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German Journal of Psychiatry

ISSN 1433-1055

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THE INTERNET: PANDORA'S BOX CONTAINING SMART DRUGS


J. M. Keppel Hesselink
From the Department of Pharmacology, University of Witten/Herdecke, Germany. Corresponding author: Jan M.Keppel Hesselink, MD, PhD, Professor of Pharmacology


 
 
Received: January 12, 1998 

Published: December 6, 1998

Introduction

'Smart drugs', 'smart products', 'ecodrugs', 'smarties', or just 'SM's' are just a few terms for a new class of drugs, heavily promoted via the Internet (the Net), not for patients but for healthy individuals. These drugs have certain characteristics in common and are frequently used within the context of special subcultures (such as the rave scene). However, their use is more widely spread and is definitely not restricted to these subcultures alone. Psychiatrists need to understand that especially younger patients might make use of these drugs, in varying doses and often in combinations with psychiatric medication1. Furthermore, healthy people looking for the source of eternal life and for boosting various bodily and mental functions should also be made aware of the dark side of this business. 

'Smart drugs' are not easy to define. A restricted definition would describe these drugs as not belonging to a certain pharmacological class, taken with the purpose of enhancing cognitive functions. Under this restricted definition many drugs belonging to the class of nootropics (see Table) can be found on the Net. These drugs are often promoted as mental boosters, mind enhancers, mind boosters, brain boosters, cognition boosters, intelligence boosters, etc. However, some of the smart drugs are taken to enhance, to 'boost' a variety of other functions too, such as sexuality, physical endurance, muscle power and volume, emotionality, intelligence and more generally speaking to extend one's life span. The definition of these drugs on the Net very often links their intake to certain New Age ideals, describing them as pharmaceuticals, herbal products or nutrients which 'enhance a myriad of mental functions that we depend on to be happy, successful, productive, and fulfilled people'2. A third group of drugs sometimes referred to as smart drugs are phytopharmaceuticals, or products of herbal origin, such as mushrooms. We will not discuss these products in this article. According to the advocates of smart drugs on the Net, these drugs should be used to enhance many mental and physical functions and to combat ageing in general. The drugs are 'natural' and have a low toxicity and a broad therapeutic window. 

What drugs are advertised via the Net? Selegiline and androstenedione as aphrodisiacs, metformine against wrinkling of ageing skin, phenytoin to improve memory, intelligence, learning and concentration, gamma-hydroxybutyrate (GHB) to increase sexual desire, creatine to increase muscle mass, hormones such as dihydroepiandosterone and pregnenolone as fountains of eternal youth, melatonin as a hypnotic, anti-jet lag drug and to combat ageing in general. Other drugs belonging to the smart drugs are the class of nootropics (aniracetam, oxiracetam, piracetam, and hydergine) and a variety of different drugs such as modafinil, vasopressin, L-tryptophan, tacrine, ondansetron, growth hormone, propranolol, centrophenoxine, parlodel, yohimbine and many more (see Table). Many of these drugs are psychotropic drugs and tinker with the neurotransmitter systems. The dopaminergic, noradrenergic or cholinergic pharmacological activity they have might pose a serious threat for the patients using these drugs together with psychiatric Rx drugs. It is amazing that all of these drugs are freely and easily accessible via global mail order companies that ship these drugs to customers all over the world after having obtained an order via the Net. 

The many general statements about these drugs in the Net all try hard to point out that smart drugs are all effective, many of them replacing natural hormones or certain chemicals in the brain that decline with normal ageing. They claim that research clearly indicates that smart drugs are among the safest in the world and that these drugs work as indicated, proven by many thousands of studies conducted over the past decades. 

