“Lithium may well be an essential trace element. It is widely distributed, has been detected in sea-water and in many spring and river waters, in the ash of many plants, and in animal ash.”
(John Cade, 1949)
Lithium is a mineral that is both salt and metal resulting in its ability to conduct electricity. It’s also the most effective psychiatric medication for reducing suicidal behavior [
The suicide prevention effect of lithium: more than 20 years of evidence- a narrative review.
- Cipriani A.
- Hawton K.
- Stockton S.
- Geddes J.R.
Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis.
]. Yet it remains at the bottom of the list of the twenty five most frequently prescribed psychiatric medications in the US [
Grohol, J. PsychCentral Jul, 2018. https://psychcentral.com/blog/top-25-psychiatric-medications-for-2016/.
]. Furthermore, despite the forged evidence that it is the best treatment for Bipolar Disorder [
- Severus E.
- Taylor M.J.
- Sauer C.
- Pfennig A.
- Ritter P.
- Bauer M.
- Geddes J.R.
Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis.
], it’s underutilized even for this ferocious condition. The bias against more frequent use may be from the need to monitor at high doses along with the false belief that synthetic medications are superior. But what if undetectably low doses could be both safe and hyper-effective for anxiety and mood symptoms? Not just as an adjunctive treatment [
Low dosage lithium augmentation in venlafaxine resistant depression: an open-label study.
] but as a first line option.
There is growing evidence that “subtherapeutic” doses of lithium are not subtherapeutic at all but rather foster constructive behavior [
Phelps, 2016 “Low-Dose Lithium: A Different, Important Tool,” Psychiatric Times 9/13/16 http://www.psychiatrictimes.com/bipolar-disorder/low-dose-lithium-different-important-tool.
- Faucet J.
- Clark D.
- Aagesen C.
A double-blind placebo-controlled trial of lithium carbonate therapy for alcoholism.
], delay destructive behavior [
- Devanand D.P.
- Pelton G.H.
- D’Antonio K.
- Strickler J.G.
- Kreisl W.C.
- Noble J.
- Marder K.
- Skomorowsky A.
- Huey E.D.
Low-dose lithium treatment for agitation and psychosis in Alzheimer disease and frontotemporal dementia: a case series.
] and have neuroprotective utility [
- De-Paula V.J.
- Gattaz W.F.
- Forlenza O.V.
Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons at subtherapeutic concentrations.
]. From ground water studies of associated lower rates of suicide, homicide, psychosis, and Alzheimer’s disease [
Schrauzer, (1990) “Lithium in drinking water and the incidence of crimes, suicides, and arrests related to drug addiction,” Biologic Trace Elements May; 25:105-13https://www.ncbi.nlm.nih.gov/pubmed/1699579.
Association of lithium in drinking water with the incidence of dementia.
- Mauer S.
- Vergne D.
- Ghaemi S.N.
Standard and trace-dose lithium: A systematic review of dementia prevention and other behavioral benefits.
Could Lithium in drinking water reduce the incidence of dementia?.
] to large sample studies like the Texas LITMUS (that explicitly used low lithium doses) study [
- Nierenberg A.A.
- Friedman E.S.
- Bowden C.L.
- Sylvia L.G.
- Thase M.E.
- Ketter T.
- Ostacher M.J.
- Leon A.C.
- Reilly-Harrington N.
- Iosifescu D.V.
- Pencina M.
- Severe J.B.
- Calabrese J.R.
Lithium treatment moderate-dose use study (LiTMUS) for bipolar disorder: a randomized comparative effectiveness trial of optimized personalized treatment with and without lithium.
] to anecdotal evidence from eminent psychiatrists [
The new news about lithium: An underutilized Treatment in the United States.
RR Fieve, Moodswing: The third revolution in psychiatry. New York: Morrow, 1975.
], all of the above have been influential in pursuing the question: How low can we go to benefit from lithium while avoiding the side effects of higher doses?
This study is to assess the effectiveness of low-dose lithium carbonate (4.1 mmol/150 mg) enhancement in an addiction treatment center as a substitute for or supplement to synthetic antidepressants and antianxiety medications. The logic being that if standard dosing of lithium is so effective at reducing imminently suicidal behavior, then perhaps low-dose lithium could be useful in reducing the “slow-motion suicide” of addiction manifested in self-sabotage and self-harm. We also recommended this dose of lithium to attempt to improve alcohol and substance induced effects on mood and sleep. Its ability to deepen sleep, elevate mood and improve hopefulness could be useful for patients struggling with all the above.
