L-Carnitine in the Treatment of Psychiatric and Neurological Manifestations: A Systematic Review

Objective: L-carnitine (LC), a vital nutritional supplement, plays a crucial role in myocardial health and exhibits significant cardioprotective effects. LC, being the principal constituent of clinical-grade supplements, finds extensive application in the recovery and treatment of diverse cardiovascular and cerebrovascular disorders. However, controversies persist regarding the utilization of LC in nervous system diseases, with varying effects observed across numerous mental and neurological disorders. This article primarily aims to gather and analyze database information to comprehensively summarize the therapeutic potential of LC in patients suffering from nervous system diseases while providing valuable references for further research. Methods: A comprehensive search was conducted in PubMed, Web Of Science, Embase, Ovid Medline, Cochrane Library and Clinicaltrials.gov databases. The literature pertaining to the impact of LC supplementation on neurological or psychiatric disorders in patients was reviewed up until November 2023. No language or temporal restrictions were imposed on the search. Results: A total of 1479 articles were retrieved, and after the removal of duplicates through both automated and manual exclusion processes, 962 articles remained. Subsequently, a meticulous re-screening led to the identification of 60 relevant articles. Among these, there were 12 publications focusing on hepatic encephalopathy (HE), while neurodegenerative diseases (NDs) and peripheral nervous system diseases (PNSDs) were represented by 9 and 6 articles, respectively. Additionally, stroke was addressed in five publications, whereas Raynaud’s syndrome (RS) and cognitive disorder (CD) each had three dedicated studies. Furthermore, migraine, depression, and amyotrophic lateral sclerosis (ALS) each accounted for two publications. Lastly, one article was found for other symptoms under investigation. Conclusion: In summary, LC has demonstrated favorable therapeutic effects in the management of HE, Alzheimer’s disease (AD), carpal tunnel syndrome (CTS), CD, migraine, neurofibromatosis (NF), PNSDs, RS, and stroke. However, its efficacy appears to be relatively limited in conditions such as ALS, ataxia, attention deficit hyperactivity disorder (ADHD), depression, chronic fatigue syndrome (CFS), Down syndrome (DS), and sciatica.


Background
L-carnitine (LC), also referred to as Acetyl-L-Carnitine, Vitamin BT, and Carnitine, with a chemical formula of C 7 H 15 NO 3 , is classified as an amino acid that facilitates the conversion of fat into energy.LC has been extensively researched and utilized since its discovery over a century ago [1].LC is ubiquitously present in the natural environment.Red meat serves as the primary reservoir of LC, while it can also be endogenously synthesized by the human body to fulfill physiological requirements [2].In humans, the presence of LC is observed in a wide range of mammalian tissues, encompassing the brain as well [3].
Nutrients 2024, 16, 1232 2 of 37 Although endogenously synthesized LC is sufficient to maintain serum carnitine levels in healthy individuals, dietary carnitine may be necessary during specific life stages and in conditions such as aging and diabetes.Therefore, LC is considered a "conditionally essential" nutrient [4].Additionally, Levocarnitine is recognized as a pharmaceutical agent in clinical settings.Substantial evidence supports the neuroprotective effects of LC, making it extensively employed for the prevention and treatment of neurological and psychiatric disorders [5].However, although a large number of preclinical studies have shown the benefits of LC supplementation for central nervous system diseases, the results of clinical studies in specific areas have been inconsistent.Therefore, our goal was to systematically review the published clinical studies of LC in the treatment of various neurological and psychiatric disorders.A systematic review of the diseases with a sufficient number of clinical studies was conducted to give more convincing evidence and conclusions for the clinical application of this amino acid-based nutritional medicine and supplement and dietary supplement, and also to point out the limitations and deficiencies of the use of LC in the treatment of neurological and psychiatric disorders.

Methods
The aim was to identify studies reporting LC as a treatment to improve all common psychiatric and neurological disorders.We did not compare LC treatment with other treatments, and we considered all clinical study designs.Our main objective was to consider the improvement of all outcomes reported in the review of clinical studies and to determine the incidence of adverse effects (AEs) of LC treatment.

Level-of-Evidence Ratings
Although we considered conducting a meta-analysis on each psychiatric and neurological disorder, the lack of standard outcomes and the limitations in study design prevented a meta-analysis of any identified disorder.As an alternative, we provide a grade of recommendation (GOR) for each psychiatric and neurological disorder based on the level of evidence (LOE) for each study.Using a well-established scale [6,7], each study was individually assessed to determine the LOE, ranging from levels 1 to 5 (see Table 2).After assessing all identified studies for each disorder, a GOR ranging from A (solid evidence) to D (limited, inconsistent, or inconclusive evidence) was assigned (see Table 3) to each disorder.Since a treatment could receive a GOR of D for several reasons, we

