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TECHNICAL PROFILE OF BROMO-DRAGONFLY SUMMARY Bromo-DragonFLY is potent synthetic psychedelic substance belonging to the benzodifuran class of substances. A number of in vitro and in vivo animal studies have shown that Bromo-DragonFLY is a potent 5-HT2A receptor agonist. There is evidence from seizure data, of its availability in Europe since 2006. However, there are user reports to suggest its use prior to this. Most of the Bromo-DragonFLY seizures have been reported from the Scandinavian region (Sweden, Norway, Denmark and Finland) with smaller seizures from Poland and the UK. It is available in the form of blotters / impregnated paper, similar to that seen with lysergic acid diethylamide (LSD), and also as powder and liquid. The predominant route of use is oral ingestion of blotters / paper and/or liquid (this appears usually to be dropped onto sugar lumps prior to consumption). There are some reports of nasal insufflation of powder. Current reported doses are 800-2000 micrograms, although there have been reports of ‘stronger potency’ preparations available prior to 2006. There is no evidence to suggest that Bromo-DragonFLY is easily available to users through Internet “legal high” suppliers or established street level drug dealers. It appears that the only source of Bromo-DragonFLY is from chemical suppliers based particularly in China; although it does not appear to be easy to obtain. There is no information on the purity of Bromo-DragonFLY although analysis of some seizures has shown that other recreational drugs were detected together with the BromoDragonFLY. 1 User reports suggest that Bromo-DragonFLY has hallucinogenic properties and that these are the effects desired by users. In addition users report stimulant effects similar to amphetamines. The information on the acute health effects of BromoDragonFLY is limited to user reports and three published case reports of individuals presenting to healthcare services with acute Bromo-DragonFLY toxicity. Commonly reported unwanted effects include headache, sweating, prolonged insomnia, confusion, agitation / psychosis, nausea, diarrhoea, seizures, tachycardia, and hypertension. There have been two reports of peripheral limb ischaemia potentially related to Bromo-DragonFLY, one of these led to the individual requiring amputation of the fingers of one hand. There have been four deaths reported to the EMCDDA where Bromo-DragonFLY was detected at post-mortem (two in Denmark and two in Sweden). In addition there is an unconfirmed report of a potential Bromo-DragonFLY related death in Norway. In conclusion, Bromo-DragonFLY is a potent 5-HT2A agonist, with potent psychedelic effects, and there are a three published reports of acute health effects and four confirmed fatalities related to its use. However, currently, there is no evidence of widespread use of Bromo-DragonFLY in Europe. It is likely that this low rate of use explain the relatively limited number of reports of significant acute health effects and death related to Bromo-DragonFLY. Should the supply of Bromo-DragonFLY and/or the prevalence of its use increase, in view of its pharmacological effects and toxicological profile, there is the potential for significant morbidity with associated healthcare utilisation and increased numbers of Bromo-DragonFLY related fatalities. 2 SECTION A. PHYSICAL, CHEMICAL, PHARMACEUTICAL AND PHARMACOLOGICAL INFORMATION A1. Physical and Pharmaceutical Information A1.1. Physical and Chemical Description The systematic (IUPAC) name for Bromo-DragonFLY is (1-(8-bromobenzo[1,2-b;4,5b']difuran-4-yl)-2-aminopropane). It is also known as bromo-benzodifuranul- isopropylamine and by users as “ABDF”, “DOBFLY”, “spamfly”, “placid”, “3C-BromoDragonfly” and “DOB-Dragonfly”. There are no official synonyms, non-proprietary names or trademark names for Bromo-DragonFLY. Bromo-DragonFLY is a synthetic psychedelic substance related to the phenethylamine family, although it has a distinct structure and belongs to the benzodifuran class of substances. The molecular formula for Bromo-DragonFLY is C13H12BrNO2, equating to a molecular weight of 294.15 g/mol. The hydrochloride salt decomposes at 240°C. The chemical structure of Bromo-DragonFLY is shown below: Bromo-DragonFLY was first