Since moving to southern Oregon about 18 months ago, I have become aware of a psychedelic drug I had never heard of called “Bromo-DragonFLY”, “DragonFLY”, “B-Fly” or just “FLY”. It is also referred to by the letters: BrDF, 2C-TFM and ABDF. The young people who made me aware of the drug range in age from 18 to 24 and most describe their experience with this substance as mildly or sometimes ambivalently negative: “too intense”, “LSD for robots”, “rat poison”, “lasts too long and leaves you drained”, “definitely not for everyone, just too powerful”.

“B-FLY”, bromo-benzodifuranyl-isopropylamine was synthesized in the 1990s and was first used in rat brain research at Purdue in 1998. Though some have told me that it was developed as a rat poison, I could find no references to verify this claim. Dr. Alexander “Sasha” Shulgin describes FLY as a phenethylamine psychedelic but the phenyl ring of this molecule is bound between two dihydrofuran rings giving it more potency and longer lasting effects than most other phenethylamines (A Shulgin & A Shulgin, 1998, PIHKAL: a Chemical Love Story. Transform Press: Berkeley, CA 4^th printing). The molecular representation of this chemical resembles a dragonfly and hence its street name. By 2005, FLY began to appear as a street drug notably in Ashland, Oregon, Queensland, Australia, Germany, Sweden and Denmark.

As with all illicit street drugs, there are reports of discrepancies in the liquid, blotter paper and other dosage forms of Bromo-DragonFLY. What one gets from street purchases of the drugs is further complicated by the fact that the molecule can form two distinct chiral or optical isomers and especially by the fact that originally 5 other related synthetic molecules are also called FLY. At least 2 of these have already been misrepresented as Bromo-DragonFLY in street sales. In addition to Bromo-DragonFLY; 2C-Fly, 2C-B-Fly, 3C-Fly, Fly, and DOM-Fly were also synthesized by 1996 (AP Monte, et al, 1996. Dihydrobenzofuran analogues of hallucinogens. J of Medicinal Chem, 39:2953-2961; EC Reed & GS Kiddon, 2007. The characterization of three FLY compounds (2C-B-Fly, 3C-B-Fly, and Bromo-DragonFLY, DEA Microgram Journal, 5[14]:4-12). This may explain reports of a stronger “European or German Batch” of the drug that was on the streets in 2005 replaced by a less potent “American Batch” in 2006.

I found very few scientific papers on FLY but discovered three recent postings about B-Fly on the Drug Enforcement Administration (DEA) Microgram Bulletin site, and its Microgram Journal site.

An August 2007 Bulletin posted a brief entry about the seizure of a dropper bottle from an Ashland, Oregon resident that contained a clear, colorless, aqueous liquid. The individual was suspected of selling drugs and the liquid was analyzed to be 1-(8-bromobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminopropane which is the more precise chemical/technical name for Bromo-DragonFLY (DEA August 2007, “Bromo Dragonfly” [bromo-benzodifuranyl-isopropylamine] in Ashland, Oregon, DEA Microgram accessed 4/3/08). Both the DEA Microgram Bulletin and Journal have excellent information on street drug trafficking accompanied by photos. (DEA Microgram Bulletin February 2008. “Bromo-dragonfly” in Queensland, Australia, 41[2]:16-17;EC Reed & GS Kiddon, Jan-Dec 2007. The characterization of three FLY Compounds [2C-B-FLY, 3C-B-FLY, and Bromo-DragonFly] DEA Microgram Journal, 5[14]:4-12 both accessed on 4/3/08). I don’t recommend these web sites for anyone in recovery because the photos could evoke strong cravings.