Level-of-Evidence Ratings
Although we considered conducting a meta-analysis on each psychiatric and neurological disorder, the lack of standard outcomes and the limitations in study design prevented a meta-analysis of any identified disorder.As an alternative, we provide a grade of recommendation (GOR) for each psychiatric and neurological disorder based on the level of evidence (LOE) for each study.Using a well-established scale [6,7], each study was individually assessed to determine the LOE, ranging from levels 1 to 5 (see Table 2).After assessing all identified studies for each disorder, a GOR ranging from A (solid evidence) to D (limited, inconsistent, or inconclusive evidence) was assigned (see Table 3) to each disorder.Since a treatment could receive a GOR of D for several reasons, we specified if the treatment received this rating because the evidence was a single case report or series (SC), demonstrated a neutral effect (NE), or was found to be possibly detrimental (DE).Prospective high-quality RCT (medium-sized with N between 50 and 100 or large-sized with N over 100, and/or higher validity trials based on adequate follow-up, intent-to-treat analysis, baseline similarity, equal treatment and dropout rates) 2a SR of cohort (prospective, nonrandomized) studies with homogeneity 2b Individual cohort (prospective, nonrandomized) study or low-quality RCT (small-sized with N less than 50 and/or lower validity trials based on adequate follow-up, intent-to-treat analysis, baseline similarity, equal treatment and dropout rates) 3a SR of case-control (retrospective) studies with homogeneity 3b Individual case-control (retrospective) studies 4 Open-label trials, case series or reports 5 Expert opinion without critical appraisal or based on physiology or bench research We summarized and synthesized information on various psychiatric and neurological disorders from several aspects.The level of evidence (LOE) for each study was identified as per Table 2 and then the grade of recommendation (GOR) for each psychiatric and neurological disorder was summarized according to Table 3.Since the GOR is based on the quality of clinical studies, not necessarily outcomes, we outlined whether LC should be recommended for specific psychiatric and neurological disorders based on the strength of evidence and the findings of the studies.A study was assigned a score of 1 for positive outcomes for all primary and secondary measures and 0 for negative outcomes for all measures.Studies were given a score of 0.5 if they were positive in a few but not all outcomes, primary or secondary, or only in subgroup analyses.On the basis of points, the positive percentage of total studies was calculated.If the overall percentage was less than 50%, independent of GOR, then based on the present study, the recommendation to use LC to treat that particular disease was "no".If 100% of the studies were positive and the GOR was A or B, then the recommendation to use LC for that particular disease was "YES".If the positive percentage was between 50% and 100% or the GOR was C or D, the treatment was recommended as "mixed".Clinical treatment was recommended as "none".The number of studies was based on actual trials rather than the number of articles to avoid duplication.For each psychiatric and neurological disorder, Table 4 provides details of each study and the result-based LOE score and GOR rating.Additionally, a summary of all studies for each disease is discussed.Following a discussion of the potential effectiveness of LC, a further section discusses the reported AEs based on reports from controlled clinical trials.The final discussion synthesizes this information and summarizes the potential clinical applications of LC in psychiatric and neurological disorders as well as their mechanisms of action.

Evidence of Effectiveness of LC in the Treatment of Psychiatric and Neurological Disorders
A total of 60 articles met the inclusion criteria.These articles included a number of psychiatric and neurological diseases, including HE, ALS, ataxia, ADHD, CTS, CD, DD, CFS, HE, migraine, multiple sclerosis (MS), NDs, NF, PNSDs, RS, sciatica, and stroke.

Neurodegenerative Diseases
LC has been used in several clinical trials for the remission and treatment of NDs.These include Alzheimer's disease (AD) and Down syndrome (DS).Alzheimer's disease (AD), the most common type of dementia in the elderly, is a serious neurodegenerative disease which is associated with progressive cognitive deterioration, such as memory loss and logical reasoning ability decline [8].Down syndrome (DS), caused by trisomy 21 (HSA21), is the most common genomic disorder of intellectual disability.The syndrome takes its name from Down, who described its clinical prescription in 1866 [9,10].Both are shown in Table 5.

Alzheimer's Disease
In 1991, a 24-week randomized, double-blind, controlled, parallel small clinical trial (N = 71; LOE 2b), LC was used to treat elderly patients aged over 65 years with AD, and the treatment group performed significantly better than the control group on psychological tests [11].In a larger cohort of people with AD at an average age of about 75 years, 2 g of LC per day appeared to have benefits on all measures in the elderly [12].
Additionally, a 1994 study also showed that 3 g of LC per day in patients with or suspected of AD around the age of 70 showed significant improvements in some indicators [13].Since then, there has been no significant association between LC and improvements in AD, except in a 1996 clinical trial [14].The remaining four studies from 1998 to 2018 showed that LC had a significant effect on the improvement of disease indicators in patients with AD [15][16][17][18].
In summary, a total of two level 1b and three level 2b LOEs indicated that LC treatment was helpful for the recovery of some indications in patients with AD.However, based on most trials, only part of the indicators changed, and most of the trial period was too long.Therefore, the consistency and effectiveness of the intervention for all patients cannot be guaranteed, so the statistical results still need to be considered with caution.Of course, based on the present results, we can still consider LC as an option to alleviate AD.

Down Syndrome
An article published in 2004 described a study (N = 40; LOE 2b) which involved 40 men in their 20s with DS receiving a 6-month LC supplement of 10 mg/kg for the first month, 20 mg/kg for the second month, and 30 mg/kg for the third to sixth months.The final results showed that LC supplementation did not significantly improve the improvement of the relevant indicators in DS patients [19].
In this study, since the number of included studies was less than 10, the Harbord test was used to test for publication bias.

Amyotrophic Lateral Sclerosis
ALS is also known as motor neuron disease (MND).It is a rare and specific ND that causes progressive weakness and selective degeneration of motor neurons and death from respiratory failure within 3 to 4 years [20], and the current information about LC in clinical use for the palliation of amyotrophic lateral sclerosis is relatively scarce.This review summarizes a total of two articles, as shown in Table 6 below.A small clinical trial (N = 82 LOE 1b) in 2013 showed that LC supplementation improved disease indicators and nutritional status in ALS patients with daily supplementation of 1000 mg LC in 40 patients aged 40 to 75 years, while the control group was still given the same amount of placebo [21].However, larger phase 3 clinical trials are still needed to verify the effect of LC.In 2023, a clinical trial (N = 90 LOE 3a) with daily supplementation of 3 g LC in the experimental group and equivalent placebo in the control group was conducted.However, LC had no significant effect on ALSFRS-R and FVC in ALS patients.In summary, only one grade 2b study showed that LC provided certain help in the treatment of ALS patients, and the number of studies was relatively limited, so the role of LC in ALS patients remains to be discussed [22].

Ataxia
Ataxia, defined as impaired coordination of voluntary muscle movements, is a neurological disorder characterized by varying degrees of dysfunction in the cerebellum or connected pathways, resulting in abnormalities in balance and coordination [23,24].Clinical trial reports on the effects of LC supplementation on ataxia symptoms are presented in Table 7 below.In 2000, a grade 3a, double-blind, crossover, self-controlled trial (N = 24 LOE 3b) showed improvement in some clinical measures with a daily dose of 2000 mg of LC in patients with cerebellar ataxia, but there was only one report that was not of high enough grade to show the effect of LC supplementation in patients with ataxia.The results were due to chance.More experiments are urgently needed to clarify this [23].