synthesized at Purdue University, Indiana, USA in the 1990s as a research probe to investigate brain serotonin receptor structure and activity [Monte AP 1996]. The key precursor in the synthesis of Bromo-DragonFLY is 3 tetrahydrobenzodifuran, and the methods of synthesis have been described previously in detail [Monte AP 1996, Chambers JJ 2001]. A1.2. Physical/pharmaceutical form Bromo-DragonFLY is available to users in the form of blotters / impregnated paper similar to that seen with lysergic acid diethylamide (LSD) and there has been some confusion amongst users in this regard. It has also been reported to be available in powder form (often pink or white) and as a liquid (users often drop liquid onto sugar lumps prior to consumption). A1.3. Route of administration and dosage There are limited user reports relating to the use of Bromo-DragonFLY; Erowid states that by January 2009 they had only received approximately 50 first hand reports of Bromo-DragonFLY [Erowid 1]. From these reports it appears that it is predominantly used by the oral route, but there are user reports of use of powder Bromo-DragonFLY by nasal insufflation and of users dropping liquid BromoDragonFLY onto sugar cubes [Erowid 2]. Although there is reference on Erowid to the potential use of Bromo-DragonFLY by injection [Erowid 1], we have been unable to find first hand user reports to confirm this. Information available from Erowid user reports appears to suggest that the ‘potency’ of Bromo-DragonFLY in 2005 was stronger and typical doses used were 200-400 micrograms [Erowid 1]. This was commonly known as the ‘European batch’ of Bromo-DragonFLY. Since 2006, only a less potent batch known as the ‘American batch’ has been reported to be available with typical doses of 800-2000 micrograms. 4 As mentioned below, in Section D, the dose used in the single published case report of Bromo-DragonFLY toxicity presenting to healthcare services was not known. In a reported fatality from Denmark the user was reported to have ingested around 1 mL of Bromo-DragonFLY liquid (concentration 0.69mg/mL) [Andreasen MF 2009]. A2. Pharmacology, including pharmacodynamics and pharmacokinetics There are no formal pharmacokinetic studies looking specifically at BromoDragonFLY. User reports appear to suggest onset of desired effects within 20-90 minutes of oral ingestion, although there are some reports of slower onset of action when it is taken on a full stomach. User reports suggest onset of desired effects within 30-60 minutes of nasal insufflation. Desired effects are reported by users to last 6-12 hours, followed by a come down phase of 4-12 hours. Reports by users suggest a prolonged ‘after effect’ phase of up to 36 hours following use [Erowid 3]. There have been a number of published studies looking at the pharmacodynamics of Bromo-DragonFLY and related dihydrobenzofuran analogues in a number of in vitro and in vivo animal models [Monte AP 1996, Parker MA 1998, Chambers JJ 2001, May JA 2003]. These studies suggest that Bromo-DragonFLY is the most potent of the dihydrobenzofuran analogues with high affinity binding to the 5HT2A receptor [Monte AP 1996, Chambers JJ 2001]. Furthermore, the R-isomer of BromoDragonFLY is more potent with a higher 5-HT2A binding affinity than the S-isomer [Chambers JJ 2001]. Drug discriminating studies using LSD-trained rats have shown that Bromo-DragonFLY substitutes for LSD greater than other structurally similar compounds [Monte AP 1996]. 5 A3. Psychological and behavioural effects There are no published formal studies assessing the psychological and/or behavioural effects of Bromo-DragonFLY in humans. Therefore, the psychological and behavioural effects related to Bromo-Dragon-FLY use in humans are based on users’ reports [Erowid 2], and the published case reports of acute Bromo-DragonFLY toxicity (these are summarised in Section D1.2.3.). The desired psychological and behavioural effects reported by users appear to be typical of an hallucinogenic substance. The reported hallucinogenic effects include: visual changes, ‘shimmering lights’, ‘visual morphing with rainbow trails’, ‘high resolution colourful visuals’, increased energy; increased associative thinking; an altered perception of time and space; and ego softening. In addition to these hallucinogenic effects, there appears to be widespread reports from users of stimulant effects similar to amphetamines [Erowid 2, Erowid 3]. Users widely report a prolonged duration of come down / after effects following use of Bromo-DragonFLY. This, and other unwanted effects, will be discussed in Section D1.2. below. A4. Legitimate uses of the product There are no known uses of Bromo-DragonFLY as a research, industrial or cosmetic compound. It is not a recognised medicinal product in its own right and is not used for the synthesis of any other medicinal products or active pharmaceutical ingredients (API) and is not recognised as a metabolite of any of these. 