Key words psychedelic - lithium - hallucinogen - harm - risks
Introduction
After more than 6 decades of research into and popular use of classic psychedelics
(defined here as a class of drugs that produce a unique profile of subjective effects
and have a principal site of action at the 5HT2A receptor, such as LSD or psilocybin), recent promising trials investigating the effects
of psilocybin therapy for the treatment of depression [1 ]
[2 ], anxiety and depression in cancer patients [3 ]
[4 ], tobacco smoking [5 ], and alcohol use disorder [6 ] have inspired additional medical, commercial, and public interest in using psychedelics
as treatments for psychiatric disorders. Interest has also grown in understanding
whether psilocybin therapy may be effective for a wider range of indications [7 ]
[8 ]
[9 ].
Depressive episodes in individuals with bipolar disorder (“bipolar depression”) in
particular have been discussed as targets of interest, with at least one study planned
in patients with bipolar II disorder (Clinicaltrials.gov identifier NCT04433845).
However, the risk of adverse events in this patient population merits special consideration
in light of the possibility of precipitating mania and concerns about possible interactions
with other drugs commonly used to treat bipolar disorder.
Bipolar disorder is a chronic condition characterized by episodes of mania or hypomania
and predominantly depressive episodes [10 ]. Pharmacologic treatment of bipolar disorder can be challenging due to the need
to address alternating extremes of mood [11 ]. Treatment usually includes “mood stabilizers” such as lithium, certain anti-epileptic
drugs, and anti-psychotics. Lithium remains the gold-standard treatment with particular
efficacy for relapse prevention and treatment of acute mania [12 ]
[13 ]. However, treatment options specifically targeting depressive episodes in bipolar
disorder are limited.
Modern psychedelic trials typically exclude people with bipolar disorder [14 ]. This was considered to be a prudent safety measure, given the potential for precipitating
psychosis or mania in patients with a personal or family history of schizophrenia
or bipolar spectrum disorders [15 ], but it also leaves open the question of whether psychedelic drugs may be effective
in treating patients with bipolar depression. The combination of promising evidence
for psilocybin in treating unipolar depression, the fact that bipolar depression is
difficult to treat, the lack of clear information on problematic drug interactions,
the increasing availability of psilocybin mushrooms, and the extensive positive media
coverage of anecdotal reports suggesting therapeutic benefits of psilocybin in depression
may lead individuals with bipolar disorder to take psychedelic drugs in addition to
continuing their existing medications.
There is very little information concerning the effects of concurrent psychedelics
and mood stabilizers. An online survey noted 2 subjects who reported taking LSD while
on lithium (600 mg and 1000 mg) and described intensified subjective effects from
LSD [16 ].
Here we report on anecdotal descriptions of reactions to the use of psychedelic drugs
when taken with a concurrent mood stabilizer. Data were drawn from a systematic search
of self-reported experiences posted or published in public online forums focused on
psychedelic drugs. While this method cannot conclusively determine safety, it could
establish some signal for risk in the potential for harmful interactions between psychedelic
and typical therapeutic drugs.
Methods
Data collection
Three websites were used as data sources—Erowid.org, Shroomery.org, and Reddit.com.
These are publicly accessible sites and online communities that include user-created
and user-driven content in which people can anonymously share information related
to psychedelic drug use. These online communities frequently receive “trip reports”
(henceforth experience reports), or descriptions, often quite detailed, of psychedelic
drug experiences. Though mostly anonymous, individuals typically post under a pseudonym.
Experience reports on these websites are organized in a fashion that is amenable to
automated collection and analysis of these reports (see individual descriptions below).
For this paper, reports from each internet site were filtered for duplicate usernames
to eliminate double-reporting on the same individual to the extent possible.
Most experience reports did not include demographic information such as age, prior
psychedelic use, psychiatric and medical history, etc. in any systematic way, so these
were not collected.