Attention Deficit Hyperactivity Disorder
Attention deficit hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder characterized by inappropriate development and impaired inattention, motor hyperactivity, and impulsivity, which often persist into adult difficulties [25].Clinical trials on the effects of LC supplementation on ataxia symptoms are reported in Table 8 below.In 2007, a multi-site parallel double-blind randomized trial (N = 112 LOE2b) was conducted in the United States of America for the intervention of LC in children with ADHD around the age of 8 years.The daily dose of LC was determined according to the weight of the children.The intervention lasted for 16 weeks.The results showed that there was no significant difference between the experimental group and the control group [26].In conclusion, because of the few studies on the relationship between LC supplementation and ADHD and the inconclusive results, we are still not sure whether LC supplementation is necessarily beneficial for children with ADHD at present.

Carpal Tunnel Syndrome
Carpal tunnel syndrome (CTS) is the most common and widely studied nerve entrapment syndrome, and it is caused by compression of the median nerve in the wrist as it passes through a fibrous canal with limited space.This canal, known as the carpal tunnel, contains the carpal bones, the transverse carpal ligament, the median nerve, and the flexor digitorum tendon.Edema, tendinopathy, hormonal changes, and manual activities can lead to increased nerve compression, sometimes causing pain, as in the case of tendinopathy.In more severe cases, muscle weakness innervated by the median nerve may occur, resulting in hand weakness [27].There is only one current study on the association between LC supplementation and CTS, as shown in Table 9 below.In a multicenter, self-controlled trial conducted in 2017 at the Department of Neurology and Psychiatry, Sapienza University, Italy (N = 82 LOE3A), patients with CTS had a mean age of 47.1 years.LC was administered intramuscularly at a dose of 1000 mg daily for the first 10 days and orally at a dose of 1000 mg daily for the next 110 days.The results showed that LC supplementation significantly improved neurophysiological parameters in patients with CTS [28].However, this experiment was self-controlled, and the interference of confounding factors cannot be excluded.The level of evidence is low, and the number of people involved is not enough, being less than 100.Therefore, more people and larger trials are needed to determine the effect of LC in patients with CTS.At present, there is only one study in this area, and the amount of experimental evidence is insufficient.

Cognitive Dysfunction
Cognitive dysfunction (CD) involves deficits in attention, executive function, working memory, processing speed, learning, episodic memory, and/or visuospatial memory domains, and is common in various neurological and psychiatric disorders [29].Studies on the effects of LC supplementation in patients with cognitive impairment are shown in Table 10 below.In 2003, a large double-blind controlled clinical trial was conducted at the Department of Psychology, University of Wales-Swansea et al., UK, with an LOE of 1b.In 100 women with a mean age of 21.8 years, a daily supplement of 500 mg of LC improved cognitive function, but whether it improved decision-making was not known [30].In 2008, at the University of Catania, Rome, Italy, Michele Malaguarnera et al. conducted a single-center, randomized, double-blind, controlled trial with an LOE of 2b and 48 controls receiving 4 g of LC or placebo daily.The results showed that LC supplementation could reduce the fatigue state of patients with CD.Compared with the control group, the cognitive ability and some physical functions of the patients in the experimental group were significantly improved [31].Finally, more recently in 2022, Giulia Malaguarnera et al. also conducted a randomized observational double-blind placebo-controlled trial (N = 92 LOE2a) which showed that LC reduced the incidence and severity of degenerative diseases in elderly patients.It also successfully improved the patients' memory and cognitive function [32].In summary, we have strong evidence that LC improves cognitive and memory functions in patients with CD.Therefore, it can be concluded that LC supplementation is beneficial for patients with CD.

Depressive Disorder
DD is a heterogeneous neurological disorder formed by the interaction of multiple factors [33].It is also a long-term, recurrent disease with high rates of disability and mortality.Its occurrence has a neurobiological basis and is related to brain function and structure abnormalities [34].This review summarizes two studies on the effects of LC supplementation in patients with depression, as shown in Table 11 below.In 1994, a single-blind cohort study (N = 481 LOE3a) showed that a daily supplement of 1500 mg of acetylcholine in DD patients significantly improved their memory, reduced their stress, and significantly improved their negative mood [35].Additionally, a grade 2b study in 2012 with 80 participants also showed that daily administration of 1 g LC for 7 weeks could achieve similar effects as the antidepressant fluoxetine, with statistically significant improvements in various measures of depression and anxiety [36].In summary, although there are few studies on the efficacy of LC supplementation in patients with DD, they can basically confirm the effect of LC firmly, so we think that LC as a drug to relieve symptoms of patients with DD is theoretically feasible.

Fatigue Syndrome, Chronic (CFS)
Chronic fatigue syndrome is a clinically defined disease [37][38][39][40].It is characterized by severe disabling fatigue and a spectrum of symptoms highlighted by self-reported attention and short-term memory impairments, sleep disturbances, and musculoskeletal pain.A diagnosis of chronic fatigue syndrome can only be made after other medical and psychiatric causes of chronic fatigue disorders have been ruled out [41].There is only one experimental study of LC supplementation in patients with chronic fatigue syndrome, as shown in Table 12 below.[42].However, since there was only one relevant study and the number of subjects was insufficient, more and larger trials are still needed to prove the relief effect of LC on CFS.