Less scientifically reliable web sites like Vaults of Erowid, Drug Forum, Wikipedia and Cannabis Culture Forums have interesting postings on B-FLY along with practical advice. Although these sites can be easily corrupted by people adding or changing information, I found the content to be consistent with what is known about the dosage and effects of this drug. These sites indicate B-FLY is sold in liquid, powder, blotter paper and tablet forms on the street. Inconsistencies regarding which “fly” chemical are sold or what chiral form of the drug is used produces conflicting reports of threshold doses and effects. The “European Batch” is said to be active at 200 to 500 ug doses while the “American Batch” requires 800 to 1800 ug. These variances between threshold and common dose ranges of B-FLY products create a potential for drug overdose problems. Additionally, many users state that the onset of its effects, though usually 30 to 90 minutes after oral ingestion, can be delayed for up to 6 hours which can lead to “double dosing” (the ingestion of another dose of B-FLY thinking that the first dose was inadequate to cause any effects) and/or the use of additional drugs while waiting for the effects to kick in. A couple of deaths from abuse of this drug have been noted in Norway and Sweden. The R-(-) chiral form of the drug is thought to be the more active stereoisomer.

B-FLY is usually described as a powerful hallucinogen though some have said that it is milder with significant entactogenic and empathogenic activity. Like phenethylamine psychedelics, it causes: anorexia, mood elevation, physical and emotional stimulation, and increased associative thinking. Strong effects associated with its use include hallucinations, visual distortions, muscle tension, memory loss, confusion and even acute anxiety reactions with depersonification, derealization, and panic. One southern Oregon youth described watching thick smoke billow from his feet (visual hallucination), and multicolor blood gurgling (auditory hallucination) from his TV onto the floor during the “roller coaster” phase of a DragonFLY trip. The “roller coaster” phase is described as mentally oscillating between peaks of psychedelic drug effects and feelings of complete normalcy with no hallucinogenic effects. This oscillation begins after the plateau effects of psychedelics are over; the peak effects then become less intense as the drug experience is on the wane. The total duration of a B-FLY can vary from 6 hours to 4 days due to the variations in the molecules sold as the drug. Almost every reference strongly recommends against use citing the potential dangers of its effects, the lack of research, and the unreliability of products sold as Bromo-DragonFLY.

Early research on dihydrobenzofuran indicates that its psychedelic effects are due to its agonistic action on serotonin receptors. B-FLY has strong binding and activation of 5-HT2A, 5-HT2B and 5HT2C serotonin receptors (AP Monte, et al, 1997. Mescaline derivatives. J of Medicinal Chem, 40(19):2997-3008).

Bromo-DragonFLY is not scheduled as a controlled substance in the U.S. but it could be considered a chemical analog of other Schedule I drugs like DOB or 2C-B. If the DEA declares it as such, consumption or possession would be prosecuted under the 1986 Federal Analogue Act.

When a new synthetic psychedelic drug like B-FLY, Tripstasy (2-CB), Blue Mistic (2C-T-7), and Foxy Methoxy (5-methoxy-N,N-diisopropyl-tryptamine) makes its debut on the street it generates my sense of amazement at the complexity of the brain’s chemical processes. It also reminds me of the lifelong work of Drs. Alexander and Anna Shulgin who have created hundreds of these substances in their quest to better understand those processes.

Darryl S. Inaba, PharmD., CADC III

Last month Ovation Pharmaceuticals was granted FDA Fast Track designation for its anti-seizure medication vigabatrin (Sabril®) a potential treatment for methamphetamine and cocaine addiction. (http://www.medicalnewstoday.com/articles/94989, php Medical News Today, accessed 2/5/08). The “Fast Track” designation, mandated by the FDA Modernization Act of 1997, is reserved for products with the potential to treat a serious or life-threatening condition for which there are no available treatments and also have the potential to address an unmet medical need. Vigabatrin is a GABA-transaminase (GABA-T) inhibitor, which blocks the brain enzyme responsible for metabolizing the amino acid neurotransmitter gamma-aminobutyric acid (GABA). This mechanism causes a two- to three-fold increase in GABA brain levels. Animal and human research indicates that drug craving is associated with increased dopamine activity in the nucleus accumbens septi of the brain. Environmental cues or triggers associated with drug use dramatically increase the levels of dopamine in the nucleus accumbens. It is believed that GABA modulates or reduces the dopamine levels in that area of the brain and abolishes the cue-induced increase. (MR Gerasimov, et al., 2001, GABAergic blockade of cocaine-associated cue-induced increases in nucleus accumbens dopamine. European Journal of Pharmacology, 414(2-3): 205-209)