6 There are some reports of other 5-HT2A agonists decreasing ocular pressure in animal models [May JA 2003], which could potentially be beneficial in treatment of ocular hypertension and/or glaucoma in humans. However, it is not clear whether Bromo-DragonFLY has these effects; in addition it has psychotropic effects which would limit its clinical application in this area. SECTION B. DEPENDENCE AND ABUSE POTENTIAL B1. Animal in vivo and in vitro data There are no published animal or in vitro studies investigating the dependence / abuse potential of Bromo-DragonFLY. B2. Human data There are no published reports of dependence to Bromo-DragonFLY. User reports appear to suggest single rather than recurrent use of Bromo-DragonFLY possibly due to the prolonged come down / after effects experienced by users. SECTION C. PREVALENCE OF USE There are reports to the EMCDDA European Information System and Database on New Drugs, of seizures of Bromo-DragonFLY from 6 European and neighbouring countries; these reports date from November 2006. In addition, there was one seizure of 3mL of liquid found to contain Bromo-DragonFLY in the USA in 2007 [DEA Microgram Bulletin]. 7 Country Amount and Details of the Seizure Denmark 2007: one seizure 2009: one seizure. Finland 2007: 19 seizures of 218 blotters and one seizure of 13mL of liquid. 2008: 26 seizures of 1308 blotters and one seizure of 4mL of liquid. 2009: one seizure of 54 slips and 5 seizures of 86 blotting papers. Norway 2007: 2 seizures of 7 units of paper. 2008: one seizure of “one dose”. 2009: 4 seizures of “64 doses”. Poland 2009: one seizure of 35 tablets. Sweden 2006: one seizure of blotters containing Bromo-DragonFLY and 4iodo-2,5-dimethoxyamphetamine (DOI). 2007: 3 seizures totalling 559g of powder, 8 seizures totalling 875 “units of paper”, 7 seizures of 28 “units of lump sugar” and 1 seizure of 0.5mL of liquid. 2008: 2 seizures totalling 4.12g of powder, 10 seizures totalling 128 “units of paper”, 18 seizures of 65 “units of lump sugar” and 2 seizures of 6.8mL of liquid. 2009: 2 seizures totalling 1.5 “units of paper” and 1 seizure of 3 “units of lump sugar”. UK 2008: 1 seizure of liquid absorbed onto a brown sugar lump also found to contain methylenedioxymethylamphetamine (MDMA) and one seizure of powder. 8 There are currently no co-ordinated national or European population surveys on Bromo-DragonFLY use. In addition, the recent MixMag survey did not report on either life-time use or recent use within the last month of Bromo-DragonFLY [Dick 2010]. SECTION D. HEALTH RISKS D1. Acute health effects D1.1. Animal Data There is no published animal data on the acute health effects of Bromo-DragonFLY. D1.2. Human Data D1.2.1 User Reports There have been no large scale published user surveys on the acute health effects experienced by Bromo-DragonFLY users. There are numerous user reports on Erowid of acute health effects following BromoDragon FLY use [Erowid 2, Erowid 3]. Commonly the unwanted effects include excessive hallucinogenic effects and/or stimulatory effects with prolonged come down / after effects. Other reports acute health effects include: - Headache - Sweating - Prolonged insomnia - Confusion - Symptoms similar to psychosis 9 - “Twitches” in the legs - Generalised feeling of cold and/or of hot - Nausea - Diarrhoea - Tightness in the jaw It is not possible to determine the incidence of these symptoms based on the user reports available and it is important to note that these are unconfirmed anecdotal reports from users. It is interesting to note that user reports do not mention peripheral cyanosis / skin discoloration / blue extremities suggestive of ischaemia that