Hepatic Encephalopathy (HE)
Hepatic encephalopathy (HE) is broadly defined as brain dysfunction caused by hepatic insufficiency and/or portosystemic shunt, which manifests as a wide range of neurological or psychiatric abnormalities ranging from subclinical changes to coma [43].However, etiologic factors that lead to chronic liver diseases (CLDs), such as alcohol-related liver disease, nonalcoholic fatty liver disease, viral hepatitis, and primary biliary cholangitis, can all affect the brain through mechanisms independent of liver failure/dysfunction triggering [44][45][46][47].In this review, we examine 11 studies on the relief of symptoms of HE by LC supplementation, all of which are shown in Table 13 below.There are many studies on the relationship between LC supplementation and HE.In 2002 at the Department of Clinical and Experimental Medicine, II University of Naples, Naples, Italy.A 4-week, parallel, double-blind, randomized controlled trial (N = 27 LOE2b) was conducted on elderly patients with HE receiving 6 g of LC daily versus equivalent placebo for 4 weeks.The results showed that 14 of the 16 patients treated with LC had normal ammonia levels.In terms of psychological tests, both neuropsychological tests and cognitive ranking tests were significantly better in the LC supplement group than in the non-intervention group [48].A 2003 randomized controlled trial (N = 78 LOE2a) analyzed daily 4 g LC supplementation for 60 days in patients with midlife HE around 50 years of age.The results are still optimistic.For patients in the experimental group, the effects of LC supplementation seem to be quite ideal, as not only were the serum ammonia concentrations of patients significantly reduced, but the number connection test A (NCT-A) and the West Haven criteria were also significantly improved [49].Similarly, in 2005 and 2006, three clinical trials of LC supplementation in patients with HE were conducted, with levels of evidence of 1b, 2b, and 2b, respectively, showing that LC significantly improved the patient's condition [50][51][52].
Additionally, the results of four clinical trials or prospective cohort studies in 2008 and 2011 showed that LC supplementation was beneficial in patients with HE, including those with advanced cirrhosis complicated by HE, both in terms of blood ammonia levels, fatigue, depression, and neurological tests such as cognitive and mobility.There were statistically significant differences between patients with HE who were supplemented with LC and those who were not supplemented with LC [53][54][55][56].
Finally, there were two evidence level 2b and 1b experimental studies from 2015 and 2021, respectively.The former was a prospective cohort study, and the latter was a multicenter, double-blind, phase 3 clinical trial.However, the results of these two experiments are not particularly clear, indicating that LC supplementation has no significant effect on the improvement of liver function and quality of life in patients with HE, but it can appropriately improve the cognitive ability and some neurological function indicators of patients with HE [57,58].It can be seen from the above that although LC supplementation has different effects on the improvement of clinical indicators in patients with HE, most of the experimental results are very good.Therefore, it is clear that LC supplementation is beneficial to patients with HE, significantly improving their quality of life, physical function, and psychological status.

Migraine Disorder
Migraine disorder (MD) is a chronic neurological disorder characterized by moderate or severe headache attacks and reversible neurologic and systemic symptoms.The most characteristic symptoms associated with MD include photophobia, phonophobia, skin hyperalgesia, and gastrointestinal symptoms such as nausea and vomiting [59].Additionally, patients may have a variety of other neurological symptoms, such as vertigo, dizziness, tinnitus, and cognitive impairment, and MD often begins with premonitory symptoms hours or days before pain onset [60].The most common premonition symptoms include fatigue, inattention, and neck stiffness.However, other psychological symptoms (anxiety, depression, irritability), arousal (drowsiness), neurologic symptoms (photophobia), and cranial parasympathetic symptoms (lacrimation), as well as general symptoms (e.g., yawning, increased urination, nausea, diarrhea, and food cravings), can precede the onset of pain [61,62].
This review summarizes two studies on the effect of L-carnitine supplementation on MD symptoms, as shown in Table 14.In a 2012 double-blind randomized controlled trial (N = 70 LOE2a), 500 mg of LC was administered daily to migraine patients for 12 weeks.The results are clearly positive and show that LC supplementation is effective in alleviating symptoms in patients with MD [63], but the number of participants in this study is limited, and larger clinical trials are needed to confirm the relevant effects.However, in 2015, a triple-blind crossover controlled trial (N = 141 LOE1b) with the same intervention showed no significant improvement in MD symptoms [64].In summary, there are two studies with similar research methods, but the results are not quite uniform.Therefore, we cannot conclude that LC supplementation is beneficial for symptom relief in patients with MD.

Multiple Sclerosis
Multiple sclerosis (MS) is a chronic inflammatory disease resulting in demyelination and neurodegeneration of the central nervous system.Although its etiology is still unclear, it has been established that environmental factors and susceptibility genes are involved in the pathogenesis of the disease.Results from immunological, genetic, and histopathological studies of patients with MS support the concept that autoimmunity plays a major role in disease pathogenesis [65].However, it is also widely accepted that MS is not only an inflammatory but also a neurodegenerative disease [66].The course of multiple sclerosis is highly variable.However, in most patients, MS is characterized by recurrent episodes of clinical symptoms followed by complete or partial recovery, the classic relapsing-remitting form of MS (RRMS).After 10 to 15 years of disease, this pattern progresses in up to 50% of untreated patients, during which time clinical symptoms slowly lead to progressive deterioration over a period of many years, a stage of disease defined as secondary progressive MS (SPMS).However, in approximately 15% of MS patients, disease progression continues from onset (primary progressive multiple sclerosis (PPMS)) [67].Table 15 shows the studies in this review that investigated the remission effect of LC supplementation in patients with MS.In 2004, at the Department of Neurological Sciences, University of Rome 'La Sapienza', a single-center, pilot, randomized, double-blind, crossover controlled trial conducted in Italy (N = 36 LOE2a) showed a benefit of LC and amantadine supplementation in patients with MS on measures of fatigue symptoms, but no significant effect on other secondary outcomes [68].Overall, there was only one article and its sample size was very limited, so whether LC supplementation is beneficial in patients with MS, and how beneficial it is, needs to be further studied.

Neurofibromatosis
Neurofibromatosis (NF) is a benign and heterogeneous peripheral nerve sheath tumor which originates from the connective tissue of the peripheral nerve sheath, especially the endoneurium.It is an autosomal dominant genetic disease [69].In this review, we analyze one related study on LC, as shown in Table 16 below.In 2021, a single-center open-label clinical trial (N = 70 LOE2a) of LC supplementation (1000 mg/d) for 12 weeks in pediatric patients with NF showed that LC supplementation was safe and feasible, but it still needs to be confirmed in phase III clinical trials [70].In conclusion, clinical trials of sufficient size and quantity are needed to determine whether LC supplementation in patients with NF actually has a benefit.

