The diffusion of performance and image-enhancing drugs (PIEDs) on the internet: the abuse of the cognitive enhancer piracetam.

Introduction: Performance and image-enhancing drugs (PIEDs), also known as “lifestyle drugs,” are increasingly sold on the Internet to enhance cognitive as well as sexual, muscular, attentive, and other natural capacities. Our analysis focuses on the misuse of the cognitive enhancer piracetam. Methods: A literature review was carried out in PsychInfo and Pubmed database. Considering the absence of peer-reviewed data, review of additional sources of unstructured information from the Internet was carried out between February 2012 and July 2013. Additional searches were conducted using the Global Public Health Intelligence Network (GPHIN), a secure Internet-based early warning system developed by Health Canada and the World Health Organization (WHO), which monitors media reports in six languages, Arabic, Chinese, English, French, Russian, and Spanish. Results: Piracetam is sold via illicit online pharmacies with no need of prescription at low prices. Buyers, mainly healthy individuals, purchase the product to enhance study- and work-related performances as well as for recreational purposes. Its nonmedical use is often associated with the occurrence of side effects such as hallucinations, psychomotor agitation, dysphoria, tiredness, dizziness, memory loss, headache, and severe diarrhoea; moreover, several users declared to have neither felt any cognitive improvement nor psychedelic effects. Conclusions: This is a new and fast-growing trend of abuse that needs to be extensively monitored and studied also by using near real-time and unstructured sources of information such as Internet news and online reports in order to acquire rapid knowledge and understanding. Products sold online might be counterfeits and this enhances related health risks.


INTRODUCTION
In recent years, a rapidly spreading of substances known as 'Performance and image-enhancing drugs' (PIED), also known as 'lifestyle drugs', has been recorded (Evans-Brown, McVeigh, Perkins, & Bellis, 2012). PIEDs are mainly sold online, via illicit online pharmacies, as the most immediate way to enhance cognitive, sexual, muscular, attentive, and other natural capacities, even if their level of safety, composition, and legal status are mostly unknown (European Monitoring Centre for Drugs and Drug Addiction [EMCDDA], 2010; EMCDDA, 2011; Advisory Council on the Misuse of Drugs [ACMD], 2011; Corazza et al., 2011;Schifano et al., 2006;Larance, Degenhardt, Copeland, & Dillon, 2008). These also include a wide range of pharmaceutical products, which can be bought without a prescription and at discounted prices, such as Pregabalin and Adderall (Orizio et al., 2009;Littlejohn, Baldacchino, Schifano, & Deluca, 2005).
In particular, this article will focus on piracetam, a cognition enhancer, which has been abused by healthy individuals to enhance their functions in study-and workrelated performances Schifano et al., 2003).
Piracetam is a cyclic derivative of the neurotransmitter γ -aminobutyric acid (GABA), originally marketed in 1971 by UCB Pharma. It was the first 'nootropic' drug (Giurgea, 1972), an agent that acts on cognitive function 1850 O. CORAZZA ET AL. without causing sedation or stimulation (Winblad, 2005). It was found originally to be effective as a protective agent in hypoxia-induced amnesia.
Although piracetam is a derivative of GABA, its mechanism of action appears to be unrelated to the properties of this neurotransmitter. Piracetam affects a number of neuronal proteins; some evidence suggests that piracetam can act at the α-amino-3-hydroxy-5methyl-4-isoxazole-propionic acid (AMPA) receptor as an allosteric modulator binding in six different positions (Ahmed & Oswald, 2010) and that it may have an effect on N-methyl-D-aspartate receptor (NMDA) glutamate receptors (Cohen & Müller, 1993). However, although the exact mode of action of piracetam is a matter of debate, there is increasing evidence that its underlying effect is to restore cell membrane fluidity (Fassoulaki, Kostopanagiotou, Kaniaris, & Varonos, 1985;Peuvot, Schank, Deleers, & Brasseur, 1995). Restored membrane fluidity induced by piracetam may have a number of physiologic consequences including restored neurotransmission (Winblad, 2005), increased oxygen consumption in the brain (Jordaan, Oliver, Dormehl, & Hugo, 1996), enhanced neuroplasticity (Brandao et al., 1996), neuroprotection (Brandao, Paula-Barbosa, & Cadete-Leite, 1995), and anticonvulsant action (Benesova, 1980). Consistent with its varied pharmacologic effects, piracetam has documented benefit in a diverse range of indications. The largest amount of data is about the therapeutic use of piracetam to treat early Alzheimer's disease and age-associated memory impairment (Waegemans et al., 2002); a large meta-analysis of all available clinical studies provided compelling evidence for the global efficacy of piracetam in a diverse group of older subjects with cognitive impairment (Waegemans et al., 2002). This proposal was later supported by observations that piracetam specifically enhances membrane fluidity in aged brain material, showing no effect in membranes from young brains (Müller et al., 1997).
Piracetam doses usually range between 2.4 g/die and 8 g/die, and even if used in the treatment of cortical myoclonus, it can be administered at higher dosages (up to 24g/die) (Winblad, 2005).
In this context, the present study aims to identify and investigate the nonmedical use of piracetam, while collecting unprecedented information on its psychoactive effects.