Experience reports were searched for a series of terms related to the use of mood
stabilizers in combination with psychedelics. Antipsychotics and antidepressants were
not separately queried, but the presence of an antipsychotic or antidepressant (among
other psychoactive drugs) was coded in all selected experience reports at a later
stage (see Coding of Reports below). Mood stabilizer search terms included: lithium, lamotrigine, valproic acid,
carbamazepine, and oxcarbazepine, including generic and trade names and different
chemical names (e. g., valproate, Depakote, etc.) Because good quality empirical laboratory
studies have been published involving coadministration of haloperidol and risperidone
with psilocybin, antipsychotics were not included in the search of the current, lower-quality
data [17 ]. Psychedelic search terms included LSD, psilocybin mushrooms, DMT, mescaline, peyote,
San Pedro, and ayahuasca, all of which are 5-HT2A receptor agonists commonly used in recreational settings.
Erowid
Erowid is a curated online resource founded in 1995 for information related to psychoactive
drugs, which also contains sections for user-generated and submitted content including
experience reports for each drug and drug class that is covered on the website. Erowid’s
reports are tagged before publication with the drugs described in each report. Erowid
has an application programming interface (API)—a purpose-built programming interface
typically used to allow programmers to gain custom access to a data source or computing
infrastructure. An API provided by Erowid was accessed via a custom python script
on August 7, 2020, and used to identify and collect experience reports for the current
analysis.
Shroomery
The Shroomery is an online community related to psychedelic drug use, nominally focused
on psilocybin mushroom use but containing information posted by users for a wide range
of psychedelic substances. The Shroomery has a specific section of its website dedicated
to experience reports. Experience report entries on Shroomery.org were accessed on
August 21, 2020, with a custom programming script written using R statistical software
[18 ] using the packages rvest [19 ] and RSelenium [20 ]. These packages allow for “web scraping,” which is a systematic search and accessing
of all of the contents of a given website without the need for an API.
In addition to specific experience reports, Shroomery.com also has a wide array of
additional forums with posts that could have relevance. These were not searched as
those posts would require excessive manual coding to extract the relevant data and
are far less likely to include codable and relevant data than the specific “trip reports”
section of the community.
Reddit
Reddit is one of the largest collections of online communities in the world, with
innumerable “subreddits” or sections dedicated to particular topics. Reddit was chosen
as a third source due to ease of access to data through an API. Posts on the subreddits
r/Drugs, r/Shrooms, r/Psychonaut, r/TripReports, r/Psychedelics, r/LSD, r/Acid, and
r/Epilepsy were accessed on August 22, 2020, with a script written in the python coding
language [21 ] and using the Python Reddit API Wrapper (PRAW), a python package designed to interface
with Reddit’s API [22 ]. Search terms were similar to the above.
Coding of reports
All experience reports (including comments, in the case of Reddit posts) that contained
both a mood stabilizer search term and a psychedelic search term were collected and
then manually coded by a research assistant and an author (SMN) for the presence of
direct first-person or witnessed second-person reports of the experience encountered
when a psychedelic was consumed by an individual who was also taking a mood stabilizer.
This step was mainly relevant for Reddit as experience reports from Erowid and the
Shroomery were already coded by drug pre-selected to involve accounts of consumption.
In contrast, Reddit posts frequently included questions and comments without specific
accounts of drug use.
Those experience reports that contained such a first- or second-hand report were then
coded for the presence or absence of the mention of other psychiatric medications
and psychoactive drugs (including caffeine, cannabinoids, benzodiazepines, and antipsychotics,
stimulants, etc.), the reported effect, and whether or not a microdose of a psychedelic
had been consumed. If the dose was not mentioned, it was assumed that the reported
experience occurred in the context of a typical psychoactive dose (i. e., not a microdose).
Experience reports that included both lithium and lamotrigine were removed (2 from
Erowid, 0 from Shroomery, and 2 from Reddit), to separately compare reports of these
2 mood stabilizers taken with psychedelics. Three Reddit posts with duplicate content
were identified and removed.
Experience reports involving “microdoses” of psychedelics—very low doses with minimal
subjective effects—were not included. Likewise, very small doses of lithium (such
as less than 30 mg, as is sometimes taken in the form of lithium orotate over the
counter) were also not included due to less likelihood of physiological effects with
low doses and the different clinical population that might take these.