Peripheral Nervous System Diseases
Peripheral nervous system diseases (PNSDs) are common neurological disorders that are commonly seen in hospitals, outpatient clinics, and general practitioner offices.Peripheral neuropathy includes a wide range of clinical syndromes that can be divided according to anatomical region and distribution of the peripheral nervous system.The first thing that can be distinguished is that in the case of mononeuropathy, a peripheral nerve is affected; in the cases of multifocal neuropathy and polyneuropathy, multiple peripheral nerves are affected.These three main categories can be subdivided into smaller groups based on etiology (compression or noncompression), course of disease (chronic or acute), or type of neuropathy (axonal or demyelinating neuropathy) [71].There are more studies on LC supplementation in patients with PNSDs, with a total of five studies, as shown in Table 17.In general, there were five studies on the effect of LC supplementation in patients with PNSDs, and the results were basically consistent.In 2002, a randomized, double-blind study (N = 333 LOE1b) showed that LC supplementation improved neurophysiological parameters and significantly reduced pain in patients with diabetic PNSDs [72].Subsequently, in 2004, a multicenter controlled clinical trial (N = 682 LOE1b) showed that LC treatment was superior to placebo in relieving pain, improving nerve fiber regeneration and vibration perception in patients with diabetic PNSD [73].In 2010, a single-center self-controlled trial (N = 30 LOE3b) showed that LC could improve neurological function and ventricular dispersion in diabetic patients [74].A 2015 clinical trial (N = 336 LOE2b) showed that LC supplementation ameliorated chemotherapy-induced peripheral neuropathy and cancerrelated fatigue symptoms in Chinese cancer patients [75].Recently, in 2016, a phase 2 trial (N = 332 LOE1a) showed that daily administration of 1500 mg LC or mecobalamin resulted in significant reductions in neuropathy symptom score and neuropathy disability score in diabetic patients.Therefore, it can be indirectly indicated that LC supplementation is beneficial for the alleviation of PNSD symptoms in diabetic patients [76].In summary, there are strong reasons to believe that LC supplementation is beneficial for symptom recovery and quality of life in patients with PNSDs.

Rett Syndrome
Rett syndrome (RS) is a severe progressive neurodevelopmental disorder with a broad spectrum of neurological and behavioral features.RS, with an incidence of 1:10,000-15,000, is the second most common cause of severe intellectual disability in women, and during its developmental regression, a substantial proportion of patients meet the diagnostic criteria for autism spectrum disorder (ASD) [77][78][79][80][81][82][83].There are three studies on the effect of LC supplementation in children with RS, as shown in Table 18.In 1999, a study by Drs Ellaway et al. at the Royal Alexandra Hospital for Children, Westmead, Australia (N = 62 LOE3a) showed that LC treatment significantly improved the well-being of patients with RS, but did not improve other indicators of RS [84].Subsequently, in 2001, Carolyn Ellaway et al. conducted an open-label randomized controlled trial (N = 83 LOE3a) in which 200 mg/kg LC was administered daily.The results showed that LC supplementation significantly improved sleep efficiency, physical movement, and verbal communication in patients with RS [85].In 2005, a controlled trial (N = 22 LOE3b) of LC (50 mg/kg daily for 6 months) in children with RS showed a significant increase in heart rate variability, suggesting that LC supplementation may reduce the risk of sudden death in children with RS [86].Taken together, all these studies suggest a beneficial effect of LC supplementation in patients with RS.

Sciatica
Sciatica is a pain radiating down the hip along the course of the sciatic nerve [87,88].Although sciatica has several causes, Mixter and Barr in 1934 extended previous observations and determined that the primary source was the compression of lumbar nerve roots by disc material through rupture of the surrounding annulus fibrosus [89].Neuroradiological studies confirm that 85% of cases of sciatica are associated with disc disorders [90,91].A study on the effect of LC supplementation in patients with sciatica is shown in Table 19.In 2008, a study in Ortopedia Pediatrica, Istituto Ortopedico Gaetano Pini, Milan, Italy, (N = 64 LOE1b) involved 1180 mg of daily supplementation in patients with sciatica.The results showed significant improvements in patients' neuroelectromyography, but no significant improvements in other indicators [92].Similarly, it seems that the presence of only one relevant study can not firmly explain the excellent effect of LC, and larger and higher-quality studies are still needed.

Stroke
Stroke is a clinical syndrome characterized by a sudden focal or global loss of brain function, presumed to be of vascular origin, that persists for more than 24 h or leads to death [93].Cerebral infarction accounts for 80% of strokes and may be caused by large vessel disease, small vessel disease, or cardiogenic embolism.Less common causes include coagulopathy, vasculitis, and endocarditis.Overall, 15% of strokes were due to primary intracranial hemorrhage and 5% were due to subarachnoid hemorrhage [94].In this review, we analyzed four studies on the effects of LC supplementation on stroke patients, as shown in Table 20.A 2013 study (N = 60 LOE2b) showed that patients were given 1000 mg or 2000 mg of LC daily for 60 days.The results showed that the scores of "attention focus" and "memory" of MMSE scale in the patients were significantly better than those in the control group, and the difference was statistically significant [95].Then, in 2017, a clinical study from Russia (N = 60 LOE2a) showed that in patients with stroke, 1000 mg/day supplementation had a certain effect on the relief of symptoms, such as neurological deficits and emotional deficits [96].Additionally, in 2020, there was a randomized controlled double-blind trial (N = 75 LOE2b) in which patients with stroke were supplemented with 1 g of LC.Blood samples were collected before intervention, and 24 h, 48 h, and 7 d after intervention to calculate the content of the biomarker S100B.LC, either alone or in combination with lipid emulsion, could reduce the level of serum biomarker S100B, thereby providing neuroprotection [97].Finally, in 2022, a single-center, double-blind, randomized placebocontrolled pilot clinical trial (N = 60 LOE3a) of 3000 mg of LC daily for 90 days in stroke patients was conducted.The results showed that the NIHSS score and MRS score of the treatment group were significantly higher than those of the placebo group [98].In general, all the above four articles basically showed that for stroke patients, either long-term or short-term supplementation of LC is very useful for the recovery of stroke patients, so it seems that we can recommend that stroke patients use an appropriate amount of LC to improve their quality of life and relieve some uncomfortable symptoms.

