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Cognitive Health Memantine Nootropics Recovery

Can Nootropics Help With Drug Abuse and Addiction?

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

«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[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.

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

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[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.

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)[3], 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)[4]. 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[5].
  • With regard to cannabis, 2.4 g/day NAC decreased craving in one 4-week open label study of 24 patients[6]; 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[7].

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[8].

NAC is generally well-tolerated. Nausea, vomiting, rash, and fever have been reported.

Memantine

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[9].

Clapp P, Bhave SV, Hoffman PL. How adaptation of the brain to alcohol leads to dependence: a pharmacological perspective. Alcohol Res Health. 2008;31(4):310-39.
Neurochemical effects of alcohol intoxication in various contexts.

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[10]. Another placebo-controlled RCT with 10-40 mg/day showed no difference[11].
  • A subsequent study of 38 patients utilising 20-40 mg/day memantine showed dose-dependent reductions in cue-induced craving[12].
  • 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[13].
  • Administration of 60 mg significantly alleviated subjectively-rated symptoms of naloxone-induced opioid withdrawal in 8 heroin-dependent patients[14].
  • 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[15].
  • Clinical data on application in cocaine[16],[17] and nicotine abuse[18] 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[19].

Summary

  • 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/
Categories
Methylene Blue Nootropics Reviews

Methylene Blue as a Nootropic? (Review)

Since its initial synthesis in 1886, the phenothiazine derivative methylene blue (MB) has been established as a highly versatile chemical agent with a diverse span of uses, ranging from treating malaria to dying textiles[1]. Within the past few years, preclinical research has suggested a possible neuroprotective benefit from MB administration. MB is believed to promote neuronal cell health by supporting mitochondrial function. Animal studies have yielded promising results in neurocognitive tests[2][3]. Here is what you need to know if you’re interested in using methylene blue.

How does Methylene Blue work?

Mitochondria are organelles within cells that play the key role of energy production. Cellular energy is stored in the form of adenosine triphosphate (ATP), one of the most important molecules in the cell. As the name suggests, ATP contains three linked phosphate groups. Removal of each group releases a large amount of energy, which is expended in supporting cellular function. Subsequent removal of ATP produces ADP (adenosine diphosphate) & AMP (adenosine monophosphate). ATP is produced within mitochondria as a final product of respiration, a series of biochemical reactions that extract energy from glucose. These biochemical reactions require oxygen & electron carriers (e.g. NADH).

Poteet E, Winters A, Yan L, Shufelt K, Green KN, Simpkins JW, et al. Neuroprotective actions of methylene blue & its derivatives. PLoS One. 2012;7(10):e48279-.
Methylene blue acts as an artificial electron carrier, promoting mitochondrial respiration. The net outcome is more energy available as ATP for cellular processes.[4]
Methylene blue supports mitochondrial respiration by functioning as an additional electron carrier[5]. MB receives electrons from NADH through mitochondrial complex I, itself being reduced to leuco-MB (MBH2). Leuco-MB then donates the electrons to cytochrome C, upon which it is recycled back to MB. These reactions serve to create a high proton (H+) concentration in the space between the inner & outer mitochondrial membranes. This leads to the passage of H+ down the concentration gradient, through mitochondrial complex V. In doing so, ADP & a phosphate (Pi) are joined to form ATP. Leuco-MB can also act as a free radical scavenger, neutralising superoxides by accepting electrons & itself becoming oxidized back to MB[6]. In this way, leuco-MB acts to prevent direct oxidative damage caused by free radicals.

Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
Methylene blue preferentially accumulates in more active neurones (A), & potentiates mitochondrial & synaptic activity (B). These processes result in increased & improved neurotransmission (C), which is thought to be the mechanism behind the neurocognitive benefits associated with MB.[7]
MB has been observed to preferentially localise in neurones that are more active[3]. Stimulated mitochondria in these neurones modulate genomic expression of proteins that further potentiate mitochondrial respiration via nuclear respiratory transcription factor (NRF-1), resulting in increased expression of cytochrome oxidase (COX), nitric oxide synthase (NOS-1), NMDA receptors, & AMPA receptors. Strengthened synaptic connections as a result of these processes result in improved memory.

The pharmacologic mechanism behind the neuroprotective activity of methylene blue is unique in that it does not involve a receptor-ligand interaction, as do most drugs. In addition, MB also exhibits an atypical dose-response curve– one that has been described as hormetic[8]. Hormesis is a phenomenon where lower doses produce optimum responses while higher doses or exposures may actually produce the opposite effect. Hormesis is an intriguing pattern that may explain the dose-responses associated with exercise & oxidative stress, where the right amount of exercise-induced oxidative stress induces a cascade of favourable physiologic adaptations that can mitigate more severe stressors[9].

Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
An example hormetic dose-response curve. Note the inverse response caused with higher doses.[10]
As previously mentioned, metabolism of MB involves reduction to leukomethylene blue (MBH2). MB is primarily eliminated in the urine (75%)[11].

What is it like?

I have tested BlueBrainBoost’s formulation with the following results. I have noticed increased energy and decreased fatigue, with an onset of up to 1 hour and duration of 2-4 hours. The only adverse effects were discolouration of the mouth and urine. I used a dosage of 10 mg (20 drops) in the morning sublingually before brushing my teeth. During this time, I was also taking 30 mg/day coluracetam, 500 mg/day ashwagandha, & 600 mg/day NAC. I suspect that coadministration of CoQ10 and creatine may have a synergistic effect based on the pharmacologic site and mechanism of action.