have been reported in clinical cases (see Section D1.2.3.). D1.2.2. Poisons Information Service Data The UK National Poisons Information Service have received two enquires concerning self-reported Bromo-DragonFLY toxicity. There was no clinical detail available concerning the first case (August 2008). The second case, in August 2009, was a 19 year old male who ingested an unknown amount of Bromo-dragonFLY and presented to the Emergency Department 4 hours after ingestion with tachycardia and agitation [Personal Communication Prof Simon Thomas]. The Swedish Poisons Centre received 22 enquiries regarding Bromo-DragonFLY toxicity from 2006 to October 2007. The most common clinical problems reported in these patients were anxiety, agitation, visual hallucinations, tachycardia and mydriasis [Personne M 2008]. By March 2008, the number of enquiries to the Swedish Poisons Centre had risen to a total of 32 [Thorlacius K 2008]. 10 D1.2.3. Published case reports of acute Bromo-DragonFLY toxicity UK Case Report: There has been one report of acute Bromo-DragonFLY toxicity from the UK [Wood DM 2009]. An 18 year old male presented after oral ingestion of an unknown amount of BromoDragonFLY and nasal insufflation of a ‘white powder’. He initially developed hallucinations and approximately 8 hours following this developed increasing agitation and had two witnessed self-terminating generalised seizures. On arrival in the Emergency Department he was drowsy with a Glasgow Coma Scale (GCS) of 3/15, heart rate 124/minute and blood pressure 182/94 mmHg. He had two further generalised seizures in the Emergency Department. He was sedated, intubated and ventilated and admitted to the Intensive Care Unit. He was extubated within 24 hours of admission. His hospital stay was complicated by an aspiration pneumonia that was treated successfully with intravenous antibiotics. He was discharged home with no long-term sequelae. Routine toxicological analysis of the serum and urine specimens using GC/MS and liquid chromatography with tandem mass spectrometry (LC/MS/MS) identified the presence of Bromo-dragonFLY (serum concentration 0.95ng/mL by LC/MS/MS) and ketamine and metabolites (20ng/mL). Cannabinoids were detected in both serum and urine. It was felt by the authors that the ketamine and cannabanoids detected were not of clinical significance. Lidocaine, lorazepam, midazolam and thiopentone 11 were detected as a result of treatment given in the ED. No other drugs or alcohol were detected using a broad toxicology screen of both the serum and urine samples. Swedish Case Reports: There are two clinical reports of acute Bromo-DragonFLY toxicity from Sweden [Personne M 2008, Thorlacius K 2008]. The first case was only reported in abstract form. This was a 20 year old male who ingested 5 or 6 blotters each soaked with 0.5mg of Bromo-DragonFLY. He initially developed hallucinogenic effects, but two days later developed cyanosis of ‘peripheral parts of the limbs’. Four days later he sought medical attention and he was noted to have rhabdomyolysis at that time. He was treated with vasodilators for a period of four days and he was discharged following this with no long-term sequelae. No toxicological analysis was reported in this case [Personne M 2008]. The second case has been reported in both abstract form (in English) and as a peerreviewed paper (in Swedish) [Personne M 2008, Thorlacius K 2008]. This was a 34/35 year old male who ingested an unknown amount of Bromo-DragonFLY together with a friend. Both collapsed following use and his friend was subsequently found dead (see section D1.2.4.). The survivor was found by his brother 17 hours later and was confused and disorientated. On arrival in the hospital he had a generalised seizure and was noted to have peripheral vasoconstriction, with worsening ischaemia of his extremeties over subsequent days. He was treated with a variety of vaso-dilating agents (glyceryl tri-nitrate, calcium channel blockers, ACE inhibitors prostacyclin analogues and nitroprusside) and sympathetic nerve block; 12 none of which were reported to be effective. He had evidence of rhabdomyolysis and associated renal failure; this was managed with standard treatment including continuous veno-venous haemodiafiltration. Due to the persistent ischaemia of his limbs he