psychotherapies involve learning and behavioral change. Traditional

ADs enhance this process slowly via BDNF-mediated mechanisms

• Ketamine causes more rapid surges in BDNF than traditional ADs AND
also activates mTORC1 to promote rapid synaptogenesis theoretically
enabling faster cognitive restructuring and behavioral change

• There is evidence that CBT extends the duration of ketamine’s

antidepressant effects

• Timing: Therapy can occur simultaneously with the ketamine treatment

or can occur later that week
CBT = cognitive-behavioral therapy.
Wilkinson ST, et al. Psychother Psychosom. 2017;86(3):162-167. Wilkinson ST, et al. Biol Psychiatry. 2019;85(6):454-465.
 Ketamine-Assisted Psychotherapy

• The first reported use of ketamine with psychotherapy was in the

1970s

• The combination of a psychedelic with psychotherapy is called

“psychedelic-assisted psychotherapy”

• Psychedelic-assisted psychotherapy that is specific to ketamine

is called “ketamine-assisted psychotherapy”

Dore J, et al. J Psychoactive Drugs. 2019;51(2):189-198. Kolp E, et al. Ketamine psychedelic psychotherapy: Focus on its pharmacology,
phenomenology, and clinical applications. International Journal of Transpersonal Studies. 2014;33(2):84-140. Schenberg EE. Front
Pharmacol. 2018;9:733.
 Ketamine-Assisted Psychotherapy Sessions
● Typically there are 3 phases:

○ Preparation
○ Administration
○ Integration

● During drug administration sessions the effects are monitored by

trained mental health professionals

● Psychotherapeutic interventions are provided during the

administration and/or integration sessions

Dore J, et al. J Psychoactive Drugs. 2019;51(2):189-198. Hasler G. CNS Spectr. 2019:1-3. Kolp E, et al. Ketamine psychedelic
psychotherapy: Focus on its pharmacology, phenomenology, and clinical applications. International Journal of Transpersonal Studies.
2014;33(2):84-140. Schenberg EE. Front Pharmacol. 2018;9:733.
 Choosing Suitable Candidates

• Indications: Unipolar (or bipolar) TRD

• Patients with bipolar disorder must be on mood stabilizers

• Exclusion criteria: Pregnancy, breastfeeding, uncontrolled

hypertension, unstable angina, increased intracranial pressure,
liver disease, untreated sleep apnea, psychosis, allergy to
ketamine, no substance misuse in the past 3 months, concurrent
benzodiazepine use*

• Safety plan in place for active suicidal ideation

*Albott CS, et al. J Clin Psychiatry. 2017;78(3):e308-e309.

 Preparation Phase

• Screening tests: Liver function tests, urine pregnancy, urine drug

screen

• Vital signs: Exact height and exact weight

• Consent form: Signed and witnessed. Psychoeducation about

ketamine and expectation management
 Administration Phase
• Check in vital signs. Hold ketamine if blood pressure > 160/100 and/or HR >
100
• Administer sublingual ondansetron 4–8 mg (if needed for nausea) then
administer ketamine (for sublingual lozenges start with 50 mg)

• Ask the patient to sit or lie comfortably, with eyes closed or an eye shade,
focusing inward perhaps on an intention for healing

• May provide non-lyrical music

• At 20 minutes ask about the following side effects: Dissociation, mood

elevation, dizziness, sedation, numbness, flushing, nausea, dry mouth or
hypersalivation, anxiety
 Administration Phase (cont’d)
• If side effects are mild, they can take an additional 50 mg for a total of
100 mg. Check in with the patient again in 10–15 minutes
• The target dose is that which provides mood elevation and
dissociation with all other side effects being relatively mild (may not
occur in the first session)
• Before the patient leaves observe and document a steady gait. Check
blood pressure to monitor for elevation or lowering. Confirm the
patient has transportation home as patients are not to drive the day of
dosing
• Patient may return to usual activities. Metabolism is quite variable so
some may feel side effects longer than others
 Potential Side Effects
Acute Side Effects
• Anxiety, irritability, mood elevation, dissociation, perceptual disturbances
• Headache, dizziness/lightheadedness, blurred vision, sedation, restlessness,
impaired concentration/attention/coordination, nausea and vomiting, blood
pressure elevation or decrease
• Hypomania/mania (screen carefully)

Long-term Side Effects

• Lower Urinary Tract Syndrome is observed in 20%–30% of chronic daily
recreational ketamine users
• Cognitive impairments were not observed or reported outside of heavy
recreational ketamine use

Short B, et al. Lancet Psychiatry. 2018;5(1):65-78.