AEs Reported in Controlled Clinical Trials
The distribution of AEs of LC in each system is shown in Table 21.Additionally, the highest incidence of AEs occurred in a triple-blind, cross-controlled trial in which LC was used to alleviate migraine symptoms, with approximately 33% of subjects reporting mild or moderate AEs.The main AEs included abdominal pain, nausea, and other gastrointestinal reactions, vomiting, headache, and so on [64].Although most trials have shown some AEs, only a few patients have reported discontinuation of LC because of serious AEs, including one patient with multiple sclerosis who discontinued the trial because of the development of insomnia and nervousness on LC [68].One stroke patient was also withdrawn from the experiment because he could not tolerate severe GI reactions after LC supplementation [98].Additionally, in a trial of LC in the treatment of chronic fatigue syndrome, eight patients dropped out because they could not tolerate the excessive stimulation and insomnia after the intervention [42].In conclusion, in most of the trials using LC for the treatment of neurological and psychiatric disorders, both oral and intravenous LC were associated with low incidence of side effects and minimal impact, making LC an excellent drug with a high safety profile for the treatment of neurological disorders.

Potential Mechanisms of Action
LC has been shown to act on multiple pathways in various psychiatric and neurological disorders, such as Oxidative Stress (OS), Inflammatory Mediators (IMs), Mitochondrial Function (MD), Fatty Acid Transport Function, and Cholinergic Neurotransmission Function, among others.This is summarized in Figure 2. Potential mechanisms of action are summarized as follows.

Oxidative Stress
OS is a state in which reactive oxygen species clusters are formed and lead to a reduction in the antioxidant potential of specific cells.At this point, the balance between reactive oxygen species (ROS) production and antioxidant levels is significantly disturbed and cell damage occurs due to excessive ROS [99].Highly reactive compounds such as hydroxyl radicals, hydrogen peroxide, superoxide, and peroxynitrite cause cellular lipid peroxidation, vital enzyme inactivation, respiratory chain dysfunction, or DNA modification.Under physiological conditions, these oxygen-derived substances are metabolized into less harmful compounds with the participation of the most important antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione reductase, and peroxidase [100].
ROS promotes the occurrence and development of neurodegenerative diseases by regulating the function of biological molecules.ROS promotes the occurrence and development of neurodegenerative diseases by regulating the function of biological molecules.ROS can target several different substrates in the cell, causing protein, DNA, and RNA oxidation or lipid peroxidation [99].
OS plays a pivotal role in the pathogenesis of numerous neurological and psychiatric disorders.It seems to be a consensus that OS has been implicated in the pathogenesis of multiple disease states and may be a common pathogenic mechanism of many major psychiatric disorders [101], including AD [99,[102][103][104][105], depression [101,103,[106][107][108], ALS [109][110][111][112][113], peripheral nervous system diseases [114][115][116], etc. ROS attack proteins, oxidize the backbone and side chains, and then react with amino acid side chains to form carbonyl functional groups.ROS attack nucleic acids in a number of ways, resulting in DNA-protein cross-linking, strand breaks, and modification of purine and pyridine bases, leading to DNA mutations [99].The brain is particularly susceptible to ROS due to high oxygen metabolism and limited antioxidant capacity.Additionally, postmortem brain samples from patients with neurological diseases showed significant oxidative damage in the brain [117].
In animal models, LC counteracts motor neuron death caused by toxic agents or trophic factor deprivation and slows disease progression [118][119][120][121].The drug also improved mitochondrial dysfunction [122], restoring synaptic transmission [123].It also has a protective effect on neuroinflammation [124].As a result, the levels of OS markers and pro-inflammatory cytokines are reduced, thereby reducing the level of OS in damaged cells [124,125].
LC, as a common antioxidant, has been shown to act as an antioxidant (free radical scavenger) and anti-inflammatory agent to protect tissues from ROS damage [126,127].Some studies have also shown that LC as an adjuvant therapy can effectively increase antioxidant activity and reduce OS index and systemic inflammatory factors in patients with coronary heart disease [128].Additionally, LC can effectively cope with OS through a number of direct mechanisms (such as free radical scavenging and Fe2+ ion chelation) and indirect effects (due to ROS and RNS production of enzymes such as XO, NOX, and iNOS, while increasing the expression of GSH, SOD, CAT, and GPx antioxidants).LC can also tightly regulate cell apoptotic signaling by decreasing pro-apoptotic proteins, namely BAX and BAD, and enhancing anti-apoptotic protein components, such as Bcl-2 protein, XIAP, and some HSPs [129].In conclusion, LC-induced protective mechanisms have the potential to combat a variety of cellular injuries; therefore, the use of LC to combat OS is warranted.In vitro studies have also shown that increasing muscle levocarnitine levels can modulate OS by modulating protein synthesis [130] [Potential Therapeutic Role of LC in Skeletal Muscle OS and Atrophy Conditions].A study by Kita et al. [131] indicates that LC supplementation increases plasma concentrations of insulin-like growth factor-1 (IGF-1) and activates the corresponding signaling pathways.In animal models, this increase in IGF-1 appears to be mediated by intramuscular microRNA levels [132].A variety of studies have reported that IGF-1 not only affects muscle hypertrophy, but also inhibits muscle protein breakdown, leading to skeletal muscle atrophy [133].Additionally, Montesano et al. found that LC increased key proteins involved in the antioxidant process.This is consistent with other studies on the antioxidant activity of LC [134].
There are also fragmented reports suggesting that LC may inhibit pro-inflammatory cytokines, improve protein synthesis or nitrogen balance, and affect requirements for lipid parameters and erythropoietin (rHuEPO), a positive acute-phase protein that is increased in inflammation [155].Inflammatory stimuli cause the release of cytokines such as interleukin (IL-1), IL-6, and tumor necrosis factor-a (tnf-a), which increase the synthesis and release of CRP [156].CRP level is an objective indicator that shows the production of pro-inflammatory cytokines and is widely accepted as an independent marker of cardiovascular risk [155].An independent clinical trial of LC supplementation in patients with osteoarthritis showed that LC significantly reduced serum levels of IL-1b and MMP-1 [157].
Other studies have shown that LC can also alleviate inflammatory cell damage by regulating inflammatory function [126,158].For example, a recent in vitro study suggested that LC may reduce inflammation by controlling the production of TNF-α and nuclear factor-κb (NF-κB) [158].A 2015 meta-analysis of six RCTS suggested that LC had a CRPlowering effect [159].A 2019 review also clearly showed that LC supplementation can reduce inflammation, especially in studies that are longer than 12 weeks [160].
LC, a known agonist of mitochondrial function, is a neuronal growth factor with antioxidant effects on central nervous system neurons, and plays an important role in the transport of long-chain fatty acids into mitochondria [191].The long-chain fatty acids are transported to the mitochondrial matrix, where beta-oxidation of the fatty acids occurs and adenosine triphosphate (ATP) is produced [192].Acetyl-LC (ALC) is an acetylated form of LC which is synthesized by carnitine acetyltransferase.Like LC, it is found in relatively high amounts in the brain [193].Although case reports were excluded from the systematic review, some illustrative cases can aid consolidation of the information.In a single case of coma induced by valproate, the patient was treated with a high dosage of carnitine (2.50 mg/kg/day).The authors speculated that valproate reduced serum and liver carnitine concentrations, suppressing mitochondrial function, which in turn caused inhibition of the urea cycle [194].
Alterations in mitochondrial dynamics lead to a range of metabolic abnormalities: impaired oxidative phosphorylation, defective mitochondrial gene expression, imbalances in fuel and energy homeostasis, increased ROS production, enhanced insulin resistance, and abnormal FA metabolism.LC and its derivatives have a favorable regulatory effect on mitochondrial diseases [4].