The use of these drugs is further stimulated by many popular books with fantasy titles such as 'Better thinking through chemistry', 'Brain Boosters, foods & drugs that make you smarter', 'Mega brain power', 'The way up from down', 'The superhormone promise', 'DHEA, fountain of youth', and many more. For certain drugs there are specialised books, with a clear focus only on the miraculous aspects of these drugs, for instance melatonin3 4 5 6. Specialised newsletters can be ordered via the net, such as 'Smart drug news: the newsletter of the Cognitive Enhancement Research Institute'7. Even serious magazines publish articles on smart drugs, without being critical8 9. 

In December 1997, JAMA discussed the results of the ad hoc working group installed by the WHO to explore the sale of medical products on the Net10. The report of this ad hoc group, entitled 'Cross-border advertisement, promotion, and sale of medical products through the Internet' warned that the safety and confidence of the public is undermined by the uncritical advertisements on the Net. The ad hoc group recommended member nations to set up mechanisms to monitor and survey cross-border advertisement, promotion and sale of medical products on the Net and urged member nations to take regulatory actions in case national laws were violated. The recommendations are the first step to solve this very complicated problem. There is a considerable lack of information and insight within the medical community concerning this issue, and few articles have so far addressed this problem11 12. Thus, the first step towards finding solutions will be to inform physicians and pharmacists about this emerging problem. This will enable them to inform patients about the ramifications of these smart drugs for their health. 

In this article, we will review claims and indications for some drugs which are of interest for the psychiatrist, as these drugs have an impact on neurotransmitter systems and a potential for abuse and dependency. We will thus focus on L-deprenyl or selegiline and gamma-hydroxybutyrate.

Classes of Smart Drugs

As already stated in the introduction, a variety of drugs with different pharmacological activities are all listed under the nonspecific term smart drugs. In the strict sense, smart drugs are the classical nootropics. Many of these drugs are on the market in Europe, South America, Asia and the eastern European countries. The safety profile of these drugs is widely known and in general does not pose a threat. Drugs such as hydergine and piracetam have been used since the 1970s. The efficacy of these drugs is most probably only marginal (if there is efficacy at all), in patients suffering from Alzheimer's disease and only few well controlled trials have been published using state of the art methodology13. Most of these drugs were evaluated in the 70s and 80s without proper neuropsychological tools, and only sparse positive information has been published. Most probably, many of the negative trials have not been published thus far, due to the publication bias for such trials. The efficacy of these drugs in patients is already debatable. The use of nootropics in healthy individuals as suggested on the Net has never been proven to be of any use. No double blind, placebo controlled trials in healthy volunteers of enough power have been published assessing the safety and efficacy of these drugs using modern, validated neuropsychological test batteries. The studies referred to on the Net by the smart drug advocates are mostly published in non peer-reviewed, obscure journals and in proceedings of congresses. The facts presented in those papers are over-interpreted by the advocates of smart drugs. Furthermore facts to support their use in man have been extrapolated from animal pharmacology without too much knowledge of the problems of many of the animal models used. 

A more worrying class being used as smart drugs are the psychotropic drugs. Especially if these drugs are used in combination with psychiatric medications, pharmacokinetic and pharmacodynamic interactions are to be expected. 

The third group of drugs are hormones. Some of these hormones, such as dihydroxyepiandosterone and pregnenolone, are precursors for the synthesis of testosterone and oestrogens. Endocrinologists would be horrified if they knew that these potent steroids, as well as potent hormones such as vasopressin, are being used as smart drugs and are freely available via the Net. 

The fourth group of drugs is a waste basket containing drugs such as metformine or propranolol together with vitamins, minerals and herbal products. The table lists these 4 classes with a few examples from each class. 

