Lithium and Psychedelics

lithium lithium carbonate lithium orotate psychedelics seizure Apr 15, 2021

[Li]thium

Lithium is unique as a ‘drug’ because it is a naturally occurring chemical element on the periodic table rather than a small organic molecule. Lithium has a similar electronic configuration as sodium and both metals carry a positive charge. Lithium is used for depression, mania, and prevention of mood episodes associated with bipolar disorders. It can also be helpful as an augmentation agent for treatment-refractory depression.

It is both one of the first treatments to be recognized as having significant psychotropic potential in persons with bipolar disorder and to this day seems to be the ‘best’ treatment for management and prevention of mania [1]. It is also known to have ‘anti-suicidal’ properties, which is unique among treatments for bipolar disorder (with the possible exception of ketamine) [2].

At therapeutic doses lithium has a narrow therapeutic index meaning that therapeutic doses and toxic dose ranges are close together. Lithium toxicity can be severe and life threatening acutely. Moreover, lithium can result in other toxicities from long-term use. For this reason, periodic monitoring of lithium levels in blood is typical, along with monitoring other factors that effect lithium levels such as adherence, kidney function, fluid and water balance, concurrent medications, drugs, or supplements, and age.

Lithium Salts

Lithium in its elemental or metal form is highly reactive, so it exists and is taken in various salt formulations. For example, lithium carbonate and lithium citrate are available by prescription for the treatment of bipolar disorder, whereas low dose lithium orotate is available over the counter as a supplement used for various mood or neurologic disorders. The different salt formulations each have different molecular weights, so 100mg of lithium orortate does not contain the same amount of elemental lithium as 100mg of lithium carbonate. Below are relative conversion ratios between various salt formulations of lithium and the amount of elemental lithium they contain.

  • Lithium Orotate = 3.83mg elemental lithium per 100mg salt

  • Lithium Carbonate= 18.80mg elemental lithium per 100mg salt

  • Lithium Citrate = 9.91mg elemental lithium per 100mg salt

Put it in the water?

Due to lithium being naturally occurring it can be found in some drinking water and our diets. Interestingly, this may confer a population level benefit as the suicide rates are lower in populations that drink water containing lithium [3]. The average amount of lithium in drinking water is ~140 ug/L (range 0-200 ug/L), which would equate to ~0.3-5mg if drinking 2-4L (1/2-1 gallon) of water daily.

Supplementation with Lithium Orotate

Amounts of element lithium when used as a supplement (10-20mg/day of the 3.83 mg lithium/100 mg orotate salt) is much lower than standard clinical doses of lithium carbonate or citrate used in bipolar disorders. Using a conversion ratio, it is calculated there would be 0.76mg of lithium in 20mg of the orotate salt. Therefore, a supplement dose of lithium orotate is approximately 1.5-3x above drinking water, yet 100-300x less than if you were taking lithium for bipolar disorder.

Salt Balance and Lithium

The kidney filters sodium and excretes it in urine, although is also capable of reabsorption to balance body water and sodium. Lithium is excreted almost entirely by the kidney and is handled similarly to sodium at reabsorption sites.

Practically, this means that stability in sodium and water balance is important to stability of levels in lithium therapy. Too little salt and dehydration can increase lithium levels to toxic ranges, too much salt and overhydration can decrease lithium levels and reduce efficacy of therapy. Therefore, persons using and prescribing lithium need be mindful of other medications, conditions, and illnesses that influence or impair salt and water balance [4]. Diuretics (hydrochlorothiazide, chlorthalidone), some blood pressure medications (ACEI or ARB), and NSAIDS (e.g. ibuprofen) are most notoriously known to increase lithium levels. It’s common counseling to keep salt and fluid intake consistent and avoid excessively hot environments or extreme exercise while using lithium.

To this end, MDMA is known to be able to cause low body sodium or hyponatremia via release of arginine vasopressin (AVP or anti-diuretic hormone), which impairs the kidney’s ability to get rid of free water. Hot environments for ingestion and hyperthermic responses to MDMA may lead to dehydration or excessive fluid intake, sustained levels of high physical activity, and salt loss via sweating [5]. Low body sodium due to excess AVP secretion (SIADH) could result in lower lithium levels due to dilutional effects associated with increased total body water or decreased reabsorption by the kidney’s proximal convoluted tubule (increased clearance of lithium and salt-wasting) [6]. Interestingly, lithium impairs the ability of vasopressin to act (thus can cause nephrogenic diabetes insipidus with long term use) and appears protective against hospitalization for SIADH in persons taking other psychotropic medications linked to hyponatremia [7]. Overall the picture is complex, yet can be reasoned that psychedelics like MDMA or behaviors associated with use may have significant effects on fluid balance or electrolytes that could impact efficacy or safety of lithium therapy.