Dopamine Neurotransmission
Many studies have shown that dopamine neurotransmission is closely related to neurological and psychiatric diseases, including depression, ADHD, and schizophrenia [195][196][197][198][199][200].In the brain, the interaction between dopamine and glutamate constitutes the pathological basis of psychiatric disorders [201].The toxicity of dopamine has been demonstrated in a variety of in vitro models, and previous experiments have demonstrated the selective toxicity of dopamine in vivo after exogenous dopamine injection into the striatum, resulting in the selective toxicity of dopamine receptor nerve terminals and the loss of dopaminergic neurons in the substantia nigra [202,203].These damages also serve as the basis for intracellular oxidative mechanisms and mitochondrial dysfunction, which eventually induce neurodegenerative diseases such as Parkinson's disease [202,203].And studies have shown that not only does dopamine have neurotoxic effects, but also that genetic inactivation of dopamine D1 and D2 receptors can play a neuroprotective role, mainly by reducing the activity of dopamine transporter to block dopamine reuptake, thereby reducing the level of dopamine in the cytoplasm [204,205].Dopamine denervation is also an important hallmark of PD.Therefore, we can conclude that dopamine plays an important role in the pathogenesis of nervous system diseases [206].
Animal studies have shown that LC can enhance dopamine D1 receptor levels in the hippocampus and prefrontal cortex (PFC), balance pro-inflammatory and anti-inflammatory cytokines, attenuate microglia activation and IM release, and subsequently enhance the survival of mature neurons in the CA1, CA3, and PFC regions.It can effectively block the uptake of dopamine in Parkinson's rats and play a neuroprotective role, and improve the cognitive function of Parkinson's rats [207].Therefore, LC may have a protective effect against dopamine-induced neurotoxicity.Although the dopamine replacement therapy levodopa is still the first-line treatment for neurological diseases such as Parkinson's disease, it still has many potential side effects, such as movement disorders.Additionally, levodopa treatment cannot improve all clinical aspects of PD patients, the most important of which is preventing the progression of non-motor symptoms [206].Therefore, it is of great significance to further explore the neuroprotective effect of LC.
There is considerable evidence that LC can help cholinergic neurotransmission in patients, and animal experiments have shown that LC (100 mg/kg/s) was administered to rats for 3 months and cholinergic activity was measured by synaptosomes isolated from the cortex.Synaptosomal high-affinity choline uptake, synaptosomal ach synthesis, and synaptosomal ach release during membrane depolarization were all enhanced in the ALCAR group.The present study demonstrates that chronic administration of LC increases cholinergic synaptic transmission, thereby enhancing cognitive function in aging rats [208].There is also evidence that pathological processes affecting cholinergic neurotransmitter system are associated with memory impairment in dementia, and LC can enhance the activity of cholinergic neurons, thereby improving cognitive function in patients.Although the effects of LC on cholinergic neurotransmission have not been clearly documented in the literature, both postsynaptic [217] and presynaptic [218] mechanisms have been proposed.
It has been shown that acute ammonia toxicity is mediated by excessive activation of NMDA glutamate receptors, and that ammonia toxicity is responsible for hepatic encephalopathy [241].LC was found to protect against glutamate neurotoxicity mediated by increasing the activation of metabolic receptors.Additionally, LC could protect cerebellar neurons from glutamate neurotoxicity in primary culture.This supports the view that the protective effect of carnitine against ammonia toxicity is due to a protective effect against glutamate neurotoxicity [242].In a randomized study of cancer patients, treatment with LC resulted in a significant reduction in plasma glutamate levels [243].
LC plays an important role in the transport of long-chain fatty acids to mitochondria [98,191].Moreover, it can induce the production of urea, thereby reducing the concentration of ammonia and improving the nervous function of the body [253].

Discussion
Based on the comprehensive analysis of relevant studies, it is evident that LC has shown promising therapeutic effects for various neurological and psychiatric disorders.However, its impact on other diseases remains unclear.Variations in therapeutic effects may stem from variances in metabolic mechanisms underlying the pathophysiology of these diseases, and the diverse effects of LC on these mechanisms.While LC demonstrates therapeutic potential across most neurological and mental conditions, its efficacy varies.Notably, LC has shown significant improvement in Alzheimer's disease, carpal tunnel syndrome, cognitive impairment, migraine, neurofibromatosis, peripheral nervous system diseases, Raynaud's syndrome, and stroke.Particularly, LC has been recognized as a mature treatment for hepatic encephalopathy and its complications.Conversely, limited benefits have been observed in neurological and psychiatric disorders such as amyotrophic lateral sclerosis, ataxia, ADHD, depression, chronic fatigue syndrome, Down syndrome, and sciatica.
In the realm of mental health, LC has exhibited positive effects in treating depression and ADHD, as evidenced by controlled studies.While two DBPCS studies demonstrated LC's positive role in treating depression (evidence level 2a and 2b), and one study indicated improvements in ADHD symptoms in children (evidence level 2b), more research is warranted to provide conclusive recommendations.Although larger, controlled trials are necessary to establish LC's efficacy, its excellent safety profile and existing evidence support its potential as a novel treatment option for psychiatric and neurological disorders.This suggests that the mechanism of action of LC may have clinical implications for use in these disorders.