Table: Some of the smart drugs promoted on the Net

Psychotropic drugs Nootropics  Hormones  Others 
deprenyl 

parlodel 

methylphenidate 

adrafinil 

modafinil 

sibutramine 

L-tryptophan 

serotonin 

dexfenfluramine 

gammahydroxy- 

butyrate (GHB) 

yohimbine 

ondansetron 

nimodipine 

S-adenosyl-metionine 

hydergine 

piracetam 

pramiracetam 

vincamine 

oxiracetam 

aniracetam 

vinpocetine 

dimethylamino-ethanol (DMAE) 

cyprodenate 

idebenone 

acetyl-l-carnitine

DHEA 

pregnenolone 

melatonin 

vasopressin 

human growth hormone 

metformin 

propranolol 

coenzyme Q 

NADH 

Ginko biloba 

L-carnitine 

vitamin complexes 

Echinacea 

Kava-kava 

Selegiline (l-deprenyl): broad mental and physical anti-ageing properties

Selegiline is promoted on the Net as a potential sexual invigorator and more generally as an antiageing therapy. 

Selegiline is an irreversible type B selective monoamine oxidase inhibitor (MAO-B inhibitor), approved for the treatment of Parkinson's disease. Comparable to another smart drug, widely promoted to boost memory, phenytoin, selegiline has high protein binding. This is the basis for potential pharmacokinetic interactions with compounds such as digitoxin and coumarin derivatives. The compound is only selective for the MAO-B enzyme in the low dosage range, and above 10 mg per day it loses its selectivity quickly and also inhibits MAO-A, potentially leading to the classical problem of hypertensive reactions14. Combined with serotoninergic compounds, the potentially dangerous serotoninergic syndrome can occur15. This syndrome is characterised by agitation, confusion, nausea, diarrhoea, hyperreflexia, tremor, rigidity, autonomic dysregulation, and coma, leading to massive rhabdomyolysis and death. This syndrome can be provoked if the patient takes a smart drug like selegiline and is treated with a serotoninergic drug such as a serotonin uptake inhibitor, tricyclic antidepressant, tetracyclic antidepressant, tryptophan, amphetamine, dextromethorphan, meperidine, or S-adenosylmethionine. A variety of these drugs belong to the class of smart drugs, which increases the likelihood of interactions, since experiments with cocktails of these drugs is recommended at various sites on the Net. 

The suggestions and arguments put forward on the Net to promote selegiline are of a simple structure. It needs to be emphasised that selegiline will be pushed even harder on the Net following the recent publication of positive results in Alzheimer patients and its potential anti-apoptotic effect16 17. 

These are the arguments put forward to support the use of selegiline as an anti-ageing drug: 

  • Selegiline protects against the death of neurons by combating free radical mediated damage and by its anti-apoptotic effects 
  • Selegiline inhibits MAO-B and reverses the age-related increase of MAO-B, which degrades dopamine. Dopamine is a key neurotransmitter and loss of it dampens our mood and our sex drive 
  • Each decade after the age of 40, 10% of all dopaminergic neurons die 
  • Selegiline in vivo slows microanatomical changes in the ageing brain such as lipofuscin accumulation 
  • Selegiline extends the life span of neurons by boosting antioxidant enzyme levels and thus protects against free radical damage 
  • Selegiline in Alzheimer patients improves mental functioning, especially memory, verbal communication and daily-living skills 
  • Selegiline extends life span in rats 
Based on these 'facts', the recommendation is that deprenyl protects against the death of dopamine producing neurons and thus it should be part of a life extension programme for anyone over 40 years of age18. 

In addition to these 'scientific claims' supporting its use on healthy individuals, personal statements can be found like: 'Seligiline is amazing! A very mentally speedy feeling, a bit odd, but you get used to it. It is almost like a cleansing, sometimes like cocaine, sometimes like LSD-25'19. This clearly indicates a potential for selegiline becoming a drug of abuse. The strong claims on the Net that this drug can be used as an aphrodisiac and as a drug to prolong and intensify life, without having troublesome side effects, and the comparison to cocaine and LSD will induce drug abuse20. 

