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L-acetylcarnitine

Posted by Iansf on March 23, 2013, at 13:22:59

From Synergy Times
TAKE-HOME MESSAGE
L-acetylcarnitine (LAC) may be useful in the treatment of various neuropsychiatric symptoms and syndromes, ranging from depression to Alzheimer's disease. A reasonably solid body of evidence supports the use of LAC in patients with pain syndromes, including painful neuropathy of diabetic and other etiology. LAC is probably ineffective in pediatric ADHD. Effective doses for various indications have generally been in the 1-4 g/day range, and treatment durations have commonly extended for months to a year. LAC appears to be well tolerated.

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THE SYNERGY TIMES

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Mar 23, 2013; Vol 13 No 32
L-ACETYLCARNITINE IN NEUROPSYCHIATRY
Over the years, a modest body of evidence has accumulated to suggest that the dietary supplement L-acetylcarnitine (LAC) has therapeutic properties in neuropsychiatric patients. A brief overview of the literature is provided below.

Antidepressant action of L-acetylcarnitine in animal models
LAC has antidepressant effects in rats with genetically programmed depression as well as in mice with stress-driven depression. The antidepressant benefits appear within 3 days of treatment; in contrast, benefits with clomipramine appear only after 2 weeks. Additionally, LAC-induced antidepressant benefits persist for 2 weeks after drug discontinuation (Nasca et al, 2013).

L-acetylcarnitine and depression
1. In a large (n=204), 12-week RCT, LAC (1 g/day) was as effective an antidepressant as amisulpride (50 mg/day) in patients with dysthymia (Zanardi and Smeraldi, 2006).

2. In a 7-week RCT in 80 elderly patients with dysthymia, LAC (3 g/day) and fluoxetine (20 mg/day) were associated with similar outcomes except in that the onset of antidepressant action was at week 1 with LAC as compared with week 2 with fluoxetine.

L-acetylcarnitine and other neuropsychiatric symptoms and syndromes
1. In a self-controlled study with a placebo lead-in phase, LAC (1.5 g/day) improved memory, general cognition, and mood in elderly subjects (Salvioli and Neri, 1994). A meta-analysis of RCTs in Alzheimer's disease found that LAC was superior to placebo with small effect sizes for an integrated summary effect (ES=0.20; 95% CI, 0.11-0.30) and for global change (ES, 0.32; 95% CI, 0.18-0.47).

2. In patients with multiple sclerosis, LAC (2 g/day) was superior to amantadine (200 mg/day) for the reduction of fatigue (Tomassini et al, 2004).

3. In a large (n=102), 10-week RCT, LAC (1.5 g/day) was superior to placebo in reducing pain and depression associated with fibromyalgia (Rossini et al, 2007).

4. A small (n=40), 6-week RCT found that LAC (500-1500 mg/day) was no better than placebo in children and adolescents with ADHD who were already receiving methylphenidate (20-30 mg/day) (Abbasi et al, 2011). Whereas one previous 1-year RCT (n=63) found that LAC reduced hyperactivity in fragile X boys with ADHD (Torrioli et al, 2008), another 16-week RCT (n=112) found that LAC was ineffective in ADHD children (Arnold et al, 2007).

5. Intravenous LAC (1-3 g/day for 10 days) rapidly reduced anhedonia and melancholia scores in a placebo-controlled trial in64 anhedonic alcoholic patients who had undergone detoxification (Martinotti et al, 2011). In the same study, oral LAC was continued to a 90-day endpoint. LAC reduced craving and increased time to the first drink (Martinotti et al, 2010).

6. In a 90-day RCT of 67 well-compensated cirrhotic patients with minimal hepatic encephalopathy, LAC (4 g/day) was superior to placebo in improving health-related quality of life outcomes, depression and cognition scores, and certain laboratory outcomes (Malaguarnera et al, 2011a). Three months of treatment with LAC (2-4 g/day) also improved cognition (Malaguarnera et al, 2011b) and reduced fatigue (Malaguarnera et al, 2011c) in patients with hepatic encephalopathy.