Effects were coded in 6 mutually exclusive categories based on the author’s description
and interpretation of the effect of the concomitant mood-stabilizing medication on
the psychedelic drug effect. 1) “seizure” was coded if the report indicated a seizure;
2) “bad trip” was coded if there was an explicit description of an overall negatively
valenced or noxious experience excluding seizure; 3) “intensified psychedelic effects”
was coded if the medication intensified the psychedelic effects excluding reports
coded as seizures or bad trips; 4) “decreased psychedelic effect” was coded if the
medication reduced the subjective psychedelic effect excluding reports coded as no
psychedelic effect; 5) “no psychedelic effect” was coded if the medication completely
prevented a subjective psychedelic effect, and 6) “neutral” was coded if there was
either no particular mention of an effect or an explicit mention of no effect on the
psychedelic experience. SMN manually coded these reports, which were then reviewed
by NG, with discrepancies resolved by discussion.
Results
Experience Reports
All reports from Erowid and the Shroomery that met search criteria also met criteria
for analysis as they were already selected to include an account of a drug experience
and organized by drugs consumed. In contrast, Reddit required a great degree of manual
coding following the search to identify reports that met the criteria for analysis.
Only reports involving lithium and lamotrigine were analyzed as there were few search
results involving valproic acid (1 on Erowid, 15 on Reddit), carbamazepine (8 on Reddit),
and oxcarbazepine (9 on Reddit). Ultimately, 96 total reports involving lithium or
lamotrigine were identified and met the criteria to be analyzed. An additional 4 reports
involved both lithium and lamotrigine and a concurrent psychedelic—these are reported
separately.
Verbatim text from all experience reports is included in the online Supplementary Materials .
Lithium reports
There were a total of 62 analyzed lithium reports across all 3 sites ([Fig. 1 ]). Erowid had 16 qualifying lithium experience reports (15 [93.8%] with LSD and 1
[6.2%] with psilocybin mushrooms). The Shroomery contained 2 lithium trip reports
(1 with LSD and the other with psilocybin mushrooms). Reddit had 44 qualifying lithium
reports (39 with LSD [88.6%], 4 [9.1%] with psilocybin mushrooms, and 1 [2.3%] with
DMT).
Fig. 1 Effects of taking a classic psychedelic in combination with lithium (n=62). The figure
shows the percent distribution of the described psychedelic experiences from websites
that archive personal reports of psychedelic use. Categories are mutually exclusive.
Of available experience reports from Erowid, the Shroomery, and Reddit involving lithium
plus a psychedelic, 29 of 62 (46.8%) reports were seizures, and an additional 11 of
62 (17.7%) were bad trips. An additional 12 of 62 (19.4%) reports were described as
intensified. Only 5 of 62 (8.1%) reports were described as neutral, with lithium not
described to affect the psychedelic experience.
Of the 55 reports of lithium plus LSD, 27 (49.1%) were seizures. Of the 6 reports
of lithium plus psilocybin, 2 (33.3%) were seizures. The sole report of lithium plus
DMT did not involve seizures. Removing the 18 lithium reports that contained another
psychoactive drug (most commonly serotonin reuptake inhibitors [n=5]), 54.5% of reports
still involved seizures.
Notably, 39% of reports involving lithium and a psychedelic included mention of emergency
medical treatment either in the form of an ambulance being called or ending up in
a hospital.
Experience reports involving an additional class of more rarely used psychedelics,
the 5-HT2A agonist drugs 2C-B, 2C-E, and 2C-I, were not included in the main analysis due to
the low number of reports (2 Erowid reports for 2C-I with concurrent lithium, 1 Erowid
report for 2C-C with concurrent lithium). However, it is noteworthy that both reports
involving 2C-I use and concurrent lithium involved seizures, and the report of the
2C-C plus lithium report was described as intensified.
Lamotrigine reports
There were a total of 34 analyzed reports of lamotrigine combined with a psychedelic
across the 3 sites ([Fig. 2 ]). Erowid had 6 reports (3 with LSD, 2 with psilocybin mushrooms, and 1 with smoked
DMT). The Shroomery had a single report (psilocybin mushrooms). Reddit had 27 qualifying
lamotrigine (or Lamictal) reports (19 [55.9%] with LSD, 7 [20.6%] with psilocybin
mushrooms, and 1 [2.9%] with DMT).
Fig. 2 Effects of taking a classic psychedelic in combination with lamotrigine (n=34). The
figure shows the percent distribution of the described psychedelic experiences from
websites that archive personal reports of psychedelic use. Categories are mutually
exclusive.
