Lobeline - Cure for meth and heroin addiction?

Matthias de L'Obel (1538-1616) was a French physician and botanist. He devised and published a system of plant classification, and served as the personal physician to William the Silent and James I. The plant genus Lobelia is named for him.

A number of Lobelia species, including Lobelia inflata (Indian tobacco) and Lobelia tupa (Devil's tobacco), produce a piperidine alkaloid called lobeline. Lobeline is a nicotine-like stimulant, which explains why L. inflata is used by Native Americans and others in the know as a substitute for regular tobacco.

Lobeline, like nicotine, enjoys long walks, romantic candlelit dinners, and binding to nicotinic acetylcholine receptors in the brain. However, it is apparently less active than nicotine at these receptors and so can actually diminish the effects of the drug. This antagonism is the basis for the use of lobeline as a treatment to help people quit smoking, although its effectiveness is still very much up for debate.

Lobeline has been shown to decrease methamphetamine self-administration in rats, while not being self-administered itself. This suggests that it could be used as a treatment for meth addiction and is unlikely to be abused on its own (unlike nicotine). The decrease in meth self-administration is thought to be due the ability of lobeline to screw around with the storage and release of dopamine by acting on the protein transporters such as VMAT2 that responsible for these processes. Dopamine release in the corpus striatum (a part of the brain) is responsible for the rewarding and reinforcing effects of methamphetamine.

Lobeline has also been shown to be capable of blocking mu opioid receptors, which are what morphine binds to in order to produce its effects. So potentially it can do a world of good for both amphetamine and opioid addiction.

- Miller DK et al. Lobeline, a potential pharmacotherapy for drug addiction, binds to mu opioid receptors and diminishes the effects of opioid receptor agonists. Drug Alcohol Depend. 2007 Jul 10;89(2-3):282-91.
- Neugebauer NM, Harrod SB, Stairs DJ, Crooks PA, Dwoskin LP, Bardo MT. Lobelane decreases methamphetamine self-administration in rats. Eur J Pharmacol. 2007 Sep 24;571(1):33-8. Epub 2007 Jun 13.

Caffeine - Drink coffee to breathe easier

Caffeine is a methylxanthine stimulant found in coffee that makes morning lectures somewhat more tolerable. Methylxanthines are methylated derivatives of xanthine. Animals produce xanthine as an intermediate in the breakdown of purines (e.g. guanine or adenine, the purine bases found in DNA and RNA) to uric acid, the stuff that causes gout and is excreted in urine. Other methylxanthines include theophylline (found in tea) and theobromine (found in cocoa, and thus in chocolate).

At the biochemical level, caffeine inhibits an enzyme called phosphodiesterase (the same target of Viagra!) and blocks the action of adenosine. These actions wake you up (and produce nervousness and insomnia at high doses), get your heart pumping (increase heart rate and increase the force of heart contraction), cause vasodilatation (except in the brain), and make you have to pee (by increasing how much urine your kidney makes).

Caffeine is used to diagnose people who have a genetic predisposition to malignant hyperthermia, a condition invoked by general anaesthesia that causes your muscles to intensely contract, producing tonnes of heat such that you run an exceptionally high fever and the enzymes in your body begin to stop working and you die very quickly. Incidentally, this terrifying condition is also a side effect of ecstasy (MDMA) use and can be treated with a drug called dantrolene.

Back in the day, caffeine was used to treat asthma, since it causes bronchodilation (relaxes the smooth muscle of the airways, causing them to expand) and so can help to reverse the constriction that occurs during an asthma attack.

- Kalant H, Grant D, and Mitchell J. Principles of Medical Pharmacology 7th ed. Toronto: Saunders Canada, 2006.

Mitragynine - Speedballing for lazy people

• the principal alkaloid situated in the leaves of Mitragyna speciosa Korth (Kratom, Biak-Biak), a rubiaceous tropical tree that is native to Southeast Asia
• people have been known to chew fresh leaves to acquire a numbing and stimulating effect, enabling them to fight fatigue and increase their tolerance to harsh working conditions
• acts like morphine via mu opioid receptors to produce analgesia, although the potency of this effect is only about one-fourth that of morphine, making it akin to less potent opioid analgesics such as codeine (Tylenol 3s, baby!) or methadone
• also produces a cocaine-like stimulating effect, likely due to it possessing a similar structure to yohimbine, an alpha2-adrenergic receptor antagonist that has stimulant activity and is best known for its alleged ability to treat erectile dysfunction (not an ad, I promise!)
  