7. Many studies show that LAC reduces pain and other discomfort in peripheral neuropathy (Grandis, 1998, De Grandis and Minardi, 2002; Sima et al, 2005; Youle et al, 2007), intervertebral disc prolapse (Memeo and Loiero, 2008), and opiate withdrawal (Janiri et al, 2009).

Mechanism of action
1. If LAC does have antidepressant action, what might be the mechanism? Nasca et al (2013) suggested that LAC acts epigenetically, through acetylation of histone proteins that regulate the transcription of BDNF and mGlu2 metabotropic glutamatergic receptors in the hippocampus and prefrontal cortex. They showed that the antidepressant action of LAC was diminished or abolished in mGlu2 knockout mice, and in animals treated with a mGlu2/3 antagonist.

2. LAC has many effects in mice: noradrenaline is increased and GABA is decreased in the hippocampus, and serotonin is increased in the cerebral cortex (Smeland et al, 2012).

Conclusions
L-acetylcarnitine (LAC) may be useful in the treatment of various neuropsychiatric symptoms and syndromes, ranging from depression to Alzheimer's disease. A reasonably solid body of evidence supports the use of LAC in patients with pain syndromes, including painful neuropathy of diabetic and other etiology. LAC is probably ineffective in pediatric ADHD. Effective doses for various indications have generally been in the 1-4 g/day range, and treatment durations have commonly extended for months to a year. LAC appears to be well tolerated.

Comments
1. Most of the literature on LAC has emerged from Italy.

2. There is no patent in force on LAC, and it is therefore unlikely that LAC will be seriously investigated as a prescription medicine. This is unfortunate, because it means that there is little hope for serious research on the drug.

References
Abbasi SH, Heidari S, Mohammadi MR, Tabrizi M, Ghaleiha A, Akhondzadeh S. Acetyl-L-carnitine as an adjunctive therapy in the treatment of attention-deficit/hyperactivity disorder in children and adolescents: a placebo-controlled trial. Child Psychiatry Hum Dev 2011; 42: 367-375.

Arnold LE, Amato A, Bozzolo H, Hollway J, Cook A, Ramadan Y et al. Acetyl-L-carnitine (ALC) in attention-deficit/hyperactivity disorder: a multi-site, placebo-controlled pilot trial. J Child Adolesc Psychopharmacol 2007; 17: 791-802.

Bersani G, Meco G, Denaro A, Liberati D, Colletti C, Nicolai R et al. l-Acetylcarnitine in dysthymic disorder in elderly patients: A double-blind, multicenter, controlled randomized study vs. fluoxetine. Eur Neuropsychopharmacol 2013 [EPub ahead of print]

De Grandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebo-controlled study. Drugs R D 2002; 3: 223-231.

Grandis DD. Tolerability and efficacy of L-acetylcarnitine in patients with peripheral neuropathies: a short-term, open multicentre study. Clin Drug Investig 1998; 15: 73-79.

Janiri L, Martinotti G, Tonioni F, Ghelardini C, Nicolai R, Galeotti N et al. Acetyl-L-carnitine in the management of pain during methadone withdrawal syndrome. Clin Neuropharmacol 2009; 32: 35-40.

Malaguarnera M, Bella R, Vacante M, Giordano M, Malaguarnera G, Gargante MP et al. Acetyl-L-carnitine reduces depression and improves quality of life in patients with minimal hepatic encephalopathy. Scand J Gastroenterol 2011a; 46: 750-759.

Malaguarnera M, Vacante M, Motta M, Giordano M, Malaguarnera G, Bella R et al. Acetyl-L-carnitine improves cognitive functions in severe hepatic encephalopathy: a randomized and controlled clinical trial. Metab Brain Dis 2011b; 26: 281-289.

Malaguarnera M, Vacante M, Giordano M, Pennisi G, Bella R, Rampello L et al. Oral acetyl-L-carnitine therapy reduces fatigue in overt hepatic encephalopathy: a randomized, double-blind, placebo-controlled study. Am J Clin Nutr 2011c; 93: 799-808.