Dosage and Formulations
According to the statistics of the above experiments, it can be known that the daily supplement dose of LC is 0.5-6 g/d, and most studies use 1.0-3.0g/d.Oral preparations were used in all studies except one for ADHD, one for peripheral neuropathy, and two for hepatic encephalopathy.Additionally, the shortest duration of treatment was only 90 min in a study of patients with hepatic encephalopathy [52].The longest duration of treatment was a study of patients with amyotrophic lateral sclerosis, which lasted 24 months [22].The duration of follow-up in most studies ranged from 3 to 12 months.The renal risks and benefits of LC in athletes and bodybuilders have not been evaluated.However, LC up to 6000 mg/day is generally considered to be a safe supplement, at least for healthy adults [254] (The Renal Safety of LC, L-Arginine, and Glutamine in Athletes and Bodybuilders).This dose is much higher than the doses used in the studies in our review and thus further confirms the plausibility of the studies in our review.In studies treating patients with Rett syndrome, doses of 50 mg/kg/day or 100 mg/kg/day were used in three divided doses [84][85][86].The patients were all adolescent girls, and if they weighed 50 kg, the daily dose of LC was 2500 mg or 5000 mg, which seems to be near the middle of the range in the studies we reviewed.This was followed by a trial for peripheral neuropathy in which intramuscular injections were initiated at 1000 mg/day according to the earlier study dose for 10 days and continued at 2000 mg/day orally for the remaining 355 days of the study [72] (Acetyl-LC (Levacecarnine) in the Treatment of Diabetic Neuropathy: A Long-Term, Randomised, Double-Blind, Placebo-Controlled Study).Additionally, a randomized controlled clinical trial in patients with stroke did not show any difference in LC supplementation between 1000 mg/d and 2000 mg/d [95].Studies of the effect of LCN supplementation on hepatic encephalopathy have used relatively large and varied doses, ranging from 1.8 to 6 g/day, and no clear association was observed between higher doses and increased efficacy or side effects.Based on most studies, the amount of LC used was about 1.0 g-3.0 g/day.Overall, the dose range of 1.0 g to 3.0 g/day was highly effective and well tolerated by patients.

Potential Adverse Effects
We note that oral LC appeared to be fairly well tolerated throughout most of this review, with no significant differences between the experimental and control groups.GI symptoms are the most common side effects and have been reported in studies of geriatric degenerative cognitive impairment, amyotrophic lateral sclerosis, cognitive impairment, chronic fatigue syndrome, migraine, multiple sclerosis, peripheral neuropathy, Rett syndrome, and stroke.Gastrointestinal AEs included abdominal pain [21,30,64]; mild abdominal discomfort, flatulence, and hiccups [15,21,75,76,98]; nausea, vomiting, and diarrhea; [21,64,75,98] and intestinal peristalsis [84].The maximum incidence of AEs occurred in a triple-blind, cross-controlled trial of LC for migraine relief, in which approximately 33% of subjects reported mild or moderate AEs.The main AEs included abdominal pain, nausea and other gastrointestinal reactions, vomiting, headaches and so on [64].Neurological side effects were also frequently reported, including headache [30,73], insomnia [42,68,75], anxiety and tension [12], and stimulation [73].Cutaneous adverse events, mainly rash, have also been reported [11,15].The remaining AEs reported included body odors such as fishy smell and urine smell [15,84], leukopenia [75], and liver dysfunction [75].Few studies have reported serious AEs leading to discontinuation of LC treatment, and in a study of LC in Alzheimer's disease, one patient discontinued treatment because of an eosinophil count greater than 20 percent [16].Additionally, in a study of chronic fatigue syndrome, eight people dropped out because of overstimulation and insomnia [42].In a study of multiple sclerosis, one patient treated with LC interrupted the trial because of the development of insomnia and nervousness [68].In a stroke study, one patient withdrew from treatment because he could not tolerate the AEs of nausea, upset stomach, and diarrhea [98].Overall, there have been a very small number and lack of consistent reports of particularly serious AEs in the treatment of LC, suggesting that LC is generally considered to be a well-tolerated and relatively safe drug.

Conclusions
The application of LC in some psychiatric and neurological diseases has been studied, and its application in some diseases is approaching maturity, so we have every reason to believe that LC is an effective drug for neurological and psychiatric diseases.Although data were limited for most conditions in terms of the quantity and quality of the studies I reviewed, the number of studies was insufficient, or the results were not sufficiently homogeneous, overall the effect trends were generally positive for many conditions.In most studies, LC treatment was safe, tolerable, and affordable.This is a drug worthy of further exploration for further development and promotion.Of course, larger numbers of randomized, controlled trials with different psychiatric and neurological disease designs are needed.Additionally, in the field of molecular biology, a large number of studies are still needed to elucidate the specific mechanism of action of LC and explain its therapeutic effects on neurological and psychiatric diseases.

Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart.

Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart.
LC has been shown to act on multiple pathways in various psychiatric and neurological disorders, such as Oxidative Stress (OS), Inflammatory Mediators (IMs), Mitochondrial Function (MD), Fatty Acid Transport Function, and Cholinergic Neurotransmission Function, among others.This is summarized in Figure2.Potential mechanisms of action are summarized as follows.

Figure 2 .
Figure 2. Potential mechanisms of action of L-carnitine.Figure 2. Potential mechanisms of action of L-carnitine.

Figure 2 .
Figure 2. Potential mechanisms of action of L-carnitine.Figure 2. Potential mechanisms of action of L-carnitine.

Table 2 .
Levels of evidence.

Table 3 .
Grade of recommendation.

Table 4 .
Overall ratings of L-carnitine based on clinical studies presented by condition.

Table 8 .
Attention deficit disorder with hyperactivity.

Table 12 .
Fatigue syndrome, chronic.In 2004, Ruud C. W et al., at the Amsterdam Research Center in the Netherlands, conducted a randomized open-label trial (N = 90 LOE2a) of daily supplementation of 4 g ALC or PLC for 24 weeks in patients with CFS.This study demonstrated that either ALC, PLC, or a combination of them as a derivative of LC can improve mental fatigue and quality of life in CFS patients

Table 17 .
Peripheral nervous system diseases.