MATERIALS AND METHODS
The literature on piracetam misuse was searched in Psych-Info and Pubmed databases. Considering the absence of peer-reviewed data on its misuse, results were integrated with a multilingual qualitative assessment of a range of websites, drug fora and other online resources (i.e.: newsgroups, chat-rooms, mailing lists, e-newsletters, bulletin boards and videos). Between February 2012 and July 2013, exploratory qualitative searches of 227 websites have been carried out in English using generic and specific keywords, such as "legal highs", "research chemicals", "online pharmacy", "piracetam", and "nootropil" in the Google search engine. These websites were monitored on a regular basis, daily (n = 32), weekly (n = 168), or monthly (n = 27) depending on relevance. Links from forums, websites, and other related material, including newspapers and magazines, were followed as well. Additional searches were carried out in the database provided by the Global Public Health Intelligence Network (GPHIN). This is a secure Internet-based early warning system that gathers preliminary reports of public health significance by monitoring global media sources in near 'real-time', 24 hours a day, on 7 days a week basis. GPHIN is operated by the Public Health Agency of Canada, and monitors news sources and websites across the globe in nine languages (e.g. English, French, Farsi, Portuguese, Arabic, Russian, Spanish, and Chinese simplified/traditional) (Keller et al., 2009). Although a series of algorithms are used and adjusted to capture relevant information, analysis of relevant data since 2003 was also carried out manually by a multidisciplinary and multilingual team of analysts. Permission for the study was granted by the School of Pharmacy Ethics Committee, Hatfield, UK (15 December, 2010; PHAEC/10-42).

RESULTS
Piracetam is sold online via illicit websites with no need for prescription (see Table 1). Some retailers require an initial 'online consultation' with an unknown 'cyberdoctor' before shipping their products in return for online credit-card payment. Products are then sent directly to the buyers, but these are often counterfeits as recently alerted by the US Food and Drug Administration (FDA) (2010).
Prices of piracetam vary according to the retailers from approximately 0.70 to 1.10 € for 1 gram; it is mainly sold in form of tablets and bulk powder (Nootropic reviews, 2013; Nootrabiolabs, 2013) (Table 1). Videos on the YouTube featuring how to use piracetam, where to get it, its effects and its dosages also emerged from our searches (Piracetam Smart Drug Secret, 2010; Smart drugs make learning easier, 2010; Piracetam Review, 2011).
A summary of the characteristics of the nonmedical use of piracetam is showed in Table 2.

Piracetam as a Cognitive Enhancer for Nonmedical Purposes
Piracetam appears to be widely used by healthy individuals to enhance cognitive functions in study-and work-related performances. The majority of the users report satisfactory improvements in different cognitive functions including learning, memory, concentration, and 'verbal intelligence'. It is taken orally with dosages up to 9.6 g/die. It is often assumed in concomitance with other psychoactive supplements including choline, caffeine, Adderall, and acetylcarnitine (Drugs-forum, 2006a;Longecity, 2007;Brainmeta, 2011). A selected number of personal accounts has been reported in Table 3.

Piracetam as a Recreational Drug
In addition to its cognition-enhancing features, piracetam is widely used from polydrug abusers for its psychedelic properties. According to online anecdotal reports, it has hallucinogenic and mood-improving effects and appears to enhance dream experiences. It is taken orally at dosages up to 80 g/die or through nasal insufflations at dosages up to 7 g/die. Piracetam is often ingested in combination with other recreational drugs to enhance its desired effects as well as to reduce the emergence of unwanted negative effects and improve sensory feelings. In particular, accounts about its concomitant use with ketamine, methamphetamine, LSD, cocaine, alcohol, and kratom have been recorded (Drugs-forum, 2005;Drugs-forum, 2006b;Drugs-forum, 2009a;Drugs-forum, 2009b;Drugs-forum, 2011;Erowid Experience Vault, 2007;Erowid Experience Vault, 2008). Some relevant user experiences are mentioned in Table 3.

