In recent years, evidence has compiled suggesting a common pathologic mechanism underlying addictive behaviours of several substances. Dysregulation of glutamatergic neurotransmission within the prefrontal cortex (PFC) and nucleus accumbens (NA) appears to predispose to a higher tendency towards drug-seeking behaviour.
Thus far, this mechanism has been associated with the addiction potential of cocaine, heroin, nicotine, cannabis, & alcohol, with possible implications for other substances and even non-drug-related compulsive habits such as pathological gambling. Discovery of this shared pathology has led to the investigation of the potential application of existing agents, such as Memantine and n-acetylcysteine.
Could nootropics targeting elements in this key glutamatergic circuit reduce symptoms and complications of substance use disorders?
«Glutamate spillover» refers to the pathologic cascade in brain chemistry that occurs with chronic abuse of certain substances that results in reinforcement of the behaviour.
Prolonged exposure to substances of abuse leads to several maladaptive changes in the glutamatergic PFC-NA pathway, specifically:
- Downregulation of glial glutamate transporter-1 (GLT1) expression in the nucleus accumbens. By removing glutamate from the extrasynaptic space, GLT1 prevents inappropriate excitatory stimulation due to an accumulation of the excitatory neurotransmitter.
- Decreased ability of presynaptic metabotropic glutamate receptor 2 (mGluR2) to inhibit glutamate release. In normal physiology, mGluR2 autoreceptors manage a feedback loop where increased extracellular glutamate levels trigger a reduction in the presynaptic release of glutamate. This auto-regulatory mechanism also serves to prevent an extracellular accumulation of glutamate.
When glutamate spillover within the non-synaptic extracellular space does occur as a result of the combination of these processes, the following sequelae are may manifest:
- Stimulation of postsynaptic mGluR5, AMPA and NMDA receptors.
- Upregulation of AMPA and NMDA receptors (increased synaptic plasticity).
- Stimulation of extrasynaptic glutamate receptors may also occur.
Increased excitatory tone due to these two processes culminates in impaired inhibition with regard to drug-seeking behaviour as well as increased risk of relapse. Furthermore, persistently elevated glutamatergic tone may lead to neurotoxicity secondary to excessive Ca2+ ion influx. This pathology has also been associated in neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s disease.
n-acetylcysteine (NAC) is a cysteine precursor that has a long history of use for indications ranging from bronchopulmonary disorders to paracetamol overdose. It produces many beneficial effects through a variety of mechanisms ranging from supporting antioxidant processes to suppressing over-reactive immune responses to inhibiting apoptosis. NAC’s glutamatergic modulation, however, is of key interest in managing substance use disorders.
NAC is converted to L-cysteine in vivo, which enhances the activity of the cysteine/glutamate exchange transporter positioned near the pre-synaptic terminal. This increases the concentration of extracellular glutamate, resulting in increased tonic activation of pre-synaptic mGluR2 autoreceptors. This causes a subsequent decrease in glutamate release. NAC also increases expression of GLT1 and the cysteine/glutamate exchange transporter, promoting the removal of glutamate from the extrasynaptic space and ‹putting it back› in the pre-synaptic area. These effects in concert have been shown to mitigate the complications from glutamate spillover, & have been tested in several small trials with promising results.
- When administered in patients with a history of cocaine addiction, NAC was shown to decrease self-reported cocaine use within the 28 days of treatment (mean 8.1 days out of 28 days before treatment & 1.1 days during treatment, p = 0.001), desire to use cocaine (F = 5.07; df = 1,13; p = 0.05), & response to cocaine cues (F = 4.79, df = 1,13, p = 0.05). A magnetic resonance spectroscopy study confirmed elevated glutamate levels in the dorsal anterior cingulate cortex of cocaine users when compared against non-users (t(7) = 3.08, p = 0.02), and also showed a reduction 1 hour after a single 2.4 g dose of NAC.
- With regard to cannabis, 2.4 g/day NAC decreased craving in one 4-week open label study of 24 patients; in a double-blind placebo-controlled trial, subjects given 2.4 g/day NAC in addition to counselling were 2.4 times more likely to test negative on urinalysis (95%CI 1.1 to 5.2) but there was no difference in number of reported days of cannabis use.