GABAergic medications increase the level or effectiveness of GABA in the brain and have attracted interest in recent years as potential anti-craving treatments for substance use disorders. Campral® (acamprosate), a medication proposed to act either directly at GABA receptors or to decrease glutamate activity was approved to treat alcohol craving in 2004. Neurontin® (gabapentin), Gabitril® (tiagabine), Lamictal® (lamotrigine), Topamax® (topiramate) and Lyrica® (pregabalin) have all been anecdotally mentioned as possible treatments for cravings in a variety of substance use disorders (i.e. alcohol, stimulants, opioids, sedative-hypnotics). Though these medications were developed and approved to treat epileptic seizures, pain, sleep disorders, anxiety or mood disorders, their ability to increase the action of GABA is causing great interest in their potential to treat drug cravings associated with chemical dependency.

Orexin, Grelin, Epigenetics, and ΔFosB Transcription Factor

Just a few years ago, a sense of tremendous excitement was generated by the annual announcements of discoveries which helped us begin to unlock the human brain’s secrets. Now, exciting developments seem to occur on a monthly basis and many seeming “breakthroughs” disappeared over time because they did not contribute to improved treatment outcomes for addictions. However, some discoveries did provide a better understanding of the neurochemistry of craving and led to the development of anti-craving medications, which have made huge contributions to treatment outcomes. Recent discoveries of brain neuropeptides, immediate alterations in neuronal genetic expression and brain proteins that bind to DNA and control their transfer of genetic information to produce drug craving have immense potential to improve treatment outcomes. These also hold the promise of better explaining differences between “normies” and those susceptible to Substance Use Disorders.

Orexin is a neuropeptide, neurotransmitter that regulates wakefulness and appetite. Orexin (also called hypocretin) was first discovered in 1998 by Dr. Masashi Yanagisawa at the University of Texas, Dallas. It was researched for appetite suppression leading to the development of an antagonist, SB334867. Narcolepsy is a disorder characterized by excessive daytime sleepiness. Narcoleptics suddenly fall asleep often at inappropriate times, situations and places. This condition has recently been attributed to a lack of orexin producing neurons in the lateral hypothalamus that also regulates thirst and hunger. Treatment of narcolepsy employs the use of stimulant drugs like methamphetamine and methylphenidate. During the 1970s, narcoleptics treated with potent stimulants rarely became addicted to those medications. National Institute on Drug Abuse scientists now speculate that orexin may be another key neurotransmitter (like dopamine, GABA and endorphins) involved in the development of addiction and craving. Animal research at the University of California and the University of Pennsylvania found that orexin stimulates a rat’s preference for morphine, cocaine and sweet food. Rats injected with SB334867, the orexin antagonist, had a 58% decrease in preference for those substances. Morphine and cocaine was found to stimulate the production of orexin causing the brain’s normal feeding and craving mechanisms to be hijacked. Animal research demonstrates that drugs like morphine and cocaine cause an increase production of orexin, which increases the ventral tegmental area (VTA) sensitivity for neural excitation for dopamine release by stimulating an increase in VTA receptors. Orexin antagonists were seen to block this effect and decrease drug craving, which may promote sustained recovery in humans. (SL Borgland, et al. (2006). Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49(4): 589-601; GC Harris, et al. (2005). A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437(7058): 556-559)

A year after orexin’s discovery, Masayasu Kojima and his Japanese colleagues discovered ghrelin, a hormone produced by cells lining the stomach. Like orexin, ghrelin also activates appetite and drug cravings in the brain’s mesolimbic reward reinforcement circuitry. (E Jerlhag, et al. (2007). Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens. Addiction Biology, 12(1): 6-16.) Confusingly, lack of sleep not excessive sleepiness stimulates ghrelin production, which increases appetite. This indicates that there are separate orexin mesolimbic mechanisms: one for arousal and another for feeding, reward and drug craving.