Martinotti G, Reina D, Di Nicola M, Andreoli S, Tedeschi D, Ortolani I et al. Acetyl-L-carnitine for alcohol craving and relapse prevention in anhedonic alcoholics: a randomized, double-blind, placebo-controlled pilot trial. Alcohol Alcohol 2010; 45: 449-455.

Martinotti G, Andreoli S, Reina D, Di Nicola M, Ortolani I, Tedeschi D et al. Acetyl-l-Carnitine in the treatment of anhedonia, melancholic and negative symptoms in alcohol dependent subjects. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 953-958.

Memeo A, Loiero M. Thioctic acid and acetyl-L-carnitine in the treatment of sciatic pain caused by a herniated disc: a randomized, double-blind, comparative study. Clin Drug Investig 2008; 28: 495-500.

Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer's disease. Int Clin Psychopharmacol 2003; 18: 61-71.

Nasca C, Xenos D, Barone Y, Caruso A, Scaccianoce S, Matrisciano F et al. L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc Natl Acad Sci U S A 2013; 110: 4804-4809.

Rossini M, Di Munno O, Valentini G, Bianchi G, Biasi G, Cacace E et al. Double-blind, multicenter trial comparing acetyl l-carnitine with placebo in the treatment of fibromyalgia patients. Clin Exp Rheumatol 2007; 25: 182-188.

Salvioli G, Neri M. L-acetylcarnitine treatment of mental decline in the elderly. Drugs Exp Clin Res 1994; 20: 169-176.

Sima AA, Calvani M, Mehra M, Amato A; Acetyl-L-Carnitine Study Group. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care 2005; 28: 89-94.

Smeland OB, Meisingset TW, Borges K, Sonnewald U. Chronic acetyl-L-carnitine alters brain energy metabolism and increases noradrenaline and serotonin content in healthy mice. Neurochem Int 2012; 61: 100-107.

Tomassini V, Pozzilli C, Onesti E, Pasqualetti P, Marinelli F, Pisani A et al. Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial. J Neurol Sci 2004; 218: 103-108.

Torrioli MG, Vernacotola S, Peruzzi L, Tabolacci E, Mila M, Militerni R et al. A double-blind, parallel, multicenter comparison of L-acetylcarnitine with placebo on the attention deficit hyperactivity disorder in fragile X syndrome boys. Am J Med Genet A 2008; 146: 803-812.

Youle M, Osio M; ALCAR Study Group. A double-blind, parallel-group, placebo-controlled, multicentre study of acetyl L-carnitine in the symptomatic treatment of antiretroviral toxic neuropathy in patients with HIV-1 infection. HIV Med 2007; 8: 241-250.

Zanardi R, Smeraldi E. A double-blind, randomised, controlled clinical trial of acetyl-L-carnitine vs. amisulpride in the treatment of dysthymia. Eur Neuropsychopharmacol 2006; 16: 281-287.

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THE SYNERGY TIMES is a regular e-newsletter which provides a capsule of information on mental health and allied sciences. While effort is made to provide accurate reviews, the onus of responsibility in the use of information lies with the reader. To subscribe to, unsubscribe from, or receive back issues of THE SYNERGY TIMES, please e-mail Dr. Chittaranjan Andrade (andradec@gmail.com).

The contents of THE SYNERGY TIMES are copyright. No part of THE SYNERGY TIMES may be reproduced without the written consent of the copyright holder (Chittaranjan Andrade, M.D.; andradec@gmail.com).

Thank you for reading THE SYNERGY TIMES. This newsletter generates a substantial, unrestricted, annual grant from the Synergy Division of Sun Pharmaceutical Industries Limited, Bombay, to registered, nongovernmental organizations which educate underprivileged children in urban and rural Karnataka. This newsletter also receives a generous, unrestricted grant from the British Association for Psychopharmacology, U.K., for the treatment of visual disturbances in the underprivileged at a general hospital in Bangalore.


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