Unwanted Effects
Several misusers reported unwanted side effects related to piracetam. The severity of the effects seems to be dosedependent; however, as the online sources can be imprecise, it is not possible to postulate a clear relation between dosages and effects. The unwanted side effects reported from piracetam misusers include psychomotor agitation, dysphoria, 'feeling weird', tiredness, dizziness, memory loss, headache, and severe diarrhoea; moreover, several users declared to have neither felt any cognitive improvement nor psychedelic effects (Drugs-forum, 2005; Drugsforum, 2006b; Drugs-forum, 2011).

DISCUSSION
To the best of our knowledge, this is the fist study on the nonmedical use of piracetam, which uncovers previously unknown psychoactive effects.

Reasons Descriptions
Online availability Piracetam is easy to purchase over the Internet, where it is sold at a discounted rate and may be adulterated Price Prices of piracetam sold online vary from about 0.70 to 1.10 € for 1 gram; Effects Improvement in learning, memory, concentration, and "verbal intelligence"; hallucinations; mood improvement; enhancement of dream experiences Dosages and way of assumption As a cognitive enhancer it is taken orally with dosages up to 9.6 g/die. As a psychedelic drug it is taken orally at dosages up to 80 g/die or through nasal insufflations at dosages up to 7 g/die Use in combination with other substances It is often consumed in concomitance with other cognitive enhancers such as choline, caffeine, Adderall, and acetylcarnitine or other psychoactive drugs such as ketamine, methamphetamine, LSD, cocaine, alcohol, and 'kratom'/Mytragina speciosa Side effects Psychomotor agitation, dysphoria, "feeling weird", tiredness, dizziness, memory loss, headache, and severe diarrhea Misusers Misusers are generally students who use piracetam to improve their cognitive performances and/or polydrug abusers who use it to experience a range of psychedelic states  (Longecity, 2007). I take 1.2-1.6 g of piracetam 3 times a day 4-5 hours spaced out between dosages. I take around 1.5-2.1 g of choline bitartrate with my breakfast. I would also add some acetyl-l-carnitine to the mix, around 1-3 g a day. The dosage, I believe, have a whole lot to do with the end-product you will experience. Superhuman memory? Well, just as a little marker of results, I've been periodically tested my digit span on the braingle site. I'm up to 14 now (Treato, 2013). I've used 1000mg of piracetam with 500mg choline source. It works, whatever that means. You feel more articulate and you can literally feel your head throb. I found improved verbal intelligence more than anything. Everything seemed to require less effort, there were less mental blocks etc. I noticed my typing speed improved, although I made more spelling errors (Brainmeta, 2011). SWIM often used caffeine (500-600 mg) with an attack dose of piracetam (8000 mg) for staying awake at night for learning. The combo works well, it really helps SWIM focus (Drugs-forum, 2006b). (Erowid Experience Vault, 2008). The most worthwile use SWIM has found for this substance was for enhancing dreams. 1-2 g taken before going to bed was found to enhance dream recall and vividness, helping SWIM wake more often with the feeling that the night had been at least as long and eventful than the day before in waking reality (Drugs-forum, 2008).