The dosage for managing consequences of substance use disorders in trials ranged from 1.2 to 2.4 g by mouth daily. Benefits on neurochemistry may occur with single doses although significant alterations in behaviour may take days to weeks. The pharmacodynamic effect also depends upon the history of substance use and individual predisposition to addictive behaviour.
NAC is significantly protein-bound (80%). It is metabolised in the liver via non-CYP450 pathways. NAC and its metabolites are primarily eliminated in the urine, with a half-life of 5.6 hours in adults.
NAC is generally well-tolerated. Nausea, vomiting, rash, and fever have been reported.
Memantine (Namenda®) is an uncompetitive NMDA receptor antagonist most commonly used in the management of moderate-to-severe Alzheimer’s disease. In addition to its glutamatergic modulation, memantine also acts as an agonist at the D2 and nicotinic acetylcholinergic receptors (nAChR). Memantine binds and inhibits NMDA receptors with low-to-moderate affinity, most effectively in states of excess glutamatergic activity (such as in substance use disorder). By blocking NMDA receptors, memantine decreases glutamatergic tone.
Upregulation of NMDA receptors has been observed with chronic alcohol consumption. Abrupt discontinuation of alcohol removes GABAergic suppression, resulting in the characteristic acute sequelae of alcohol withdrawal (symptoms of excitotoxicity): seizures, hallucinations, tachycardia, and shock. By inhibiting these receptors, memantine may theoretically attenuate symptoms of alcohol withdrawal.
- In one RCT of 18 moderate alcohol drinkers (10-30 drinks/week), 30 mg/day memantine significantly decreased alcohol craving before alcohol consumption in comparison to 15 mg/day and placebo. Another placebo-controlled RCT with 10-40 mg/day showed no difference.
- A subsequent study of 38 patients utilising 20-40 mg/day memantine showed dose-dependent reductions in cue-induced craving.
- In another RCT of 127 male patients undergoing alcohol withdrawal, administration of 10 mg memantine three times a day decreased apparent withdrawal symptom severity, dysphoria, and need for diazepam.
- Administration of 60 mg significantly alleviated subjectively-rated symptoms of naloxone-induced opioid withdrawal in 8 heroin-dependent patients.
- In a study of 67 heroin-dependent subjects, 10-30 mg/day memantine significantly reduced heroin craving, depression, and state & trait anxiety compared to placebo after 3 weeks of use. A separate treatment arm using amitriptyline 75 mg/day achieved similar results but with a higher incidence of side effects and a higher dropout rate.
- Clinical data on application in cocaine, and nicotine abuse is less promising.
The dosage for mitigating substance use disorders in trials ranged from 5 to 60 mg, with 30 mg by mouth once daily showing the best effects for alcohol abuse and 30 to 60 mg by mouth once daily shown to be most effective in limited trials for opioid dependence. Safety is best characterised at doses up to 30 mg, as this dosage is used in Alzheimer’s disease. Memantine is typically initiated at 5 mg daily then titrated by 5 mg per week up to the goal dose (30 to 60 mg depending upon the indication).
Memantine undergoes favourable non-hepatic metabolism; its metabolites are minimally active. Individuals with a history of kidney disease should consult a doctor or pharmacist before use, as memantine undergoes significant renal elimination (74% is excreted in the urine). The half-life of memantine ranges from 60-80 hours.
The most common side effects noted at therapeutic doses higher than 7 mg/day are dizziness, headache, confusion, anxiety; increased blood pressure; cough; & constipation.
- Disrupted regulation of glutamatergic pathways in the prefrontal cortex-nucleus accumbent pathway has been implicated as an underlying pathology among several substance use disorders, including cocaine, alcohol, and opioid dependence.
- Therapies such as n-acetylcysteine (NAC) and memantine have demonstrated efficacy in attenuating the symptoms of some of these disorders in small trials.