In the majority of lamotrigine reports, authors did not clearly express a view that
lamotrigine impacted the experience of the psychedelic one way or another. In 22 of
34 (64.7%) lamotrigine reports, the drug was not reported to have impacted the psychedelic
experience. In 6 of 34 (17.6%) lamotrigine reports, the psychedelic effect was decreased,
and in 3 of 34 (8.8%) reports, there was no psychedelic effect at all. No reports
were described as bad trips. The remaining 3 of 34 (8.8%) reports were described as
intensified without an overall negative valence.
Removing the 12 lamotrigine reports that included another psychoactive drug apart
from a psychedelic did not substantially change results—in 73.1% of reports, lamotrigine
was not described as affecting the psychedelic experience.
Lithium plus lamotrigine reports
Excluded from the above analysis were 4 reports that included both lithium and lamotrigine
with a psychedelic. One of 4 (25%) of these reports involved a seizure (though this
person also took the MAOI Syrian Rue), and the remaining 3 were described as intensified.
Discussion
There is a paucity of data about the concurrent use of psychedelic substances with
commonly prescribed psychiatric medications, which is concerning given increasing
public attention to psilocybin-containing mushrooms and the proliferation of enthusiastic
and uncritical media reports extolling the benefits of psychedelics such as psilocybin
for the treatment of depression and other psychiatric conditions. It is increasingly
likely that patients taking conventional psychiatric medications may attempt to treat
themselves with psychedelics.
In this study, we collected psychedelic experience reports from 3 large online sources
where individuals share such reports (Erowid.org, Shroomery.org, and relevant subreddits
from Reddit.com). This study focused on first- or second-person accounts of a psychedelic
used in combinations with the commonly prescribed mood stabilizers, lithium or lamotrigine.
Seizures were frequently associated with lithium
The most notable finding of this study is that 47% of reports of the use of a classic
psychedelic by individuals using lithium involved seizures. This was more frequently
reported with LSD but also occurred with psilocybin. As mentioned above, it is also
notable that 2 of 3 reports involving a 2C drug and lithium involved seizures (though
these were not included in the main analysis).
Affectively negative experiences (“bad trips”) were more common with lithium than
lamotrigine
In addition to reports involving seizures, lithium reports were more likely than lamotrigine
reports to be categorized as bad trips (18% versus 0%, respectively).
If seizure reports are excluded (because the categories were mutually exclusive),
then 11 of 33 (33%) non-seizure lithium reports were classified as bad trips.
Below are illustrative examples of verbatim experience reports of lithium and LSD
that were classified as non-seizure bad trips:
“Pro Tip: DON’T FUCK WITH THIS. Speaking from experience, Lithium can cause HIGHLY
UNPREDICTABLE reactions to dosing. Sometimes 3 150 ug hits do nothing or, in my case,
2 hits had me wandering around [ ... ] all night with no shoes on in full ego death,
mumbling to myself like a homeless guy, wandering into traffic, etc. I was fine, but
it was SUPER STUPID in hindsight. As such, I no longer take lithium.”[
1
]
“I took lsd while on 900 mg of lithium and experienced the worst, most horrific trip
of my life and haven’t touched lsd since. I had only taken 1 tab but the effects were
akin to having doses 5+tabs. I completely lost all touch with reality, everything
I saw was drenched in blood, and I felt my throat closing up and felt like I was on
fire-like my skin was burning. I somehow still managed to take a Seroquel despite
having lost all touch with reality which brought me out of it after an hour or so
I’m guessing (completely lost touch with time) and once I stopped hallucinating I
was unable to speak for several hours.”[
2
]
Caveats and clinical implications
The online reports used here are “low quality evidence” [23 ]
[24 ] due to lack of standardization, selection bias, and lack of clinical verification.
Furthermore, it is possible that the same individual posted multiple times on different
websites or the same websites with different usernames. In addition, the lithium reports
largely did not include information about lithium dose, so we are unable to speculate
on dose effects. Despite these caveats, the risk of potentially lethal reactions and
the absence of compelling non-causal explanations suggests that the most conservative
approach would be to assume a causal relationship—that taking a classic psychedelic
(e. g., a non-microdose of LSD or psilocybin) in combination with the therapeutic
use of lithium can cause seizures as well as increase the likelihood of otherwise
affectively negative experiences.