Is it safe?

methylene blue nootropicMethylene blue is associated with a very favourable safety profile. It is generally well-tolerated at doses lower than 2 mg/kg.[12] The most noticeable side effect of MB is blue discolouration of the oral cavity and blue or blue-green discoloration of the urine. These effects are reversible and not harmful. [13] Staining of the teeth can be removed with repeated tooth-brushing, and discolouration of the urine ceases after the drug is fully removed from the system. Other reported adverse effects include a mild headache and dizziness[14].

MB does exhibit some serotonergic activity. This is due to its inhibition of enzymatic degradation of serotonin by MAO-A. Intravenous doses higher than 5 mg/kg have led to the development of serotonin syndrome. This risk is increased in individuals already taking other serotonergic agents (e.g. tianeptine, St. John’s Wort, common antidepressants, dextromethorphan, tramadol). For these reasons, individuals at risk should avoid coadministration of MB with serotonergic agents by at least 2 weeks (or more depending upon the agent), start at low doses, & increase carefully to an effective dose.

Neurotoxicity has been associated with some preparations of MB as a result of chemical impurities. The presence of heavy metals used in the synthesis of MB can have adverse effects on neurones. Thus, only pharmaceutical grade formulations are recommended for human consumption – not lab grade, & not aquarium grade. These formulations may not meet USP standards and may contain up to 11% contaminants.

How should I take it?

Because MB’s role as a neuroprotective agent in humans is still being studied, there is as yet no recommended dosage. The animal doses used in preclinical trials roughly converts to a human equivalent dose of 0.16–0.64 mg/kg administered sublingually. Sublingual administration may produce higher bioavailability than oral administration, but causes more staining of the mouth. I calculated my dose like so:

  1. 0.16 to 0.64 mg/kg × 54.43 kg = 8.71 mg to 34.84 mg per dose
  2. 10 mg/1 mL = 8.71 mg/x mL → 0.87 mL × 20 gtt/1 mL = 17 gtt to 3.5 mL per dose SL (gtt = drops)

It should be noted that due to the hormetic dose-response curve, the response to MB may decrease with higher doses. MB is typically formulated as a 10 mg/mL solution, where 1 drop = 0.05 mL = 0.5 mg. The bottle should be shaken well before administration.

Summary

Overall, I would recommend methylene blue to individuals looking for an inexpensive extra boost in energy. I have not tested MB long enough to notice changes in cognition or memory, but the pre-clinical studies & pharmacologic literature seem to support this benefit.

  • Methylene blue supports mitochondrial respiration & strengthens synaptic connections, which may lead to decreased fatigue and enhanced cognition & recall. MB exhibits a hormetic dose-response curve.
  • The safety profile has been well-characterised, and MB has generally been shown to be well-tolerated. I believe the most important warnings are those concerning serotonin syndrome and chemical impurities.
  • The best-estimated dosage is only an approximation from animal studies. MB is not yet recommended for human consumption for the purpose of improving cognition and memory.
  • Only pharmaceutical grade formulations of MB should be used.
Methylene Blue
7.5
Focus
8
Mood
7.5
Memory
8
Stimulation
5.5
Relaxation
6.5
Safety
Reviewer 8.3
Summary
Methylene Blue improves mood, memory and energy levels, as well as mitochondrial function (and may also delay aging). I think it is a powerful tool to have in your arsenal, and the BBB solution is cheap and convenient, therefore I highly recommend it to anyone.

References   [ + ]

1. Ginimuge PR, Jyothi SD. Methylene blue: revisited. J Anaesthesiol Clin Pharmacol.
2. Callaway NL, Riha PD, Bruchey AK, Munshi Z, Gonzalez-Lima F. Methylene blue improves brain oxidative metabolism & memory retention in rats. Pharmacol. Biochem. Behav. 2004; 77:175–181.
3, 7. Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement & neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
4. Poteet E, Winters A, Yan L, Shufelt K, Green KN, Simpkins JW, et al. Neuroprotective actions of methylene blue & its derivatives. PLoS One. 2012;7(10):e48279-.
5. Gonzalez-Lima F, Barksdale BR, Rojas JC. Mitochondrial respiration as a target for neuroprotection & cognitive enhancement. Biochem Pharmacol. 2014 Apr 15;88(4):584-93.
6. Miclescu A, Basu S, Wiklund L. Methylene blue added to a hypertonic-hyperoncotic solution increases short-term survival in experimental cardiac arrest. Crit. Care Med. 2006; 34:2806–2813.
8. Bruchey AK, Gonzalez-Lima F. Behavioral, physiological, and biochemical hormetic responses to the auto-oxidizable dye methylene blue. Am. J. Pharm. & Toxicol. 2008; 3:72–79.
9. Ji LL, Gomez-Cabrera MC, Vina J. Role of free radicals & antioxidant signaling in skeletal muscle health and pathology. Infect Disord Drug Targets. 2009;9(4):428–444.
10. Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
11. Medscape® 5.1.2, (electronic version). Reuters Health Information, New York, New York.
12, 14. Ginimuge PR, Jyothi SD. Methylene blue: revisited. J Anaesthesiol Clin Pharmacol. 2010 Oct;26(4):517-20.
13. Gillett MJ, Burnett JR. Medications and green urine. Intern Med J. 2006 01;36(1):64-6.