required amputation of all of the distal phalanges of the left hand. BromoDragonFLY was detected in the urine at the time of presentation, although no further toxicological screening information was reported in this case to determine whether other compounds may have been responsible for the clinical picture. D1.2.4. Bromo-DragonFLY related deaths The EMCDDA European Information System and Database on New Drugs reports that there have been 4 deaths related to Bromo-DragonFLY (two in Denmark and two in Sweden). There is no detailed published information on two of these (one Danish and one Swedish death). Limited information is available on the other Swedish death: this was a male found dead at home after use of Bromo-DragonFLY together with a friend (clinical information relating to the friend is described in Section D1.2.3.) [Personne M 2008, Thorlacius K 2008]. No information was published on the post-mortem or toxicological findings in this case. More detailed information has been published on one of the Danish BromoDragonFLY fatalities. This was an 18 year old female who along with her boyfriend each ingested 1mL of Bromo-DragonFLY liquid (concentration 0.69mg/mL). Approximately 1-2 hours following ingestion they developed an “LSD trip” feeling, after which they both fell asleep. Approximately 6-7 hours post-ingestion the 13 boyfriend woke to find his girlfriend dead. Post-mortem toxicological analysis detected Bromo-DragonFLY in femoral blood at a concentration of 4.7microgram/kg; no other drugs or ethanol were detected. There is also an unconfirmed report of the death of an 18 year old male in Norway following use of gamma-hydroxybutyrate (GHB) and Bromo-DragonFLY [Erowid 4]. D2. Chronic Health Effects D2.1. Animal Data There is no animal data on the chronic health effects of Bromo-DragonFLY. D2.2. Human Data As noted in Section D1.2.3. there is one individual who required amputation of the digits of one hand for ‘acute limb ischaemia’ following Bromo-DragonFLY use. There are no other reported studies suggesting chronic long-term physical health effects relating to Bromo-DragonFLY use. In addition there are no reports of individuals developing chronic health problems that do not relate to acute complications following Bromo-DragonFLY use. D3. Factors Affecting Public Health Risks D3.1. Availability and Quality of the New Psychoactive Substance on the Market (Purity, Adulterants etc) It does not appear that Bromo-DragonFLY is readily available to users either from on-line Internet suppliers of “legal highs” or established street level drug dealers. It is 14 possible, although not easy, to order it directly from chemical companies synthesizing “research chemicals”, predominately located in China, for dispatch to addresses in Europe. There is no available information on the purity of Bromo-DragonFLY in seizures to date, and there is also no information as to presence and/or frequency of pharmaceutical adulterants in Bromo-DragonFLY. As noted in Section C. analysis of some seizure samples has also detected other recreational drugs. D3.2. Availability of the Information, Degree of Knowledge and Perceptions Amongst Users Concerning the Psychoactive Substance and its Effects Reports on user websites suggest that users are aware that it is effective in producing the desired hallucinogenic and stimulant effects, but that it is associated with a prolonged come down / after effect. D3.3. Characteristics and Behaviour of Users There is no available user data to be able to determine the characteristics of those using Bromo-DragonFLY. It is likely that those using Bromo-DragonFLY are a “niche” group of recreational drug users given the relatively sparse number of user reports, the difficulty in obtaining this agent and the “research chemical” nature of it. D3.4. Nature and Extent of Health Consequences The acute health effects of Bromo-DragonFLY have been discussed in Section D1.2. There is no data available from law enforcement agencies to suggest that BromoDragonFLY use has been implicated in road traffic accidents or other trauma. This 15 may be due to the fact that Bromo-DragonFLY is not routinely tested for by forensic laboratories at this time. D3.5. Long-term Consequences of Use There have been no long-term follow up studies to determine if Bromo-DragonFLY