This report summarizes the case of a 40-year-old male patient who presented with symptoms reminiscent of mania. These symptoms resolved or improved over the course of less than 24 hours. It is important to consider the wide differential diagnoses that exist for the symptoms experienced by this patient, including exacerbation of ADHD, acute manic episode, substance intoxication, delirium, supplement side effects, and various other medical conditions.

One potential cause of this patient’s symptoms is the exacerbation of ADHD. Of note, his lisdexamfetamine dose reportedly had been reduced and then self-discontinued prior to admission. His symptoms of increased energy and restlessness could be consistent with ADHD exacerbation. However, ADHD does not typically cause memory impairments, disorientation, or tangential thought processes [4], which were among our patient’s presenting symptoms. Furthermore, our patient reported reducing his dose or stopping his medication multiple times in the past without experiencing symptoms similar to the current presenting symptoms.

Another potential cause of this patient’s symptoms is bipolar mania, which is consistent with reported increased energy, restlessness, and decreased sleep for four days. However, it should also be noted that this patient had no prior history of manic symptoms and has never taken medication for bipolar disorder. He was never psychiatrically hospitalized, and symptoms resolved in a time frame that is faster than expected for a manic episode. Therefore, bipolar mania was lower on the differential diagnosis.

The case could be made that the patient’s symptoms are due to substances. The patient reports daily use of caffeinated beverages and regular cannabis use. Caffeine intoxication can induce symptoms reminiscent of mania, including insomnia, excitement, nervousness, restlessness, psychomotor agitation, and flight of ideas, all of which overlap with clinical features of manic episodes [5]. However, the patient reported consistent use of two caffeinated beverages daily for many years. He also reported that his cannabis use has been consistent for many years. The stability of the patient’s use of caffeine and cannabis makes it unlikely that these substances contributed to the patient’s presenting symptoms. Another substance to consider is amphetamines. The patient reported self-discontinuing lisdexamfetamine 1.5 weeks prior to presentation. However, the urine drug screen collected upon admission was positive for amphetamines. Nevertheless, there is no documented history of methamphetamine use in the chart; the patient denied using methamphetamines, and his history is corroborated by his partner. Additionally, it is important to mention that the patient was taking trazodone, which can result in false positives for amphetamines in the urine drug screen [6]. While methamphetamines cannot be definitively ruled out as a possible etiology, the above factors decrease the likelihood of methamphetamine use contributing to observed symptoms.

Lastly, delirium may account for the patient’s symptoms. The acute onset of symptoms, combined with fluctuating levels of consciousness, disorientation, and memory deficit, makes delirium the most likely explanation for the patient’s symptoms. A variety of etiological factors may contribute to the development of delirium, including infectious, metabolic, substance withdrawal, and acute intoxication. The patient did not have any laboratory abnormalities consistent with a major metabolic disturbance, infection, or an alternative medical cause that would explain his acute symptomatology. This patient stopped taking 40 mg lisdexamfetamine for a week and a half prior to admission due to abdominal pain, raising the possibility of withdrawal. However, withdrawal symptoms from lisdexamfetamine would be expected to include hypersomnolence and hyperphagia rather than increased energy, restlessness, and decreased sleep [4]. When considering intoxication as a cause of delirium, often the first things that come to mind are drugs and toxins. However, supplements should also be considered. This patient’s symptoms appeared shortly after he started taking a commercially available supplement. Once the supplement was discontinued, the symptoms resolved, and the patient was able to be discharged from the hospital after one day. This temporal relationship is suggestive of the supplement contributing to the patient’s presentation.

A WHO-Uppsala Monitoring Centre (UMC) causality assessment, a tool used to classify relationship likelihood in case reports, was completed. In this case, the patient’s symptoms developed within a reasonable amount of time following supplement ingestion and resolved following withdrawal of the supplement. However, alternative causes of the clinical presentation could not be definitively excluded. Given the above, restarting the supplement to evaluate for recurrence of symptoms was not appropriate, therefore supporting that the most appropriate causality category is “possible” [7].

Several popular supplements have been associated with delirium or other psychotropic adverse effects, including St. John's wort, ginseng, ephedra, and kava. St. John’s wort is used to improve mood, energy, concentration, and sense of well-being, but case reports have shown it can also cause fatigue, dizziness, headache, restlessness, irritability, insomnia, pressured speech, hypersexuality, and psychotic symptoms such as ideas of reference, auditory hallucinations, paranoid delusions, and loosening of association [8]. Case reports on ginseng, marketed to relieve fatigue and stress, describe use resulting in increased energy, decreased sleep, grandiosity, and agitation [8]. Another herbal supplement, Ephedra, has been marketed as a weight loss and exercise enhancement supplement. It acts as a stimulant in the central nervous system, producing a combination of dopaminergic and adrenergic effects resulting in improved mood, heightened awareness, decreased fatigue, and insomnia. At higher doses, it can cause restlessness and anxiety, and with prolonged use, it can be neurotoxic and lead to psychosis, severe depression, mania, agitation, hallucinations, sleep disturbances, and suicidal ideation [9].  Lastly, kava is marketed for its calming effects in patients with anxiety, but has also been shown to cause altered mental status and ataxia in some patients [10].

