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European Union's EMCDDA Scientific Committee's
Report on the Risk Assessment of 2C-I
in the Framework of the Joint Action on New Synthetic Drugs
by EMCDDA Scientific Committee
Apr 1, 2003
Citation:   Scientific Committee of the EMCDDA. "Report on the Risk Assessment of 2C-I in the Framework of the Joint Action on New Synthetic Drugs". http://www.emcdda.eu.int/policy_law/joint_action_nsd/risk_assessment.shtml. 1 Apr 2003.
NOTE: This Scientific Committee's findings were acted on by the European Council in November/December 2003, when the Council passed a rule ordering the control of the chemicals studied by this Scientific Committee. See Council of the EU Orders Ban of 2C-I, 2C-T-7, 2C-T-2 and TMA-2.


On 12 December 2002, the Horizontal Working Party on Drugs of the Council of the European Union (HWPD) decided that risk assessment of four new synthetic drugs, 2C-T-2, 2C-T-7, 2C-I and TMA-2 should be initiated. On 20 December 2002, in accordance with practice under the 1997 Joint Action, the Danish Presidency formally notified to the EMCDDA the decision of the HWPD to submit 2C-T-2, 2C-T-7, 2C-I and TMA-2 for risk assessment under Article 4 of the Joint Action on new synthetic drugs of 16 June 1997.

A meeting of the Scientific Committee of the EMCDDA extended with experts nominated by the Member States and representatives of the European Commission, Europol and the EMEA to assess the health and social risks as well as the possible consequences of prohibition of 2C-T-I was held on 31 March - 1 April 2003.

The meeting considered the following documents:

I. Review of the pharmacotoxicological data for the risk assessment of 2C-I. Report to the EMCDDA.
II. Public health risks: epidemiological evidence, EMCDDA
III. Sociological/criminological evidence, EMCDDA
IV. Europol contribution to the risk assessment on 2C-I


These documents in conjunction with further information and comments from the expert participants formed the basis of the risk assessment which is reported below.

1. CHEMICAL DESCRIPTION

2C-I is 2,5-dimethoxy-4-iodophenethylamine. Other chemical names include; 4-iodo-2,5-dimethoxyphenethylamine, (2,5-dimethoxy-4-iodophenyl)-2-aminoethane and 4-iod-2,5-dimethoxyphenethylazan.

The synthesis of 2C-I is described in PiHKAL based on initial use of 2,5-dimethoxybenzaldehyde to eventually produce a preliminary precursor, 2,5-dimethoxyphenethylamine (2C-H). The former compound 2,5-dimethoxybenzaldehyde is commercially available. The method is extensive, requiring specialist equipment and an appropriate environment. It is not clear as to the exact method of synthesis used by clandestine laboratories.

At present, 2C-I has no medical or industrial use.

2. PHARMACEUTICAL DESCRIPTION

2C-I is typically available as a powder or tablet, although 2C-I in liquid form has also been noted by the Danish Focal Point. A seized tablet was white in appearance, had an "i" logo and was approximately 6.1 mm x 2.7 mm, weighing 120 mg (Denmark 2002).

As 2C-I is obtained in the form of a powder or tablet, the primary route of administration is oral. Insufflation (snorting) and other additional routes (e.g. intravenous administration) are not mentioned in 2C-I user reports. Original studies by Shulgin involved oral administration of 2C-I doses between 15-20 mg. User reports have mentioned oral doses between 3-25 mg (typically 20 mg).


3. HEALTH RISKS

(Documents I and II)
3.1 Individual Health Risks
(a) Acute Effects
Little scientific evidence related to the activity of 2C-I on neurotransmitter systems has been yet published. Therefore, information on the neuropharmacological aspects discussed in the risk assessment meeting was based on speculative comparison with partially related compounds such as 2C-B (phenethylamine-based) and DOB (amphetamine-based), both involving bromine as opposed to iodine.