Gamma-hydroxybutyric acid: do it yourself kit 

This drug is known in Europe as Gamma-OH and in the US as GHB, and is supposed to be a compound that increases sociability and functions as an antidepressant. It belongs to the class described in the Net as sociabilisers, among which we can also find MDMA. GHB is alo referred to as the golden drink, or in French: 'or potable'. The properties advertised on the Net are: 
  • depression is replaced by an exhilarating feeling of joy and happiness 
  • anxiolytic and useful against panic attacks 
  • suppresses suicidal ideas within hours 
  • inhibits aggression 
  • enhances recall of old memories and dreams 
  • enhances feelings of love and acts as a true aphrodisiac 
GHB was available as an OTC (over the counter) drug up to 1990 and was mostly sold in health food stores. The FDA warned the public about the dangers of this drug, and the manufacture, distribution and promotion of GHB was made illegal in the US in 1990 and in a variety of other countries after reports of severe side effects including death. 

The Net has now induced a revitalisation of the GHB dream. Using beautiful clear blue and transparent ads, GHB kits, referred to as 'a pure source' are offered. These kits contain ingredients A and B 'purest ingredients only' and yield 90 grams of GHB for 80 US $. Even more dangerous are techniques described on the net for manufacturing GHB at home, 'kitchen optimised GHB synthesis'. As GHB is not legal to sell, most 'ready for use' GHB stems from small laboratories or from home chemists, and the purity and quality is not guaranteed at all. For instance, one step in the synthesis is to add sodium hydrochloride and hydrochloric acid. Not mixing the correct amounts will result in an extremely basic or acid mixture which can burn the mouth and oesophagus after ingestion! 

Furthermore, as GHB has a narrow therapeutic margin, batches produced in this way can contain different amounts of GHB and there is a risk of overdose. 

The adverse events profile of this drug include epileptic fits, coma, anxiety, somnolence, confusion, agitation, hallucinations and even respiratory and cardiac arrest21. The drug also induces physical dependence and a withdrawal syndrome may occur. There is a clear abuse potential based on its euphoric, sedative and anabolic effects. Interactions with alcohol are known and the effects of the drug are potentiated. There is an Internet site prepared by physicians of the University of Florida containing a very clear question and answer catalogue. This is one of the very few examples of balanced information about this drug on the Net22. 

Smart drugs: stupid drugs, a problem inventory 

As we have seen, there are many potential problems if one uses smart drugs. 
  1. A variety of drugs are characterised by a small therapeutic window, for instance phenytoin or gamma-hydroxybutyrate. Thus there is a considerable risk of overdosing and toxicity may emerge. 
  2. Their purity is not guaranteed, uncharacterised by-products of the production process may contaminate the formulations on offer, and these by-products may be toxic23. 
  3. Their quality is not guaranteed, as a result insufficient biological availability (phenytoin is infamous) and there is a risk of overdose if one starts to take more if the expected effect does not occur immediately. 
  4. The risk of abuse, overdosing and dependency (selegiline, gamma-hydroxybutyrate)24. 
  5. Many of the drugs will be delivered to the customer in packages with insufficient information or no package inserts, and the drugs may already have expired. 
  6. Consumers may not realise that they are using a drug with pharmacological activity which might interact with Rx drugs and might thus not inform their treating physician about their recreational use. 
  7. The safety and tolerability of many smart drugs has not been demonstrated and has not been peer-reviewed. 
  8. Especially its long term use has not been demonstrated to be safe. 
  9. The benefit-risk ratio of many of the smart drugs is negative: If they are to be taken by healthy individuals, the drugs need to be very safe, especially since the benefits are debatable and still insufficiently proven. 
  10. If adverse effects occur, the consumer is not protected, since the manufacturer will claim no liability and will often not be resident in the consumer's home country. 