References [ + ]
|1.||↑||McClure EA, Gipson CD, Malcolm RJ, Kalivas PW, Gray KM. Potential role of n-acetylcysteine in the management of substance use disorders. CNS Drugs. 2014 02;28(2):95-106.|
|2.||↑||Brown RM, Kupchik YM, Kalivas PW. The story of glutamate in drug addiction & of n-acetylcysteine as a potential pharmacotherapy. JAMA Psychiatry. 2013 09;70(9):895-7.|
|3.||↑||Mardikian PN, LaRowe SD, Hedden S, Kalivas PW, Malcolm RJ. An open-label trial of n-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:389-94.|
|4.||↑||LaRowe SD, Myrick H, Hedden S, Mardikian P, Saladin M, McRae A, et al. Is cocaine desire reduced by n-acetylcysteine? Am J Psychiatry. 2007;164:1115-7.|
|5.||↑||Schmaal L, Veltman DJ, Nederveen A,van den Brink W, Goudriaan AE. n-acetylcysteine normalizes glutamate levels in cocaine- dependent patients: a randomized crossover magnetic resonance spectroscopy study. Neuropsychopharmacology. 2012;37:2143-52.|
|6.||↑||Gray KM, Watson NL, Carpenter MJ, LaRowe SD. n-acetylcysteine (NAC) in young marijuana users: an open-label pilot study. Am J Addict. 2010;19:187-9.|
|7.||↑||Gray KM, Carpenter MJ, Baker NL, DeSantis SM, Kryway E, Hartwell KJ, et al. A double-blind randomized controlled trial of n-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry. 2012;169:805-12.|
|8.||↑||Medscape® 5.1.2, (electronic version). Reuters Health Information, New York, New York.|
|9.||↑||Zdanys K, Tampi RR. A systematic review of off-label uses of memantine for psychiatric disorders. Prog Neuro-Psychopharmacol Biol Psychiatry. 2008 8/1;32(6):1362-74.|
|10.||↑||Bisaga A, Evans SM. Acute effects of memantine in combination with alcohol in moderate drinkers. Psychopharmacology 2004;172:16–24.|
|11.||↑||Evans SM, Levin FR, Brooks DJ, Garawi F. A pilot double-blind treatment trial of memantine for alcohol dependence. Alcoholism: Clin Exp Res 2007;31(5):775–82.|
|12.||↑||Krupitsky EM, Neznanova O, Masalov D, Burakov AM, Didenko T, Romanova T, et al. Effect of memantine on cue-induced alcohol craving in recovering alcohol-dependent patients. Am J Psychiatry 2007a;164(3):519–23.|
|13.||↑||Krupitsky EM, Rudenko AA, Burakov AM, Slavina TY, Grinenko AA, Pittman B, et al. Antiglutamatergic strategies for ethanol detoxification: comparison with placebo & diazepam. Alcoholism: Clin Exp Res 2007b;31(4):604–11.|
|14.||↑||Bisaga A, Comer SD, Ward AS, Popik P, Kleber HD, Fischman MW. The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans. Psychopharmacology 2001(157):1–10.|
|15.||↑||Krupitsky EM, Masalov DV, Burakov AM, Didenko TY, Romanova TN, Bespalov AY, et al. A pilot study of memantine effects on protracted withdrawal (syndrome of anhedonia) in heroin addicts. Addict Disord Treat 2002;1(4):143–6.|
|16.||↑||Collins ED, Vosburg SK, Ward AS, Haney M, Foltin RW. Memantine increases cardiovascular but not behavioral effects of cocaine in methadone-maintained humans. Pharmacol Biochem Behav 2006;83(1):47–55.|
|17.||↑||Collins ED, Ward AS, McDowell DM, Foltin RW, Fischman MW. The effects of memantine on the subjective, reinforcing, & cardiovascular effects of cocaine in humans. Behav Pharmacol 1998;9(7):587–98.|
|18.||↑||Thuerauf N, Lunkenheimer J, Lunkenheimer B, Sperling W, Bleich S, Schlabeck M, et al. Memantine fails to facilitate partial cigarette deprivation in smokers—no role of memantine in the treatment of nicotine dependency? J Neural Transm 2007;114:351–7.|
|19.||↑||Micromedex® 1.0 (Healthcare Series), (electronic version). Truven Health Analytics, Greenwood Village, Colorado, U.S.A. Available at: http://www.micromedexsolutions.com/|