Studies involving a bromine-substituted analogue, 2C-B (4-bromo-2,5-dimethoxyphenethylamine) have shown it to be a partial agonist for 5-HT2 (5-HT2A and 5-HT2C) serotonergic receptors and a1-adrenergic receptors. At 10-6M, 2C-B also acted as a competitive 5-HT antagonist but at higher concentrations (2.8x10-5M) acted as a non-competitive 5-HT antagonist. In addition, DOB (4-bromo-2,5-dimethoxyamphetamine) was found to have high affinity for 5-HT2 receptors, whereas 2C-B was also found to have significant affinity to 5-HT1A, 5-HT1B and 5-HT1C receptors and thus was deemed to be less selective than its amphetamine-based analogue, DOB.

A recent study found 2C-I to have higher agonistic efficacy at 5-HT2C receptors compared to 5-HT2A receptors. However, further studies are required before definitive conclusions can be made.

No other specific research has been performed using 2C-I. Serotonin agonists stimulate hypothalamic neurons involved in ACTH and cortisol secretion in addition to stimulation of growth hormone and prolactin secretion (as evidenced by mescaline and DOM). It is possible, therefore, that 2C-I may produce similar effects on hormonal secretion.

Concerning the cardiovascular and thermoregulatory responses, there is also only very limited subjective evidence available from user surveys on the Internet, which indicate variable observations for these clinical features.



At present there are no animal or human data concerning general toxicity, reproductive toxicity, neurotoxicity or the mutagenicity and carcinogenic potential of 2C-I. Only subjective evidence is available from limited user self-reports involving observations of some adverse effects and toxic symptoms. In general, although users have described 2C-I as "powerful" and a "strong stimulant" with hallucinogenic properties, there is virtually no mention of adverse effects such as nausea, vomiting, muscle cramps, as reported for 2C-T-2 and 2C-T-7 in users purporting to have taken only 2C-I. However, due to the nature of the reports this may be due to selective reporting rather than absence of such symptoms. Nonetheless, some users report stomach tension, nausea, vomiting and jaw tension in instances of combining 2C-I with one or more of the following: 5-methoxy-dipropyltryptamine, cannabis, alcohol, caffeine, tryptophan, alprazolam and clonazepam. It has been noted by users that 2C-I may produce a delayed desired effect and thus users may take additional (sometimes higher) doses.

It appears that unlike other phenethylamine derivatives (including 2C-B), 2C-I is not usually present in tablets containing other phenethylamines or stimulants. This would therefore reduce the possibility of concomitant ingestion of other drugs in illicit preparations. However, as the pharmacology of 2C-I is largely unknown, it is difficult to predict with accuracy any particular potential drug interactions or contraindications. Winter et al studied the acute effects of monoamine reuptake inhibitors (SSRIs such as fluvoxamine, fluoxetine and venlafaxine) on the stimulus effects of hallucinogens (including DOM) and observed an additivity of effects rather than a potentiation. It is possible, therefore, that similar effects may occur with 2C-I. Various users report concomitant use with other drugs but specific evidence is unclear, however in some cases this did result in toxic effects (see above).

In users, anecdotal evidence indicates an onset of initial action of between 1-2 hours, however some users report slower desired effects compared to related drugs (e.g. 2C-B) or MDMA. Effects are typically described as lasting for up to 10 hours post oral dose. This compares to a duration of action of 8-12 hours for orally ingested LSD and 10-12 hours for mescaline, as mentioned by Shulgin.

(b) Clinical Effects

There have been no reported deaths or instances of non-fatal intoxication involving 2C-I. However, as for clinical toxicological investigations, the lack of reference material may compromise the analysis of post mortem cases.

There have been no scientific studies involving 2C-I users. Limited subjective user reports indicate 2C-I produces various psychedelic effects (generally comparable to other hallucinogens in particular 2C-B) and empathic effects (similar to MDMA).