Conclusion

Smart drugs available via the Net are of increasing concern. Their efficacy in healthy individuals is not proven and the proof offered on the Net is of a simple structure and is not peer reviewed. Most arguments are based on extrapolation of in-vitro or in-vivo animal experiments or are based on epidemiological data. Proof of the efficacy and safety of many of these drugs has not been generated in well controlled, methodologically sound experiments. The arguments supporting the use of smart drugs as boosters for all kinds of functions must sound like sweet music in the ears of the consumers, but the dark sides of the recreational use of these drugs is not discussed sufficiently at all. Especially psychiatrists and family practitioners should be aware of this source of drugs, since many of these drugs have a narrow therapeutic margin and can interact negatively with a variety of other Rx drugs. The problems of side effects, abuse and dependency are rarely discussed on the Net, and only the sunny side of the use of smart drugs is advertised. 

The recent recommendations of the WHO concerning the sale and advertisement of medical products on the Net should be taken seriously, and more offensive strategies to inform public and health workers about smart drugs should be developed.

References

  1. Carson WH, Markowitz JS. 'Smart Drugs'? Ann Clin Psychiat 1996;8:41-2. 
  2. NN. Smart Drug News, The newsletter of cognitive enhancement and longevity'. http://www.ceri.com/sdnews.htm. 
  3. Robinson J. Melatonin: Your Body's Natural Wonder Drug. New York: Bantam Books,1995 
  4. Pierpaoli W, Regelson W. The Melatonin Miracle. New York: Simon & Schuster,1995 
  5. Sahelian R. Melatonin: Nature's Sleeping Pill. Marina Del Rey: Be Happier Press, 1995 
  6. Bock SJ. Stay Young the Melatonin Way. New York: Dutton, division of Penguin Books, 1995. 
  7. The institute. 'Smart drug news: the newsletter of the Cognitive Enhancement Reserach Institute' ISSN 1060-8427 
  8. Cowley G. Melatonin: it's the hot sleeping pill.. Newsweek 1995, August 14: 44-46 
  9. Springen K, Peyser M. The new muscle candy. Newsweek 1998, January 12. 
  10. Skolnick AA. WHO considers regulating ads, sale of medical products on Internet. JAMA 1997;278:1723-1724 
  11. Baker LS "Smart drugs": a caution to everybody. Am J Psychiatry. 1996 Jun 1; 153(6): 844-845 
  12. Carson WH, Markowitz JS. "Smart drugs"? Ann Clin Psychiatry. 1996 Mar 1; 8(1): 41-42 
  13. Thal LJ, Carta A, Clarke WR et al. A 1-year multicenter placebo-controlled study of acetyl-l-carnitine in patients with alzheimers-disease. Neurology 1996;47: 705-711 
  14. Sunderland T, Cohen RM, Molchan S, Lawlor BA, Mellow AM et al. High-dose selegiline in treatment-resistant older depressive patients.Arch Gen Psychiatry 1994;51:607-615 
  15. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705-13 
  16. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study N Engl J Med 1997;336:1216-1222 
  17. Paterson IA, Tatton WG. Antiapoptotic actions of monoamine oxidase B inhibitors. Adv Pharmacol 1998;42:312-315 
  18. Smartnet@sirius.com.Smart basic drugs glossery data field: Deprenyl. 
  19. The entheogen Explorer Home page: http://www.entheogen.com/explorer/deprenyl.htm 
  20. Schneider LS, Tariot PN, Goldstein B. Therapy with l-deprenyl (selegiline) and relation to abuse liability. Clin Pharmacol Ther. 1994; 56: 750-756 
  21. Chin MY, Kreutzer RA, Dyer JE. Acute poisoning from gamma-hydroxybutyrate in California. West J Med 1992;156:380-384. 
  22. Okun MS. In defense against GHB. Drugs@lycaeum.org 
  23. Williamson BL, Tomlinson AJ, Naylor S, Gleich GJ. Contaminants in commercial preparations of melatonin. Mayo Clin Proc 1997 Nov;72(11):1094-1095 
  24. Galloway GP, Frederick SL, Staggers FE et al. Gamma-hydroxybutyrate: an emerging drug of abuse that causes phasical dependence. Addiction 1997;92:89-96