• changing a carbon double bond to a single bond and adding a hydroxyl group gives you 7-hydroxymitragynine, which is also found in the aforementioned plant, albeit in fairly small amounts, but is significantly more potent than morphine and so is likely primarily responsible for the analgesic effects of the plant
  

Takayama H. Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa. Chem Pharm Bull (Tokyo). 2004 Aug;52(8):916-28. Review.
http://en.wikipedia.org/wiki/Kratom

Alpha-Methyltryptamine (AMT) - Russian antidepressant turned American hallucinogen

• synthetic tryptamine monoamine oxidase inhibitor invented by the Soviets (they called it Indopan) in the 1960s to treat people with depression


• in addition to alleviating depression, it does other exciting things that have lead to its recreational use:
• at lower doses it acts as a stimulant
  
• at higher doses it causes you to hallucinate
• was essentially legal in the USA and available for purchase online prior to April 2003, at which point the DEA had it designated a Schedule 1 controlled substance because a college student died while on it
• like psilocybin and DMT, acts at serotonin receptors (specifically, the 5-HT2 subtype) in the brain and disrupts serotonin breakdown (since it inhibits monoamine oxidase)
• also called IT-290 and 3-IT
• is closely related to alpha-ethyltryptamine (also called etryptamine, α-ethyltryptamine, α-ET, AET, and Monase), which has an ethyl group in place of a methyl group, and interestingly was initially developed in the USA as an antidepressant!
  
• AET is not a hallucinogen, but instead is considered to be an empathogen/entactogen like MDMA (ecstasy, E)
  

- Boland DM, Andollo W, Hime GW, Hearn WL. Fatality due to acute alpha-methyltryptamine intoxication. J Anal Toxicol. 2005 Jul-Aug;29(5):394-7.
- http://en.wikipedia.org/wiki/Alphamethyltryptamine
- http://en.wikipedia.org/wiki/Alpha-ethyltryptamine

Harmine - MAOI and possible inspiration behind In-A-Gadda-Da-Vida

• β-carboline alkaloid found in several species of plants belongings to the families Malpighiaceae and Zygophyllacae AND in butterflies of the family Nymphalidae (how trippy is that? psychedelic butterflies...IRON BUTTERFLY FOR TEH WIN!)
• plants known and exploited for their harmine content include Banisteriopsis caapi (a vine found in South America) and Peganum harmala (Harmal/Syrian Rue, found in the Middle East)
• reversibly inhibits monoamine oxidase (MAO), an enzyme in the brain that breaks down monoamines, resulting in increased levels of these compounds in the brain (and stimulation of the central nervous system)
• monoamines include neurotransmitters (serotonin, dopamine, norepinephrine), hormones (melatonin), and hallucinogenic drugs (tryptamines such as DMT and psilocybin)
• MAO inhibitors (MAOIs) have been used to treat depression since they inhibit the breakdown of serotonin and norepinephrine, two neurotransmitters that have a role in the pathophysiology of clinical depression, suggesting that harmine may have antidepressant effects
• like synthetic MAOIs, harmine can inhibit the breakdown of tyramine, which can lead to a hypertensive emergency
• plants containing harmine are often used in combination with plants containing DMT (see: yage/ayahuasca) or other tryptamine hallucinogens in order to increase their potency/duration of action (since their breakdown is inhibited by the harmine)
• harmine is generally used in this manner, although there are reports of it having hallucinogenic effects on its own
• was/is also known as banisterine in the late 1920s, when it was used to treat postencephalitic parkinsonism (it was the first MAOI to be used in parkinsonism)
  

Sanchez-Ramos JR. Banisterine and Parkinson's disease. Clin Neuropharmacol. 1991 Oct;14(5):391-402.
http://en.wikipedia.org/wiki/Harmine

Dextroamphetamine

Hi everyone. I've got a couple of exams this week, so I'm putting D&P on the backburner for a few days. Not to worry, I shall return!

P.s. Now would be a really great time for people to send me guest posts (drugsandpoisons [at] gmail [dot] com)

Benzylpiperazine (BZP)

• methamphetamine-like stimulant that has recently been the subject of much investigation in New Zealand (where it is legal and used as a party drug)
• effects include euphoria, enhanced sensory perception (whoa, this glo stick won't stop blinking out coded messages and this trance music tastes like the ocean!), hyperactivity, and stereotypy (constant repetition of certain meaningless gestures or movements, often seen in schizophrenics)
  
• repeated use leads to sensitization (less drug required to produce same effect) and cross-sensitization to crystal meth in rats
• less potent and probably less addictive than crystal meth (but potentially addictive nonetheless!)
• several contributing mechanisms of action, with the net result being the enhancement of the effects of serotonin, dopamine, and norepinephrine (all monoamine neurotransmitters) in the brain
  