Various isolated user reports in general compare 2C-I to 2C-B due to an apparent similarity in their effects, although some users describe 2C-I as being more "deeper, more purely psychedelic and less sensory" and in some cases less intense. Hallucinogenic and visual responses have been reported in addition to empathic effects described as being similar to those of MDMA. As previously mentioned, various users report delayed desired effects compared to related drugs (e.g. 2C-B) or MDMA. This may result in some users taking additional doses or other drugs which may increase the risk of toxicity or accidental overdosage.

(c) Dependence

No specific research has been performed using 2C-I to evaluate dependence potential in animal or in humans. Although the specific pharmacology of 2C-I is unknown, speculative comparison with related compounds indicate it is unlikely to possess a physical dependence or addiction such as that exhibited by opiates, for example. However, without specific study definitive conclusions cannot be made.

(d) Psychological Effects

There are no published data concerning specific psychological effects of 2C-I either acutely or chronically. As previously described (3.1b) limited anecdotal reports from users describe various subjective psychological effects of 2C-I use. Such reports mention a general clarity of thought with little or no "psychological after-effects". However, some introspection and "negative thought-loops" were described during various user experiences.

3.2 Public Health Risks

(a) Availability and Quality of 2C-I on the Market

2C-I has been identified in 4 Member States: Denmark, Germany, Sweden and the UK.

Information based on early warning system databases suggest that 2C-I is very rare. 2C-I has been seized in Denmark in one tablet with a "i" logo and thus most probably not made available to users as ecstasy (MDMA). (b) Knowledge and Perception of 2C-I Among Users

Level of awareness of 2C-I is generally negligible except among small subgroups of experimenters who may [sic] mescaline, DOB or 2C-B as reference drugs for experienced effects. Due to lack of human research studies, level of knowledge among these particular consumer subgroups, demonstrated on Internet, appears to be more detailed than that in the general scientific community. In the absence of accurate and regulated chemical analysis of contents objective scientific knowledge remains extremely limited. Major information sources are Internet sites combined with "dance floor pharmacology" - an informal network in which information passes from friend to friend. Despite the popularity of publications warning of the potential harm associated with using health information from the Internet, a systematic search of peer reviewed literature found few reported cases of harm. This may be due to an actual low risk for harm associated with the use of information available on the Internet or to underreporting of cases or to bias.

(c) Prevalence and Patterns of Use


Evidence of 2C-I use in the EU is very limited.

Population surveys of young adults in the EU show a range of 1% in Finland to 12% in the UK have lifetime prevalence of hallucinogenic substances, most commonly "magic" mushrooms. School surveys of 15-16 year olds in the EU show that a range of 1%-5% of this age group have lifetime experience of LSD or other hallucinogen compared with 10% in the USA (EMCDDA and ESPAD).

(d) Characteristics and Behaviours of Users

2C-I users seem likely to be a part of a very small group of people with pseudo scientific interest in experimenting with hallucinogenic substances, often referred to as "psychonauts". There appears to be a trend among a small but significant minority towards a broadening repertoire of drug experience - involving a wider range of drugs and combinations. Special concerns relates to the lack of knowledge about both drug contents and about the specific harmful effects of 2C-I alone or combined with other drugs.

(e) Indicators of Health Consequences

Information on the health consequences in the population is limited to those stated in 3.1.b. with an apparently very small population of users. No information on the long-term consequences of 2C-I use is available.

(f) Context of Use

There is no scientific evidence on risk factors linked to circumstances and rituals of consumption of 2C-I.


4. SOCIAL RISKS: Sociological/criminological aspects

(Documents III and IV)

4.1 Sociological aspects

For young people outside of the ecstasy-using population there seems to be a very low probability of coming into contact with 2C-I under present conditions.

As with all illicit drug use, lack of scientific and objective information contributes to the increasing of risks. Firstly, inaccurate media coverage and overestimates of use may promote diffusion by encouraging young people to try it. Secondly, official dissemination of inaccurate information may be counterproductive, if it is not perceived as credible.