Epigenetics refers to heritable, long-term alterations in gene function that occur without changes to the underlying DNA sequence. A good analogy for the relationship of genetics and epigenetics can be found in the computer relationship of software to hardware. Genes are the hardware and epigenetics is the software that instruct genes what, where and when they are to be expressed. Once dismissed as a pseudo-science, epigenetics is now part of the powerful science of “cell memory”. Epigenetics helps explain the occasional incongruity of substance use disorder or the occurrence of schizophrenia in just one homozygotic (identical) twin. Epigenetics has drawn renewed attention to the importance of environmental factors in the development such disorders. Genes rely on random mutations and recombinations to pass on phenotypic traits from one generation to another. Epigenetics consist of several mechanisms that induce immediate and often long-term alterations in gene function within an individual. DNA methylation, imprinting, paramutation, chromatin remodeling, histone modification, RNA transcripts and prions are just some of the epigenetic processes. All are sensitive to environmental toxins and affect the long-term health of an individual. For example, chronic exposure to cocaine activates the genes in neurons to create proteins like ΔFosB Transcription Factor by the chromatin remodeling process. ΔFosB correlates with craving and cocaine self-administration in animals, and may contribute to long-lasting structural changes in cocaine abusers’ mesolimbic reward reinforcement circuitry. A unit of chromatin consists of DNA wrapped around complexes of histone proteins. This unit is also known as a nucleosome and chemical processes determine how tightly the DNA is wrapped around the histones. Chromatin remodeling occurs when the nucleosome is more or less compact, changing the DNA’s ability to interact with RNA polymerase and produce proteins. Chronic exposure to drugs like amphetamine, morphine, nicotine, phencyclidine and cocaine activates genes for the production of ΔFosB transcription factor in the nucleus accumbens by spreading out nucleosomes in those neurons to make them more available to RNA polymerase (MB Kelz, et al. (1999). Expression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine. Nature 401(6750): 272-276). This results in more ΔFosB being produced, which generates an increase in cravings and drug self-administration. Scientists are now developing chemical compounds to reverse chromatin remodeling, this is a promising new strategy to treat substance use disorders. (L Whitten (2007). Gene experiment confirms a suspected cocaine action. NIDA Notes, 21(4): 8-10; A Kumar, et al. (2005). Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48(2): 303-314.)

A Transcription Factor is a protein that binds to a specific part of the DNA double helix to control the transfer genetic information to RNA for the neuron’s synthesis of other proteins. In addition to addictive drugs, compulsive running and other compulsive behaviors increase ΔFosB Transcription Factor in the nucleus accumbens and the dorsal striatum. ΔFosB alters gene expression in these areas which results in an increased sensitivity to addictive drugs and behaviors. This triggers the initiation of and then sustains changes in gene expression that persists long after drug exposure ceases to create craving and increase drug-seeking behaviors. This type of molecular switch gradually converts acute drug responses into relatively stable adaptations, which contribute to the long-term neuronal and behavioral processes that underlie addiction. Reversal or blockage of ΔFosB production may also result in an effective treatment of substance use disorders. (EJ Nestler, et al. (2001). ΔFosB: A sustained molecular switch for addiction. Proc. Nat. Acad. Sci. (PNAS), 98(20): 11042-11046.

Orexin, Grelin, Epigenetics, and ΔFosB Transcription Factor are just a few of the many exciting developments in the expanding science of addiction. The more we learn about the root causes of behaviors associated with substance use disorders, the more questions we have. The answers seem to be getting more and more complex. In the mid 1950’s, Bill and Bob described alcoholism as, “cunning, baffling and powerful”. The 12-Step recovery process begins with Step 1: We have admitted that we are powerless over alcohol that our lives have become unmanageable. The current science of addiction better explains and profoundly validates Bill and Bob’s early conjecture about chemical dependence.

Darryl S. Inaba, PharmD., CADC III