The hypothesis then is that adding low-dose lithium for the appropriate patient would improve addiction treatment outcomes on multiple measurable levels.
The Center for Recovery and Wellness (CRW) is a residential and outpatient healthcare center in the East Village of Manhattan where the author has been the Medical Director since March 2018. At CRW, the author introduced a “Triad Approach” to address three common antecedents of addiction; physical pain, emotional pain (trauma), and inattention (Attention Deficit Disorder). This approach included standard Medication Assisted Treatment (MAT) such as the tapered use of Buprenorphine-Naloxone [
FDA Prescribing Guidelines for Buprenorphine-Naloxone. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022410s000lbl.pdf.
] for opiate dependence and psychotherapeutic strategies by a multi-disciplinary team with expertise in Dialectic Behavioral Treatment (DBT), motivational interviewing, housing placement, educational and vocational assistance, all in a self-sustained holistic setting. The combination of services provided along with addressing the sources of addiction would theoretically lead to better outcomes.
What’s even more unique than this approach is the recommendation of low-dose lithium (4.1 mmol/150 mg) for said “emotional pain.” We used broad inclusion criteria. Nearly all our clients are diagnosed in according to the DSM-5 with a singular or polysubstance dependence. Greater than 75% are also diagnosed to have an underlying psychiatric condition such as Major Depression, Post Traumatic Stress Disorder, Attention Deficit Disorder, or a substance induced condition. Furthermore, the majority have been in multiple addiction treatment facilities indicating that the standard treatments were not effective enough. Any client with a history of trauma, addiction of any type, incarceration, and or recidivism could be treated with low-dose lithium. Any patient who was pregnant, had thyroid or kidney disease, or who refused to accept low-dose lithium despite their suitability was excluded.
Each patient was provided with a multidisciplinary assessment concluding with a discussion on how and if the Triad Approach applied to them. A treatment plan was formulated with consent focusing on improving overall health, undoing effects of addiction and improving his or her ability to move forward in his or her personal and professional goals. The potential risks and benefits of low-dose lithium was discussed with each patient. About 65% of patients consented to take low-dose lithium over the period being presented. On the matter of consent, all patients upon admission are informed of our methods and options for treatment on documentation which is signed by them.
Data was retrospectively analyzed in an observational analysis with respect to changes in medication utilization, patient safety, clinic functioning, and patient outcomes. Therefore, this study has not been registered in advance. Data also underwent a regression analysis to compare low-dose lithium recipient outcomes with those patients who did not receive it.
There were two major groups of comparison and one was subdivided:
Group 1 (n = 160) was the population of patients over eight months prior to the author’s arrival and instatement of the Triad System. This group could be considered a “pseudo-control” but because this was a retrospective, observational analysis, there was no formally designated control. This concept is similar to other observational studies where we compare the introduction of a mineral like fluoride or iodine into a population and then look at dental health or thyroid health before and after.
Group 2 (n = 175) is further subdivided into 2a (n = 62) and 2b (n = 113). Group 2a are the group of patients that benefitted from the Triad System but did not take low dose lithium while 2b did take low dose lithium and would theoretically have the best outcomes of all. Essentially, we are comparing 2b with both 2a and 1, each of which are “pseudo-controls.”
Furthermore, lab data of 90 patients that were prescribed low-dose lithium was collected to confirm safety. We are also presenting macro data of the clinic’s functioning from 8 months before and after the introduction of this approach to assess more than individual outcomes.
Table 1Changes in individual medication management.
Relative to the 8 months prior, there are marked improvements at the micro (individual) and macro (population) level.
On the micro level of individual patient care:
That the very use of Buprenorphine-Naloxone (MAT) is not widespread is evidence of inconsistency in addiction treatment. Akin to not treating pain in a patient from a myocardial infarction or physical trauma, it is important to include but also important to provide a path off from. Prior to supplementing with low-dose lithium, our average dose of Buprenorphine-Naloxone was 14 mg/day with some patients as high as 24 mg/day. The current guidelines indicate that above 16 mg/day may not be advisable as it is likely to worsen constipation, sedation, cognitive dulling and make it harder to taper off [
FDA Prescribing Guidelines for Buprenorphine-Naloxone. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022410s000lbl.pdf.