While these herbal supplements have been studied with respect to adverse effects, the same cannot be said about many other supplements, which may unknowingly cause adverse effects such as delirium. The supplement that this patient was consuming did not contain the above ingredients but did contain the following: vitamin B6 (pyridoxine HCl), L-tyrosine, L-theanine, oat (straw) extract, phosphatidylserine, cat’s claw (bark) extract, L-alpha glycerylphosphorylcholine (alpha-GPC), Bacopa (leaves) extract, toothed clubmoss (whole) extract (huperzine A), L-leucine, and pterostilbene.

Cat’s claw (bark) extract, a plant from the Amazon rainforest, is marketed for its anti-inflammatory and analgesic effects for the treatment of muscle and joint pain, fever, fatigue, and other chronic inflammatory conditions. However, there are no conclusive scientific evidence-based studies that support the use of this ingredient for health purposes [10]. The known side effects include nausea, diarrhea, gastrointestinal upset, headache, dizziness, and vomiting [11].

Bacopa (leaves) extract, a creeping perennial plant described as a “calming cognitive enhancer," is marketed for memory improvement, epilepsy, insomnia, and as an anxiolytic [12]. The most common side effects of Bacopa (leaves) extract are gastrointestinal side effects, including nausea, increased stool frequency, and abdominal cramps, which are secondary to an upregulation of acetylcholine activity. The cholinergic properties of Bacopa may increase the likelihood of side effects from other cholinergic drugs due to an additive effect or decrease the effectiveness of anticholinergic medications [13]. Bacopa has not been shown to be effective for any disease or medical symptom in controlled, prospective trials in humans and is not approved in the United States as therapy for any medical condition [11].

Toothed clubmoss (whole) extract (standardized to 1% huperzine A, 400 mcg) contains small amounts of huperzine A, which is marketed for the treatment of neurodegenerative diseases, including schizophrenia, cognitive dysfunction, and dementia. This ingredient is a competitive reversible inhibitor of acetylcholinesterase and may produce cholinergic side effects, including vomiting, dizziness, headache, restlessness, excitement, fatigue, and diarrhea [14].

Pterostilbene is marketed as an agent with anti-inflammatory, antioxidant, and anti-tumor properties. Unfortunately, much is not known about this ingredient, as research articles have noted that while preliminary clinical studies are encouraging, more rigorous trials are imperative to understand the safety and therapeutic benefits. It is reported that this ingredient does not cause severe side effects, but it is unknown what side effects are being studied and measured. Additionally, long-term safety data are lacking, and some studies have concerns about potential liver toxicity [15].

Oat (straw) extract is marketed for psychotropic indications, including improved cognitive function in terms of working memory and dual task performance. One study reported that side effects were “minor” but did not list what side effects were experienced by participants [16].

Lastly, the supplement taken by the patient also includes L-tyrosine, L-leucine, L-theanine, vitamin B6, L-alpha GPC, and phosphatidylserine. There is limited data about the safety profile of some of these supplement ingredients and a lack of substantial evidence of beneficial use in the literature, with the exception of vitamin B6 for deficiency states.

While individually the above supplements may cause minor side effects, it is important to consider the additive effects of these ingredients and also potential interactions with prescribed medications. In addition to the side effects of herbal supplements, the pharmacokinetic and pharmacodynamic properties of drug-herb interactions must be kept in mind. Pharmacokinetic interactions between an herbal supplement and a drug can occur when the herbal supplement shares the same mechanisms of absorption, distribution, metabolism, and excretion as the drug. As a result, the drug’s concentration at the site of action may be altered. Additionally, drug-herb interactions may result in pharmacodynamic interactions, which can occur when an herbal supplement directly affects the mechanism of action of the drug, unrelated to the drug’s concentration [17]. For example, cat’s claw can cause herb-drug interactions, as it is an inhibitor of the CYP3A4 enzyme, therefore increasing the concentration of drugs that are metabolized by this enzyme [6]. Additionally, Bacopa (leaves) extract has an inhibitory effect on CYP3A4. This is relevant to the current patient, as he was taking trazodone, which is a substrate for CYP3A4. Physicians should be aware of this ingredient as it has a major impact on many CYP isoforms, including CYP2C9, CYP2C19, CYP1A2, CYP2D6, and CYP3A4 [18]. It is crucial to consult pharmacists or herbal specialists to assess the safety of certain herbal supplements and the potential drug-herb interactions that may be at play.

There are several limitations of this study. First, as with all descriptive studies, it is not possible to prove a cause-and-effect relationship. Second, this is a case report on a single patient and is therefore not a representative population. Consequently, it is not possible to generalize the findings. Third, much of the relevant data was obtained retrospectively using the patient’s electronic medical record, making the study findings reliant upon the accuracy and completeness of the documentation. Finally, it is not possible to test the supplement for potential contaminants or rule out all possible cofounders that may have contributed to the patient’s presentation.