Other aspects of psychedelic use may also shift fluid or electrolyte balances which could impact lithium therapy. For example, dietas associated with ayahuasca use could drastically reduce dietary sodium intake and result in increased lithium levels. Ayahuasca frequently leads to vomiting and/or diarrhea which could also impact fluid and electrolyte balance.

Mechanism of Lithium & Serotonergic Potentiation

Lithium has a complex mechanism of action and appears to modulate monovalent cation binding sites (e.g. sodium) as well as second messenger cascades intracellularly. It appears to effect monoamine neurocircuitry such as those associated norepinephrine, dopamine, acetylcholine, and serotonin. Due to reports of serotonin toxicity occurring with lithium in combination with other drugs with serotonergic mechanisms it appears to increase or enhance serotonin neurotransmission [4]. However, lithium is commonly combined with other serotonergic reuptake blocking antidepressants (SSRIs, SNRIs) or atypical antipsychotics (5HT2A receptor blocking agents) in clinical practice. It has been argued that cases of toxicity reported with SSRI/SNRI antidepressants and lithium, usually have other explanatory factors (e.g. elderly age, illnesses with fluid or electrolyte imbalances), supratherapeutic doses, or could be attributed to the effects of either drug alone [4, 8]. Screening, close monitoring, or excluding those positive for such factors may reduce risks associated with combinations of drugs involving lithium.

Psychedelic Interactions with Lithium

Serotonergic Psychedelics (MDMA, LSD, psilocybin, DMT, mescaline)

There is scant data to inform how psychedelics interact with lithium. If lithium potentiates serotonin and other monoamine neurotransmission, it is logical to think psychedelic experiences and risks of their adverse effects could be potentiated also.

One small study of 10 people and subjective reports with LSD reported potentiated experiences [9]. Anecdotes found on Erowid highlight possible adverse effects, with several cases of seizures documented with LSD and lithium in combination [10]. Other anecdotes report similar phenomenon with MDMA or psilocybin - either potentiated experiences or seizures. There is no information on doses of lithium taken in these sources, but assuming they were taking clinical doses (600mg/day or more) seems reasonable as the descriptions are cases in which the persons were diagnosed with bipolar disorder or another refractory mood condition.

Ayahuasca (MAOIs)

Clinically, lithium has been combined with monoamine oxidase inhibitors for refractory depression on occasion without precipitating serotonin syndrome, although given potentiation of serotonin neurotransmission and other reports of serotonin toxicities involving lithium, it is a moderate-high risk combination [11].

Ibogaine

Lithium is known to lead to changes in cardiac conduction that have led to arrhythmias and electrocardiogram (EKG) monitoring is recommended with lithium therapy. Medications affecting the cardiac conduction may increase risks of lithium therapy (e.g. amiodarone). Bradycardias (slow heart rates) and arrhythmias are adverse effects of ibogaine, which could be increased with concurrent lithium use.

Ketamine

Lithium has been combined with ketamine during clinical trials of persons using ketamine to treat bipolar depression and appears safe in this context [12, 13]. Lithium does not need to be stopped or held for persons to undergo ketamine assisted therapies. Current data supports lithium to be the safest and most effective psychedelic for persons requiring therapy with lithium. 

What About Bipolar Disorder?

One major risk that is introduced by stopping or holding lithium to work with serotonergic psychedelics are risks associated with loss of lithium’s therapeutic efficacy resulting in mania or mood decompensation. Especially if lithium were stopped abruptly, discontinuation syndromes or extreme symptoms could emerge. Additionally, serotonergic psychedelics are considered relatively (bipolar II) or absolutely (bipolar I) contraindicated with bipolar disorders due to cases of precipitating mania [14-18]. It may be overly activating to discontinue mood stabilizers and use activating substances like psychedelics in their absence for persons predisposed to mania.

Unless encouraging data emerges that can speak to efficacy and safety it is best to avoid psychedelic use in persons with significant history of mania

This said, it is difficult to say exactly how severe the risks of using psychedelics are in persons with bipolar disorder. For example, use of serotonin blocking antidepressants or stimulants are also relative contraindications in bipolar disorder (at least without conjunctive mood stabilizers) due to ability to precipitate mania, yet are not uncommon prescriptions for persons suffering from a bipolar condition. Heavy alcohol, cannabis, or caffeine use is also associated with mood decompensation in bipolar disorder.

Whether serotonergic psychedelics have higher risks of exacerbating mania than antidepressants, stimulants, or other substances is unknown. Overall psychedelics result in liberation of psychic material, perceptual distortion, and reduced executive function [19]. Moreover, commonly reported aspects of psychedelic use – expansive feelings and emotional ranges, a sense of embodying God or an inflated sense of Self, loosening of thought and belief structures, fantastical experience, or anxious ego dissolutive effects seem to have overlap with aspects of manic states. Many atypical antipsychotics have anti-manic effects and have pharmacologically opposite effects to psychedelics at 5HT2A receptors.