The application of the Triad Approach is the larger framework for how we address the current addiction crisis at CRW. With a significant amount of addiction stemming from untreated physical pain, emotional pain or the effects of inattention, addressing any or all the above is now a core principle at CRW. With patients, I’ve likened MAT to crutches and treating underlying conditions as strengthening the body, so crutches are eventually unnecessary. Pragmatically, this means that an opiate dependent patient with symptoms of residual emotional trauma and inattention (ADHD) would be provided a trial of low-dose lithium, low-dose stimulant, and conservative dose MAT which over time would be tapered. In addition, DBT in groups, individual therapy, vocational/educational assistance, improved diet, exercise options, and medical care improvements have all been part of the treatment provided at CRW. This holistic combination of the right pills and the right skills has left patients more ready for independence and less conditioned for dependence.
While most of the above interventions are labor intensive, they are also evidence based and hence not break-throughs in addiction treatment. All except for the use of low-dose lithium that again seems to have enhanced both pharmacologic and psychological treatments that existed prior at CRW.
Upon the author’s hiring as medical director, over half of inpatients had been using a benzodiazepine or analog (Zolpidem) for anxiety and insomnia management. With increasing evidence of their long-term toxic effects on sleep depth, overdose enhancement, reduced memory consolidation, rebound anxiety, depression induction, and dementia acceleration [
- Agarwal S.D.
- Langdon B.E.
], we made it a point to explain to patients and staff the importance of avoiding these medications. Exceptions would be made for necessary tapering or on a case by case basis. We theorize that this concerted effort towards “Zero Benzo” was enhanced by the use of low-dose lithium so that within three months and since, we nearly eliminated the need of these medications.
In my outpatient practice and as outlined in the Agarwal paper on the underreported “benzodiazepine crisis” [
- Agarwal S.D.
- Langdon B.E.
], I have frequently been presented with cases where patients have been taking standing doses of benzodiazepines for months to years and others that take as-needed doses for just as long. As a result, not only is neurochemistry altered but a psychological component of this medication as a “rescue pill” is created. This duo of effects makes tapering challenging and treating the underlying core of their anxiety even more so. For such cases, I’ve seen consistent rates of voluntary and comfortable tapering by supplementing low-dose lithium and providing simultaneous education and supportive therapy.
Beyond polypharmacy, defined as “more drugs being prescribed than are clinically appropriate in the context of a patient’s comorbidity”, we have also noted the effort to avoid using atypical antipsychotics unless multiple tiers of medication classes are provided a trial of. Furthermore, the reduction of using unnecessary atypical antipsychotics have helped patients in their metabolic profile goals. Of course, in cases where there is residual psychosis from substance abuse, such medications are indispensable to get patients back to high functioning status.
Considering the importance of complete care, we would be doing patients a disservice if we did not address and encourage smoking cessation. Electronic cigarette usage was not utilized due to storage and fire safety concern, but they may be a viable, temporary weapon in reducing the myriad effects of standard smoking if regulated models are used. Also, by increasing screening for and treatment of underlying ADHD, we removed the need for extraneous stimulant use. Clinical assessment and the use of the Harvard ASRS scale were utilized in screening (ASRS v1.1) [
ASRS Scale for ADHD. https://add.org/wp-content/uploads/2015/03/adhd-questionnaire-ASRS111.pdf.
The use of two atypical antipsychotics is growing less common but the use of singular atypical antipsychotics as hypnotics and mood stabilizers is more common than before, even in children [
Harrison, Joyce N. Cluxton-Keller, Fallon. Gross, Deborah. Journal of Pediatric Healthcare, October 2011.
]. This has led to control of potential self-harm and agitation but with a significant side effect burden. Weight gain, sedation, cognitive dulling, and hypercholesterolemia are some examples. Moreover, the use of redundant synthetic antidepressants (two different serotonin increasing medications) increases chances of sexual side effects, and medication interactions without proportional improvements in functioning.
With low-dose lithium supplementation, patients at CRW have a more tailored regimen. As a result, the above side effects were less seen and overall functioning was improved (Table 2
Table 2Changes in lab values for patients that were taking/did take low-dose lithium.
Absence of any negative changes in labs for kidney, WBC, or thyroid functioning as well as any associated changes in EKG, allergic reactions or a detectable Lithium level.
The most important consideration is whether low-dose lithium carbonate of 150 mg/day is as safe as it is effective. With daily monitoring of self-reported side effects, labs and examinations reviewed prior to admission, and at regular intervals during, we can safely report that there were no discontinuations of low-dose Lithium due to the typical medical concerns of standard Lithium dosing (levels of 0.6 mmol/L to 1.2 mmol/L). There were discontinuations or refusals secondary to bias, stigma, or from online directed misinformation (n = 23). Consistent education in sessions, and recommendations to search and read vetted articles (see references) on “low-dose lithium” improved and prevented much of the reflexive fear. Our data also serves to help reassure the provider that at doses of 150 mg, the vigilance of monitoring labs is not equal to when higher doses are used. This may remove a barrier to a trial for both patient and provider.