Effects of piracetam in combination with other recreational drugs
Yet all of Piracetam + LSD trips had one thing in common − they were profoundly powerful, although LSD dosage was 1/4 to 1/2 of what I usually take without Piracetam (Erowid Experience Vault, 2001). It increases many folds effects of stimulants and hallucinogens, while decreases or eliminates negative symptoms (Erowid Experience Vault, 2001 Prescription drugs such as piracetam are, nowadays, widely accessible on the Web through online pharmacies . These are often illicit; they do not guarantee drug quality and, in 81.4% of cases, they sell medications without any medical prescription (Orizio et al., 2009;Littlejohn, Baldacchino, Schifano, & Deluca, 2005). Marketing strategies are used to appear as professional and trustable health websites while showing pictures of doctors or licensed pharmaceutical products. In this context, it appears clear why the issue of the misuse of prescription drugs is continuously becoming more relevant Schifano et al., 2011;.
In terms of misuse, piracetam can be considered both a 'common' recreational and a performance enhancing drug (Graham et al., 2009) taken with the aim to enhance personal and professional performances. At the same time, as it has emerged from this study, users seem to be aware that they are doing something unhealthy; for this reason, they are alerted about possible adverse reactions that these products might induce and they are usually prepared to ask medical assistance, when necessary. However, they do not consider themselves drug addicts. This can lead to various health risks, including the consumption of pharmaceutical products without any medical supervision, or counterfeit medicines containing unknown and possible toxic contaminants.
The misuse of piracetam to achieve enhanced professional results was found to be particularly popular; several reports were written in Italian (TGMOnline, 2008;Myhelpforum, 2012), and a range of related YouTube videos were also identified (Piracetam Smart Drug Secret, 2010; Smart drugs make learning easier, 2010; Piracetam Review, 2011). Most of the users feel safe with piracetam and think that it can be taken at any dosage without any risk; this attitude probably stems from the high dosages of piracetam usually prescribed by physicians (expressed in grams and not in milligrams) and from the general idea that something that is legal (and openly available for sale on the Internet) must necessary be safe . Conversely, the misuse of piracetam as a recreational drug seems to be limited to individuals, often marginalized, with a history of recreational polydrug misuse.
From a clinical point of view, although cases of piracetam dependence have not been described, physicians should be aware of piracetam misuse issues, so that signs and symptoms of possible piracetam side effects may be recognized. Moreover, as piracetam is often sold through unreliable online sources, misusers may present with an increased risk of ingesting a range of adulterated products with potential toxic effects (Evans-Brown, McVeigh, Perkins, & Bellis, 2012).
When considering the question of who might use online pharmacies to buy piracetam or other drugs, it is possible to identify at least three prerequisites. These are (1) literacy: using the Internet to order drugs requires basic literacy and numeracy skills; (2) Internet access: the largest increase in Internet access has been seen in those with the highest incomes; and (3) credit card ownership. In summary, these misusers are most likely to come from the socioeconomically privileged sections of society, where high levels of education and employment are likely to be the rule rather than the exception. For these reasons, the stereotypical image of the 'drug-abusing patient' may need to change, in favor of a new class of 'expert' patients who use a website to obtain a self-diagnosis and a treatment, often without medical prescription.
One could wonder about the limitations of carrying out a risk of misuse assessment of a drug while taking into account the online comments only; in fact, it may be inappropriate to trust information obtained from the Internet without independent verification. However, in the absence of relevant peer-reviewed data, this seems to be the only valid method to obtain preliminary information about new and emerging phenomena (Schifano et al., 2003;Corazza et al., 2013); moreover, the Web monitoring has proved that Internet is an important source of information for understanding users' point of view about the effects of drugs: writing in a Web forum allows the user to hide his/her identity and to comment without any hesitation. Giovanni Martinotti is currently Senior Researcher in Psychiatry and Academic Lead of the Research Unit on Addiction at the Department of Neuroscience and Imaging, University "G.d'Annunzio" of Chieti-Pescara. In his career, he has developed a strong clinic and academic expertise in the field of substance abuse, as well as other forms of addiction including pathologic gambling and behavioral addictions. He is author/coauthor of more than 180 papers on peer-reviewed journals with impact factor and he has published 11 books as editor and one monograph. He is also associate editor of different scientific journals. He has recently been elected president of the Young Section of the Italian Society of Psychiatry.
Professor Fabrizio Schifano is one of the very few physicians with training and specialist qualifications in both psychiatry and clinical pharmacology and has contributed to the biomedical science as well as the clinical science of addiction. He has also made a significant contribution to several areas in addiction psychiatry and general psychiatry, including: stimulant synthetic drugs, mortality studies (Professor Schifano co-supervises and co-leads the National Programme on Substance Abuse Deaths (npSAD)), the Internet and drugs. This is a new area of research and Professor Schifano is the Principal Investigator of the third consecutive EU Commission-funded, multi-centre Psychonaut/ReDNet research programme. Results from these studies have provided the only comprehensive and multilingual analysis of the information available online on psychoactive compounds to date.

GLOSSARY
Cognitive enhancers: Cognitive enhancers are drugs to treat cognition deficits mainly used in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention-deficit hyperactivity disorder, or aging.

Nootropics:
The term nootropics was coined by the father of piracetam Corneliu Giurgea in 1972; it derives from the Greek words "nous", meaning "mind", and tropein, meaning "to bend/turn". Novel psychoactive substances: Novel (or new) psychoactive substances (NPS) are an ever-increasing group of synthetic, semi-synthetic, or natural compounds, often advertised and sold as 'legal' and 'safer' alternatives to illicit drugs. Online pharmacies: Online pharmacies are often illicit online shops selling medications of possible counterfeit nature without any medical prescription or control. PIEDs: Performance and image-enhancing drugs (PIEDs) are a range of substances used to enhance cognitive as well as sexual, muscular, attentive, and other natural capacities. Piracetam: Piracetam is a cyclic derivative of the neurotransmitter γ -aminobutyric acid (GABA). It was the first "nootropic' drug, originally marketed in 1971 by UCB Pharma. Recreational Drugs Use: Recreational drug use is the use of a drug (legal, controlled, or illegal) with the intention of enhancing life (increasing euphoria, blocking unhappy memories, or creating pleasure).