Thus, we advise individuals taking lithium to avoid taking classic psychedelic drugs.
Reports of psychedelic microdoses were not included, thus we are unable to comment
on this. It is possible that seizure risk could be mitigated by first tapering and
discontinuing lithium, but there is not enough information to make a recommendation.
The benignity of experience reports with lamotrigine does not mean that it is necessarily
safe to administer psychedelics to those prescribed it, but the relative lack of signal
for increased risk in the analyzed reports could aid future decision-making for clinical
trials. For example, a trial of psychedelic treatment for bipolar disorder involving
the continuation of mood stabilizers might avoid lithium in favor of lamotrigine due
to a lower probability of risk.
Mechanistic conjectures
There are several possible explanations for seizures in individuals who take psychedelics
while using lithium. One possibility is that those who are prescribed lithium may
have unique propensities for seizures independent of any risks associated with lithium
itself. The current data are limited in that we do not have any medical history information,
including seizure risk. People with unipolar depression do have a higher risk of seizure
disorder than the general population [25 ]
[26 ]
[27 ], though it is less clear if this is true for bipolar disorder.
A second possible mechanism is that co-administration of lithium and psychedelics
could increase systemic concentrations of 1 or both drugs leading to seizures. Though
lithium has been found safe to administer to patients with epileptic disorders, elevated
lithium levels confer an increased risk for seizures [28 ]. Classic psychedelics are known to increase cortical excitability [29 ] and can also, in rare cases, precipitate seizures [30 ]. However, a metabolic interaction affecting systemic concentrations of either drug
is unlikely due to a relative lack of overlap in their metabolic pathways. LSD and
psilocybin undergo hepatic metabolism to more water-soluble forms before excretion
through urine and other body fluids [31 ]
[32 ]. Lithium, in contrast, is principally renally excreted without undergoing any hepatic
alteration.
A third explanation involves changes in local concentrations of lithium and/or psychedelics in the brain. Sartorius et al. also
report a case of serotonin syndrome that developed within hours of ECT in a patient
who had been treated with lithium, though this did not result in seizures [33 ]. This raises the question of whether some of the seizures described in these reports
occurred in the context of serotonin syndrome. A review of the reports that included
seizures found that a substantial portion of cases presented with other signs that
may be consistent with serotonin syndrome, including diaphoresis, tachycardia, vomiting,
mydriasis, agitation, confusion, and loss of coordination. However, these additional
symptoms are more difficult to interpret as they may overlap with the expected effects
of psychedelics.
A final and more likely category of explanation would be that concomitant use of lithium
and psychedelics results in a synergistic effect on neurotransmission or second messenger
effects that increase the likelihood of seizures. The psychoactive effects of psychedelics
are mediated primarily by 5-HT2A agonism, and 5-HT2A agonism by psychedelics is generally understood to increase cortical excitability
[29 ]
[34 ]. Psychedelics also have an indirect effect of reducing the tonic activity of the
locus coeruleus [35 ]
[36 ]
[37 ]
[38 ]. Locus coeruleus activation can be protective against seizures [39 ]
[40 ]
[41 ]
[42 ]
[43 ]
[44 ], suggesting that psychedelic reduction of tonic locus coeruleus activity may represent
a potential indirect mechanism by which psychedelic drug administration could reduce
the seizure threshold.
Conclusion
Almost half of online psychedelic experience reports involving lithium and a classic
psychedelic (a non-microdose of LSD or psilocybin) involved seizures (47%) and 18%
involved otherwise negative experiences. Furthermore, 39% of these reports involved
emergency medical treatment. In contrast, lamotrigine was not judged to have impacted
the experience of the psychedelic drug in the majority of lamotrigine plus psychedelic
experiences (64.7%). Removing all reports that mentioned concurrent use of other psychoactive
drugs (most commonly serotonin reuptake inhibitors) did not alter these general findings.
Although we acknowledge the substantial limitations of data based on anonymous online
psychedelic experience reports, we believe that at present, lithium should be considered
a contraindication to psychedelic use.