Lithium levels were undetectable (<0.1 mg/dl) in serum at 150 mg/day. At such a dose hair sampling would be most appropriate for accurate measurement but this was not cost effective at CRW. There may be significant relevance in measuring at this level for both medical and supplement standardization according to recent research in Moscow [
Mimica N, Prejac P. Trace Elements and Electrolytes Vol 00 Feb, 2019 https://www.researchgate.net/publication/331001159_Assessing_lithium_nutritional_status_by_analyzing_its_cumulative_frequency_distribution_in_the_hair_and_whole_blood.
Consistent reports of motivation, hope, dream recall, unbroken sleep, and unique success stories related to sobriety and progress. We have presented data but the people behind the numbers illustrate powerful stories, archetypes even.
An 18 y/o young man with a history of polysubstance dependence, violence, incarceration, victim of child abuse, and untreated ADHD completing the program on low-dose Li and stimulant with certification, employment and housing: “I feel like this really made a difference, I’m just…better.” Pt was discharged on 4 mg Buprinorphine/Naloxone every morning, Lithium Carbonate 150 mg once a day, and Dextroamphetamine 20 mg extended release every morning.
A 26 y/o man with a history of multiple failed rehab attempts for opiate dependence gains OSHA certification (occupational safety) and employment while on 4 mg MAT and low-dose Li. “I’m sleeping good, feeling good about myself, and the future.”
A 47 y/o male veteran with PTSD, MDD, alcohol dependence, multiple failed rehab attempts, and obesity worsened by olanzapine loses 10 Kg after we substitute low-dose Li for the olanzapine. He gains hope, control over self-destructive impulsivity, and is effusive in his appreciation.
A 31 y/o mother with a history of childhood sexual abuse, domestic violence, suicide attempts, psychiatric hospitalizations, failed rehab attempts for opiate dependence takes low-dose Li for the first time. She sleeps deeper, dreams, finds both blame and forgiveness for her pain, motivation to be self-constructive, completes DBT and is discharged with employment as a receptionist and housing back with her family.
The stories are cinematic, expected by now after seeing the effects of low-dose Li but still surprising, and refute the belief that addiction treatment is a revolving door frustrating family, patient, provider, and system. It is sensible that the medication most effective for reducing suicide is also showing benefits in reducing the slow-motion suicide of addiction. As a result of this reduced regression, we are seeing improved traction in each patient’s unique progress, towards their authentic ascension.
On the macro level of clinic outcomes, changes were significant but with more variables and time, the effects may be less directly linked to the introduction of low-dose lithium. Still, data seen from our “dashboard” retrospectively from the 8 months prior compared to the 8 months after shows progress between group 1 and 2.
More average census means more patients are staying, more are coming in and fewer are leaving prematurely. The combination of the approach and content of treatment have been favorable to the bottom line of CRW and its patients.
This is more evidence that providing a clear mission of treating the underlying reasons for addiction has found acceptance over and over in our clients. Moreover, to be able to improve retention this dramatically implies that our enhanced care model is also being executed well.
This metric is a result of considering new, current and increased employment during the entirety of a patient’s length of stay. To have doubled it before and after March 2018 considering that all vocational/educational services were identical is a testament to the power of the “Triad” approach. It’s elementary that providing patients who have untreated ADHD with stimulants will enhance performance towards goals. From GED attainment to vocational certifications, college entrance, and improvement at the jobs they get. The addition of low-dose lithium may enhance achievement by preventing past inclinations of self-sabotage and igniting both innate value and the value gained from contribution.
This dramatic change is also related to our services combined with the a more progressive approach. Vocational readiness is measured using a combination of stability measurements such as participation, medical readiness and logistics.
Finally, an improvement in completion rate, while modest, is significant. Its lower margin relative to prior metrics is secondary to the many variables that affect it such as length of stay, and difficulty of the program itself. Still, as this approach becomes more ingrained within the culture of CRW, we expect a widening of this gap.
A deeper dive was conducted into the data to compare the outcomes when looking at the variable of low-dose lithium use. We found that even when Triad Approach, patient outcomes improved over the prior approach but when patients also utilized Low-dose Lithium, their rate of completion nearly doubled. To confirm this effect, we would have to move to a blinded study using a robust sample. This leads us to limitations of the current analysis.