Low Dose Ketamine for Depression

Could ketamine be the next breakthrough treatment for depression?

Reviewed by Lybi Ma

Key points

• Low dose ketamine provides relief for individuals suffering from treatment-resistant depression.
• Ketamine increases levels of brain-derived neurotropicfactor in the brain.
• BDNF increases neuroplasticity in the brain including the production of new neurons and new synapses.
• Ketamine is improving for a wide range of neuropsychiatric disorders.

By Mitchell Liester and Rachel Wilkenson

Ketamine

The word brings both fear and hope.

We would like to offer support, structure, and clarity to those on the frontlines of neuropsychiatric care concerning the dangers of misuse of this scheduled substance; at the same time, we must acknowledge the promising clinical trial research describing a new mechanism of action for this amazing medicine. Treatment-resistant cases of mental illness seem to be the rule rather than the exception in psychiatric clinics. Traditional therapies often remain ineffective. As anyone in our field is aware, the battle for survival with mental wellness urges us to develop more effective treatment options. However, the frontiers of life bring ever-present risk.

We offer the following clinical observations for outpatient low-dose sublingual racemic ketamine use, specifically commenting on dose, frequency, and target populations. This conversation is especially important in the context of the proliferation of unregulated ketamine clinics that may threaten safe use.

Proposed Mechanism of Action

Rather than receptor blockade or ion channel disruption, which have been the suggested mechanisms of action and theoretical path to efficacy for most traditional psychotropics, ketamine and other psychoplastogens (therapeutics that are capable of promoting structural and functional neural plasticity) are hypothesized to achieve lasting change by increasing the production of a protein called brain-derived neurotrophic factor (BDNF). This protein stimulates the brain to produce greater numbers of neurons and more synapses, which are connections between these neurons. Interestingly, these synapses begin as neuronal projections that look like tree branches and are called dendrites (Latin: resembling a tree).

This branching pattern of growth is described mathematically as the Golden Ratio or Fibonacci Sequence. Layer upon layer, synapses microscopically appear similar to the fungi that support plant root systems through a network called mycelium. A comparison of the growth patterns in the brain and in the plant kingdom demonstrates them to be remarkably similar. Furthermore, ketamine has been found to exist in nature, where it is produced by the fungus Pochonia chlamydosporia.

Clinical Observations

Over our four and a half years of clinical experience using low-dose sublingual racemic ketamine in patients with treatment-resistant disease, it has become increasingly clear that patients fare best on a long-term daily micro-dosing schedule rather than a short- or long-term high and intermittent dosing schedule. The high-dose models, which are used by intravenous, intranasal, and also some oral medication programs, seem to precipitate intense and immediate side effects, and possibly trigger addictive behaviors, while recovery from neuropsychiatric disorders is not sustained. However, when ketamine is micro-dosed daily, side effects are minimized, abuse is very rare, and the healing pattern over months and years of consistent treatment mirrors a timeline of histological growth and solid improvement.

The dosage of ketamine varies depending upon the route of administration. Doses of sublingual ketamine in our clinics typically range from 6 mg to 180 mg daily. This is true for the treatment of depression as well as other neuropsychiatric disorders. The bioavailability also varies with the route of administration: for sublingual ketamine, approximately 30 percent of the dose enters the circulation.

Our team initially focused on treatment-resistant depression, where patients did not see improvement through trials of at least two traditional antidepressant medications. With the enduring success of this approach and the surprising tolerability of the micro-dosing format, we have extended use to bipolar depression, PTSD, and anxiety disorders. Furthermore, while monitoring comorbid conditions such as ADHD, cognitive impairment, and even dementia, our observations have revealed improved cognitive performance after 9-18 months of treatment in many patients.

Much of the literature supports our observations: recent studies from Yale and the University of Minnesota confirmed measurable cognitive improvement with repeat IV ketamine treatments. And, randomized, placebo-controlled phase II clinical trials utilizing an oral ketamine wafer have demonstrated very similar outcomes in treatment-resistant depression populations.

Important Considerations for Providers

We offer the following considerations when using low-dose sublingual ketamine:

1) Ketamine should not be used in patients who have aneurysms, brain hemorrhage, pregnant and breastfeeding patients, or those who have demonstrated hypersensitivity or allergy to ketamine.
2) Birth control should be discussed with patients before initiating treatment with ketamine, as well as a mutually agreed-upon plan to discontinue use if an unplanned pregnancy occurs.
3) Baseline labs including a comprehensive metabolic panel, urine drug screen, pregnancy test, and if indicated an EKG (for patients with pre-existing cardiac disease) should be obtained and documented for ongoing monitoring.
4) Vital signs including blood pressure and heart rate should be monitored as both can increase, especially within the first 30 minutes of dosing.
5) We recommend carefully informed and documented consent, including a discussion of known risks of ketamine use (consider drug package insert data for esketamine nasal spray), as well as acknowledgment of the off-label use and possible unknown risks.
6) Certain comorbidities may require medical clearance from specialty care or closer monitoring for side effects. For example, individuals with pre-existing renal impairment may benefit from repeat tests of kidney functioning, such as serial eGFRs. Also, individuals with pre-existing cardiac diseases such as palpitations may require clearance from a cardiologist. It is our experience that these populations may also require lower doses of ketamine, or with advanced renal disease, ketamine may not be appropriate.
7) The risk of potential abuse should be discussed, with ongoing monitoring and a mutually agreed upon plan to discontinue ketamine if misuse occurs. Notably, most patients, in our experience, describe decreased cravings for their former substance of abuse through their treatment with ketamine, finding sobriety refreshingly easier than expected.

Within these parameters, we have seldom found abuse or overuse of low-dose sublingual ketamine and have frequently observed reliable positive outcomes. Many patients outgrow a need for more traditional psychotropics and often express surprise at their improvement. However, given the many considerations that go into individualized treatment plans and close monitoring, the administration of ketamine by medical professionals in appropriate settings is paramount.

Overall, ketamine is a well-tolerated, highly effective medication for treatment-resistant depression, and has been helpful in the management of other neuropsychiatric diseases. Some patients decide to continue treatment for one to four years and report additional transformation of neurological and psychiatric functioning, including improvements in neuropathy; mood stabilization; increased resilience; healing of past traumas with a reduction in PTSD symptoms; reduced use of addictive substances; resolution of personality disorders; increased cognitive function; accelerated learning; expanded creativity; and shifts in perception that contribute to transcendent perspectives. One theory to explain these changes echoes back to the possible growth of brain circuitry with repeated long-term dosing of psychoplastogens.

This raises the question, does ketamine enhance multiple domains of brain function? Further studies are needed to determine the range of possible applications for this fascinating psychoplastogen. In the meantime, this medicine is offering relief to those who live with treatment-resistant depression, as well as numerous other neuropsychiatric disorders, and those who may have lost hope that a solution to their suffering could be found.

Rachel Wilkenson, MD, is an integrated psychiatrist who has dedicated her career to helping the underserved. She is passionate about whole-body health and blending scientific rigor with the use of natural compounds to enhance recovery from severe treatment-resistant illness.