In challenge to conventional psychiatric wisdom a case was reported in which a young female with history of bipolar I disorder with psychotic features overdosed on LSD (~1200μg), had a (pseudo) ‘seizure’, awoke in the hospital the next morning and proclaimed “It’s [bipolar illness] over”. She experienced stabilization of mood without further episodes until post-partum depression occurred 13 years later [20]. I report the case with high levels of interest and desire to not simply cherry-pick cases of precipitating mania without presenting the converse situation. This said, please don’t read this to mean that overdose of psychedelics is likely a curative treatment for bipolar disorder.

More data is required to understand or quantify risks and benefits of psychedelic use generally, while even less is available for persons with bipolar disorder. Unless encouraging data emerges that can speak to efficacy and safety it is best to avoid serotonergic psychedelic use in persons with significant history of mania. Depressive states of bipolar disorders in therapeutic settings with close monitoring and post-use support may turn out to carry significant benefits with lower risks than use in presence of mania [21].

Elimination and Washout of Lithium

Lithium has a half-life of ~24 hours, therefore a period of 5 days would be predicted to be sufficient time to eliminate it from the body’s system. There would be little predictable risk of adverse drug reactions due to combination with serotonergic psychedelics with this approach. Lithium could be re-started 24-48 hours after serotonergic psychedelic use (LSD, MDMA, psilocybin, mescaline) without risk of adverse reactions due to drug interaction.

It is more appropriate to taper and discontinue lithium and observe a period of relative mood stability off of the medication before attempting work with psychedelic therapies opposed to abrupt discontinuation, especially when a significant history of mania or suicidality is present.

Conclusion

Lithium is a complex medication and may be able to potentiate effects of serotonergic psychedelics, creating risks of intensified psychological experiences, seizures, or acute toxicity. There are also considerable risks in stopping or discontinuing lithium in persons with history of bipolar disorders, mania, or suicidality. Currently, persons using lithium for bipolar disorder are not likely to be appropriate candidates for psychedelic-assisted psychotherapy with serotonergic agents. Lithium has been used with ketamine in clinical trials for bipolar depression with acceptable safety and good effects.

 

 References

1.         Butler, M., et al., AHRQ Comparative Effectiveness Reviews, in Treatment for Bipolar Disorder in Adults: A Systematic Review. 2018, Agency for Healthcare Research and Quality (US): Rockville (MD).

2.         Smith, K.A. and A. Cipriani, Lithium and suicide in mood disorders: Updated meta-review of the scientific literature. Bipolar Disord, 2017. 19(7): p. 575-586.

3.         Vita, A., L. De Peri, and E. Sacchetti, Lithium in drinking water and suicide prevention: a review of the evidence. Int Clin Psychopharmacol, 2015. 30(1): p. 1-5.

4.         Finley, P.R., Drug Interactions with Lithium: An Update. Clin Pharmacokinet, 2016. 55(8): p. 925-41.

5.         Gillman, K., Venlafaxine-lithium toxicity: suitability for use in the elderly. J Clin Pharm Ther, 2007. 32(5): p. 529-31.

6.         Bonson, K.R. and D.L. Murphy, Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, monoamine oxidase inhibitors or lithium. Behav Brain Res, 1996. 73(1-2): p. 229-33.

7.         Brown, M. LSD and Antidepresants. 2002; Available from: https://erowid.org/chemicals/lsd/lsd_health3.shtml.

8.         Campbell, G.A. and M.H. Rosner, The agony of ecstasy: MDMA (3,4-methylenedioxymethamphetamine) and the kidney. Clin J Am Soc Nephrol, 2008. 3(6): p. 1852-60.

9.         Gross, P., et al., Natriuretic factors and lithium clearance in patients with the syndrome of inappropriate antidiuretic hormone (SIADH). Eur J Clin Invest, 1989. 19(1): p. 11-9.

10.       Falhammar, H., et al., Reduced risk for hospitalization due to hyponatraemia in lithium treated patients: A Swedish population-based case-control study. J Psychopharmacol, 2020: p. 269881120937597.

11.       Fein, S., et al., The combination of lithium carbonate and an MAOI in refractory depressions. Am J Psychiatry, 1988. 145(2): p. 249-50.

12.       Diazgranados, N., et al., A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of general psychiatry, 2010. 67(8): p. 793-802.

13.       Zarate, C.A., Jr., et al., Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry, 2012. 71(11): p. 939-46.

14.       Carhart-Harris, R.L. and K.J. Friston, REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics. Pharmacological Reviews, 2019. 71(3): p. 316-344.

15.       Janikian, M. Bipolar and Psychedelics: An Investigation into the Potential and Risks. 2020; Available from: https://psychedelicstoday.com/2020/05/11/bipolar-and-psychedelics/.

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