A proportion of more 'innovative' drug users appear to be motivated to use by a desire to experience the full diversity of sensations.

4.1.1 Social Consequences

There is currently no scientific evidence of negative social consequences. However, 2C-I carries potential risks common to other hallucinogenic substances that are already under control.

4.1.2 Consequences for the Social Behaviour of the User

There is no specific evidence on consequences of the use of 2C-I that could be linked to disorderly conduct, acquisitive crime or violence. However, the described by users delayed desired effect of 2C-I may have implications for the ability to drive and use machinery.

4.1.3 Other Social Consequences

There is no indication that 2C-I in particular is associated with any major value conflicts or has any important implications for social institutions beyond those described for similar compounds.

4.2 Criminological Aspects

Law enforcement agencies from all fifteen Member States reported to Europol that there is no information available that would suggest large-scale production, distribution of and/or trafficking in 2C-I or a role of organised crime in these activities. Belgium and Italy replied that the main reason for the lack of information is the fact that the substance is not controlled in their country and, therefore, no records are being kept in the law enforcement systems.

Germany and Sweden reported on the production, in 1999, of limited quantities of 2C-I. This related in both countries to one case only, involving small "kitchen-type" laboratories.

Three Member States reported to Europol on seizures of 2C-I, which were small, both in terms of numbers and seized quantities. Denmark reported a seizure, in April 2002, of one tablet of 2C-I. The tablet was sent to a forensic laboratory by a psychiatrist working in the drug field. Germany reported a seizure, in 1999, of 0.3 grams of 2C-I, seized in a "kitchen-type" laboratory in Brannenburg, Bavaria. Sweden reported one seizure, in 1999, of a small amount of 2C-I that was produced in a "kitchen-type" laboratory. No link to organised crime was established.

The UK REITOX Focal Point reported to the EMCDDA on a small seizure of 2C-I in 1999.


5. POSSIBLE CONSEQUENCES OF PROHIBITION

5.1 Legal Status

An analysis of the legal status of 2C-I in the Member States shows that the drug is controlled in 5 EU Member States. 2C-I is non-controlled drug in the USA.

In Germany, 2C-I was placed under permanent control on 19 June 2001. The substance was already under control on a temporary basis since 1999. The arguments for placing these kinds of drugs under permanent control, which can be found in the legal text 'Funfzehnte Betaeubungsmittelrects-Aenderungsverordnung-15 BTMAndV" of 19 June 2001, are the following: (i) substances being used as 'ecstasy drugs'; and (ii) produced by illegal labs modifying the chemical structure of illegal drugs in order to achieve that these will not fall under the law ('designer drugs').

In the UK, 2C-I fells[sic] within the definition of a controlled substance (Class A) by virtue of a generic description as set by the Misuse of Drugs Act 1977.

In Ireland, 2C-I is a controlled drug under Schedule 1 of the Misuse of Drugs Acts, arising from the generic control approach.

Denmark has placed 2C-I under control since May 2002 ('Bekendtg0relse nr 305 af 16. maj 2002 om aendring af bekendtg0relse om euforserende stoffer').

In Greece, the drug is controlled under Table A of the Law 1729/87.

5.2 Possible Consequences of Prohibition

The meeting acknowledged that 2C-I is already under control in 5 Member States. The meeting noted that due to its structural features 2C-I seems to be comparable with substances already classified under the Schedules I or II of the 1971 United Nations Convention on Psychotropic Substances. The meeting also noted that 2C-I has no medical or industrial use.

Arising from the above, there was a strong opinion that there is a little scope for alternative to prohibition as a measure of control. A widely agreed argument was that possible control measures would enhance the capacity for detection and monitoring of the drug on the market and limit the potential for expansion of the supply and use of 2C-I. Another supporting argument was that exempting 2C-I from legal control would send an inaccurate message about the comparative safety of the substance. It was stressed that the increased availability of information about the drug would also stimulate the gathering and dissemination of analytical information for public health purposes.