• was originally designed in a lab to be an anthelmintic (works against parasitic worms) agent, to be used to expel wormies (particularly roundworms and pinworms, I don't recommend clicking those links!) from farm animals, on the basis of its structure resembling a group of compounds that are capable of paralyzing parasites (detaching them from the intestinal wall and thus permitting them to be pooped out)
• was found to be not very good at de-worming and, being a stimulant, caused restlessness and anorexia in animals, so it was scrapped
• tested in the early 1970s as a potential antidepressant, stopped when people realized it had amphetamine-like properties that probably were making things worse (especially if anxiety was a comorbidity with the depression, nothing like being hyperactive and anxious at the same time!)
• can cause serious toxicity in some people, as there have been reports of seizures that can progress to status epilepticus as well as severe respiratory and metabolic acidosis
  

- Brennan K et al. Chronic benzylpiperazine (BZP) exposure produces behavioral sensitization and cross-sensitization to methamphetamine (MA). Drug Alcohol Depend. 2006 Nov 22; [Epub ahead of print]
- Gee P et al. Toxic effects of BZP-based herbal party pills in humans: a prospective study in Christchurch, New Zealand. N Z Med J. 2005 Dec 16;118(1227):U1784.
- http://en.wikipedia.org/wiki/Benzylpiperazine

Cathinone

• more affectionately (and chemically) known as beta-ketoamphetamine
• an amphetamine-like stimulant that is the primary psychoactive (does things to your brain) compound found in khat (Catha edulis), a flowering evergreen shrub that is native to East Africa
• is present mostly in the shoots and leaves (insert dry literary panda joke here) of the plant, which are often chewed or brewed into tea
  
• methcathinone, a synthetic designer amphetamine that became popular in Russia in the 1960s, is a methyl derivative of cathinone
• is converted into cathine and norephedrine, two less active amphetamine-like compounds, as the plant matures and when it is dried - hence fresh young plants contain the highest concentrations of cathinone, and so will produce the greatest stimulant effects

Ford M, Delaney KA, Ling L, and Erickson T. Clinical Toxicology. Philadelphia: W.B. Saunders Company, 2001.

4-Methyl-aminorex

• has been compared to methamphetamine (crystal meth, crank) in terms of its effects (both are stimulants that produce intense euphoria) but has a longer duration of action (typically >12 hours)
• the infinite creativity and apparent rampant dislike of pronouncing and/or spelling actual chemical names in the street drug community has resulted in this compound also being called: Euphoria, U4EA (clever!), U4Euh (!), 4MA, 4-MAR, and 4-MAX
• derivative of the appetite suppressant (anorectic) aminorex, which was popular in Europe in the 1970s (hmm...something popular in Europe in the 1970s that causes one to lose their appetite...could it be, oh i dunno, ABBA?! OH HE'S ON FIRE TODAY FOLKS!)
• both aminorex and U4Euh (it's growing on me) have been associated with pulmonary hypertension (which is pretty bad, but there are worse things)
  
• apparently is relatively easy to synthesize in your kitchen using old cookware and phenylpropanolamine (an OTC diet pill)
  

Gaine SP, Rubin LJ, Kmetzo JJ, Palevsky HI, Traill TA. Recreational use of aminorex and pulmonary hypertension. Chest. 2000 Nov;118(5):1496-7.
http://en.wikipedia.org/wiki/4-Methyl-aminorex

Dimenhydrinate - Yes, it can make you hallucinate

• better known to car sickness aficionados as Dramamine or Gravol
• used to prevent or treat the nausea and emesis (barfing, puking, ralphing, spewing, vomiting, that sort of thing) associated with motion sickness, radiation sickness, being under general anaesthesia, chemotherapy, Ménière's disease, etc.
• is actually a combination preparation of two drugs: diphenhydramine (also known as Benadryl, an antihistamine that produces sedation and helps alleviate allergies, nausea and vomiting) and 8-chlorotheophylline (a derivative of theophylline, a relative of caffeine found in tea that is used to counteract the sedation of the first drug)
• in large doses can cause convulsions (young children are particularly susceptible), ataxia (loss of muscle coordination), stupor (just like it sounds), hallucinations (yes, people do abuse it to trip out...just spend the $5 on pot already!), coma, and respiratory depression

Kalant H, Grant D, and Mitchell J. Principles of Medical Pharmacology 7th ed. Toronto: Saunders Canada, 2006.

Arecoline - Nicotine's younger and better travelled brother

• alkaloid stimulant present in the betel nut, the seed of the Betel palm (Areca catechu)
  
• the nut is chewed in numerous Asian countries by hundreds of millions of people as a pick-me-up
• chewing the nuts results in a wonderful red-brown discolouration of the mouth, staining of the teeth, oral lesions, and potentially oral cancers (Google image the rest of these yourself, I'm getting too grossed out)
  
• thought to be responsible for addiction to chewing the nuts (haha nut chewing) due to its nicotine-like effects on the brain
  
• nicotine being the addictive substance in tobacco
• no medical use (haha nut chewing) although it has been shown to improve memory and other mental functions
  

Kalant H, Grant D, and Mitchell J. Principles of Medical Pharmacology 7th ed. Toronto: Saunders Canada, 2006.