users are at greater risk of health deterioration later in life, or of developing chronic or life-threatening medical conditions. D3.6. Conditions Under Which the New Psychoactive Substance is Obtained and Used, Including Context-Related Effects and Risks As noted in Section D3.1. Bromo-DragonFLY is not readily available either from online Internet suppliers of “legal highs” or established street level drug dealers. It appears that the only source of Bromo-DragonFLY is through direct supply from chemical companies. User reports suggest that Bromo-DragonFLY is mostly used within the home environment, although there have been some reports of use within discotheques/nightclubs and outdoor music festivals [Erowid 2]. SECTION E. SOCIAL RISKS E1. Individual Social Risks There is currently no information available to comment on this. E2. Possible Effects on Social Environment There is currently no information available to comment on this. 16 E3. Possible Effects on Society as a Whole There is currently no information available to comment on this. E4. Economic Costs As noted in Section D1.2. there are very few reports of individuals presenting to healthcare services with acute health effects, therefore it is not possible to be certain of the overall costs associated with Bromo-DragonFLY toxicity at this time. E5. Possible Effects Related to the Cultural Context There is no data available to suggest that Bromo-DragonFLY use is associated with particular demographic / socio-economic groups in society. E6. Possible Appeal of the new Psychoactive Substance to Specific Population Groups within the General Population There is no data available to suggest that Bromo-DragonFLY use is associated with specific sub-population groups. Dr Paul Dargan and Dr David Wood Guy’s and St Thomas’ NHS Foundation Trust King’s Health Partners London, UK March 2010 17 REFERENCES Andreasen MF, Telving R, Birkler RI, Schumacher B, Johannsen M. A fatal poisoning involving Bromo-Dragonfly. Forensic Sci Int 2009; 183: 91-96. Chambers JJ, Kurrasch-Orbaugh DM, Parker MA, Nichols DE. Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT(2A/2C) receptor agonists. J Med Chem 2001; 44: 1003-1010. DEA Microgram Bulletin: Intelligence Alert ‘Bromo Dragonfly’ (Bromo-benzodifuranylisopropylamine) in Ashland, Oregon. [Last Accessed 11th March 2010]. http://www.justice.gov/dea/programs/forensicsci/microgram/mg0807/mg0807.html Dick D, Torrance C. MixMag Drugs Survey. MixMag 2010; 225: 44-53. Erowid 1: Bromo-Dragonfly Dosage [Last Accessed 11th March 2010]. http://www.erowid.org/chemicals/bromo_dragonfly/bromo_dragonfly_dose.shtml Erowid 2: Bromo-Dragonfly Reports [Last Accessed 11th March 2010]. March 2010]. http://www.erowid.org/experiences/subs/exp_BromoDragonfly.shtml Erowid 3: Bromo-Dragonfly Effects [Last Accessed 11th http://www.erowid.org/chemicals/bromo_dragonfly/bromo_dragonfly_effects.shtml 18 Erowid 4: Reported GHB-Related Death May Not Have Been GHB: Bromo-Dragonfly is Confirmed by Toxicology [Last Accessed 11th March 2010]. http://www.erowid.org/chemicals/bromo_dragonfly/bromo_dragonfly_death2.shtml May JA, McLaughlin MA, Sharif NA, Hellberg MR, Dean TR. Evaluation of the ocular hypotensive response to serotonin 5-HT1A and 5-HT2A receptor ligands in conscious ocular hypertensive cynomolgus monkey. J Pharmacol Exp Ther 2003; 306: 301-309. Monte AP, Marona-Lewicka D, Parker MA, Wainscott DB, Nelson DL, Nichols DE. Dihydrobenzofuran analogues of hallucinogens. 3. Models of 4-substituted (2,5dimethoxyphenyl)alkylamine derivatives with rigidified methoxy groups. J Med Chem 1996; 39: 2953-2961. Parker MA, Marona-Lewicka D, Lucaites VL, Nelson DL, Nichols DE. A novel (benzodifuranyl)aminoalkane with extremely potent activity at the 5-HT2A receptor. J Med Chem 1998;41:5148-5149. Personne M, Hulten P. Bromo-Dragonfly: a life threatening designer drug. Clin Tox 2008; 46: 379-380. Thorlacius K, Borna C, Personne M. Bromo-dragon fly--life-threatening drug. Can cause tissue necrosis as demonstrated by the first described case. Lakartidningen 2008; 105: 199-200. 19 Wood DM, Looker JJ, Shaikh L, Button J, Puchnarewicz M, Davies S, Lidder S, Ramsey J, Holt DW, Dargan PI. Delayed onset of seizures and toxicity associated with recreational use of Bromo-dragonFLY. J Med Toxicol 2009; 5: 226-229. 20