There was also an opinion that prohibition could provoke the stigmatisation of small self-limiting groups of 2C-I users. Another opinion was that the limited scientific evidence makes it very difficult to express a definitive view on the possible consequences of legal control of 2C-I.

There was a consensus that possible control measures should not restrain the dissemination of accurate information on 2C-I to users and to relevant professionals for preventive and harm reduction measures. Marginalisation of 2C-I users should be avoided.


6. CONCLUSIONS
The Scientific Committee of the EMCDDA extended with experts from the Member States and representatives of the Commission, Europol and EMEA have considered the health and social risks as well as the possible consequences of prohibition of 2C-I and in accordance with Article 4 of the Joint Action submit the following conclusions:

6.1 2C-I has structural features of phenethylamines which are associated with stimulant and hallucinogenic activity. Therefore it seems to be comparable with substances already classified in the Schedules of the 1971 United Nations Convention on Psychotropic substance. For example, 2C-B (4-bromo-2,5-dimethoxyphenethylamine) - Schedule II.

6.2 Specific scientific risk assessment for 2-C-I is extremely difficult due to the very limited peer-reviewed scientific data. However, information based on analogy to 2C-B and DOB and evidence classified to evidence level IV indicate the following:

6.3 2C-I is a synthetic drug first synthesised by Shulgin.

6.4 Seized/available material includes powder, tablet (white, "i" logo) and liquid preparations.

6.5 No current medical or industrial use.

6.6 Confirmed 5-HT2C and 5-HT2A serotonergic receptor agonistic activity and potential 5-HT1 and alpha-1-adrenergic receptor agonistic activity.

6.7 Users report hallucinogenic/visual effects (similar to 2C-B, LSD and mescaline) and emotional/empathic responses (similar to MDMA); however, no scientific data are available.

6.8 Self-reporting users have only mentioned oral ingestion of 2C-I.

6.9 Due to the lack of specific scientific evidence, acute or chronic toxicity of 2C-I has not been confirmed in humans but toxic effects cannot be excluded.

6.10 Anecdotal reports from users suggest that 2C-I might have an unexpected slower onset of desired effects compared with related drugs (e.g. 2C-B) or MDMA. This may result in some users taking additional doses or other drugs which may increase the risk of toxicity or overdosage.

6.11 There have been no reported cases of fatal or non-fatal intoxication.

6.12 There is currently no scientific evidence of negative social consequences. However, 2C-I carries potential risks common to other hallucinogenic substances that are already under control.

6.13 There is no evidence that would suggest large-scale manufacture and trafficking of 2C-I or a role of organised crime.

6.14 2C-I has been identified in 4 Member States. It is already controlled in 5 EU Member States.


7. RECOMMENDATIONS
7.1 A strong opinion expressed at the meeting was that due to the indication for hallucinogenic/stimulant properties and due to a potential serious risk for health, 2 C-I should be a controlled substance. However, some experts felt that there was insufficient scientific evidence to make such a recommendation.

7.2 The meeting also recommends that a possible decision to place 2C-I under control should not inhibit the gathering of information about drugs on the market and the dissemination of accurate information on 2C-I to users and to relevant professionals.

7.3 The major chemical precursor of 2C-I, namely 2,5-dimethoxybenzaldehyde is commercially available. The meeting recommends, should the substance be put under control, that the Drug Precursors Committee set up under Article 10 of Regulation 3677/90 and Directive 92/109/EEC closely examine the situation of this precursor chemical which is involved in the synthesis of 2C-I and which is not yet subject to any measure of surveillance.

7.4 The meeting reiterates its previous recommendation that, when a new synthetic drug is notified for risk assessment, arrangements be made for the provision of reference standard material and associated analytical data to forensic and toxicology laboratories within the European Union. The meeting further recommends that 2C-I be included within the UNDCP proficiency testing programme.

Lisbon, 31 March - 1 April 2003