 Integration Phase

• We have conducted weekly ketamine-assisted group therapy for

patients receiving ketamine in our clinics since 2016

• Therapeutic techniques offered include: guided imagery,

mindfulness, Emotion Modulation Therapy (EMT), Mindful Self-
Compassion (MSC), CBT, and Dialectical Behavioral Therapy
(DBT)

• The most important aspect of ketamine-assisted psychotherapy is

for patients to create a meaningful narrative of healing for
themselves
 Integration Phase (cont’d)

• Wilkinson et al. (2017) found that CBT may sustain the effects of
ketamine in TRD

• Dakwar and colleagues (2019) indicated that a single dose of

ketamine combined with a mindfulness-based program improved
a range of treatment outcomes in cocaine dependent adults

• These researchers suggest that the effects of ketamine might be

sustained when combined with behavioral treatment

Wilkinson ST, et al. Psychother Psychosom. 2017;86(3):162-167. Dakwar E, et al. Am J Psychiatry. 2019;176(11):923-930.
 Case Example #1

• 65-year-old multi-ethnic male with TRD receiving twice a month

oral ketamine (75 mg) and attending ketamine-assisted therapy
group
• He credits ketamine with significant interpersonal and
occupational functional improvements
• In ketamine sessions he reports a sense of interconnectedness
with others, a renewed feeling of clarity about his life’s purpose,
and moments of ineffability
 Case Example #2
• 53-year-old Caucasian female with TRD, chronic suicidal ideation, and
polysubstance dependence in sustained remission

• Treatment has included psychiatric hospitalizations, partial

hospitalizations, and intensive outpatient programs

• After 6 ketamine infusions with a maximum dose of 100 mg her Global

Distress Score (GDS) on the Adult Outcomes Questionnaire (AOQ)
decreased from 35 to 23

• She no longer felt the need for ketamine and has been in sustained
remission from MDD for years. She continues on maintenance
psychiatric medications
 Case Example #3

• 39-year-old single adopted Caucasian female formerly employed

in tech with TRD (failed about 8 medications) who came to me
unable to work, finished with therapy and unable to engage in a
treatment plan

• Experienced adoption as a primal wound. Filled with rage at

adopted parents for having ripped her away from her mother and
family (biological mother had died while she was searching for her
– biological father was in prison)
 Case Example #3 (cont’d)
• We got to the target dose in 2 sessions (150 mg) and in the 3rd session it
was clear that development of the transference had been accelerated. The
patient no longer wanted to wear her eye shade and preferred to lie back and
engage me face-to-face. She exhibited a new sense of humor and became
willing to teach me about the psychology of adoption

• There were mystical qualities to her experience including a feeling of de-

differentiation, a sense of unity. She developed the conviction that
“everything would be OK”. Forgiveness of self and others has been a
common theme

• In 4 weeks—1 session at home and 1 supervised weekly—she was starting

to look for work and by the 6th week she was employed. She remains well 6
months later despite being laid off because of COVID
 Case Example #4

• 35-year-old single Caucasian male with severe chronic pain and

TRD employed on and off in tech

• He has been taking SL ketamine once weekly for 4 years without

needing to increase his dose and with no suspicion of misuse

• In his opinion SL ketamine is “not a miracle” but “it means that I

can keep going”
 Cautions

Inform patients that mood fluctuations may occur during treatment

and have a plan in place for worsening symptoms

If therapeutic or expected side effects lessen over time evaluate

psychosocial stressors, possible changes in hepatic metabolism,
or the possibility of diversion. Diversion is a felony and minimized
with clinic administered ketamine

During the consent process outline reasons for discontinuation of

treatment (ie, if you suspect misuse)
 Billing and Malpractice
Billing
• 99214 office visit ketamine lozenge
• 90838 add on code for psychotherapy
• 99354 Observation code
• 99355 Observation code
• 96127 Assessment

Malpractice
Approval for ketamine-assisted psychotherapy includes a detailed
consent and a detailed protocol. Inform malpractice insurance
carrier of use of ketamine.
 Practical Take-Aways

• A step-by-step protocol for the provision of KAP on an

outpatient basis

• Insurance, reimbursement, and billing tips related to KAP

• Educational resources to enhance the provision of KAP

Q&A