Some science behind the scenes

Thebaine

Thebaine (paramorphine)  is not used therapeutically, nor is it used ‘recreationally’ partly because it apparently  ‘tastes crappy!’ [from one brave psychonaut], has a stimulating effect rather than a relaxing effect and also because its other effects as a lone drug are extremely unpleasant and dangerous.

Its most dangerous side effect is to cause convulsions and it does this in animals as well as human beings.  There have been studies on rhesus monkeys, skates, frogs, sparrows, pigeons, mice, guinea pigs, rabbits, cats and dogs and in every case thebain produced convulsions.  In the rhesus monkey thebain on its own also produced  transient tremors, restlessness, and hyper-irritability.  Other effects produced by thebaine include nausea, vomiting and myoclonus - brief, involuntary twitching of a muscle or a group of muscles caused by sudden muscle contractions.

Which left everyone wondering why a lovely little flower like the opium poppy should contain it.  The answer maybe of course is that it is its natural insecticide – its defence mechanism against being eaten.  It occurs in the parts of the plant which are threatened by other wildlife – the leaves, the root and to a lesser extent the stem.  The seed pod, practically speaking, contains very little thebain – well under 1% - in many samples it has been as low as 0.4%, but the seeds can contain more.

Thebaine is a very minor constituent of opium extracted from the ‘normal’ poppy Papaver Somniferum,  but forms a larger percentage in other poppies such as Papaver bracteatum, and in substances such as poppy straw.  It also occurs in quite large amounts in the roots of Papaver somniferum, but is found in greater abundance (3%) in the roots of the oriental poppy (Papaver orientale).  Tasmanian poppies  - Papaver somniferum Norman  - which were bred for medicinal rather than recreational use are extremely rich in thebaine principally because they were bred as the precursor to pharmaceuticals.

Thebain’s main use commercially is in the production of pharmaceutical drugs.  It is converted industrially into a variety of compounds which include both opiate pharmaceuticals and stimulants and include oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine and etorphine.

Despite being virtually useless as a ‘recreational drug’, thebaine is still controlled under international law, and is listed, for example,  as a Class A drug under the Misuse of Drugs Act 1971 in the United Kingdom and is controlled as a Schedule II of the Controlled Substances Act in the United States of America.

It has caused much debate as to its receptor binding capability.  Although the drugs above have all been derived from thebain, nothing can be learned about the receptor binding of thebaine from these products, which all have their own rather unique bindings – Buprenorphine's analgesic effect, for example  is due to partial agonist activity at mu-opioid receptors and it is also a kappa-opioid receptor antagonist with none of the side effects of thebaine.  

Mu and delta binding

In one of the very few scientific studies of thebaine receptor binding made public, the following results were published. 

  • The (-)-isomer of thebaine  - the (-)-isomer of thebaine is the naturally-occurring constituent of opium.  It was found that it  has poor antinociceptive activity and induces convulsions. It binds to μ and δ opioid receptors.  Naltrindole, which is a highly potent, highly selective delta opioid receptor antagonist used in biomedical research, did not block either the convulsions or lethal effects, suggesting that the delta-opioid receptor system was not directly involved in this action.  (-)-thebaine was more effective at the delta-opioid receptor
  • The (+)- isomer of thebaine  - is the enantiomer of  the (-)-isomer of thebaine.  It also binds to the μ and δ opioid receptors, but (+)-thebaine is more effective at the mu-opioid receptor

At first sight this would all seem straightforward, thebaine, as found in opium is a potent delta agonist, a much less potent mu agonist and it also works via some other receptor[s] as yet unknown which give it its rather nasty side effects.  But there are other confusing results.

Rhesus monkeys given thebaine showed no real signs of the dependence or ‘addiction’ one would expect with a μ-opioid receptor agonist.  Furthermore, when administered naloxone, not only did they show no signs of withdrawal symptoms but one poor little monkey died.  Now Naloxone has an extremely high affinity for μ-opioid receptors in the central nervous system. Naloxone is a μ-opioid receptor competitive antagonist, and its rapid blockade of those receptors often produces rapid onset of withdrawal symptoms. Naloxone also has an antagonist action, though with a lower affinity, at κ- and δ-opioid receptors.

What we might conclude from this is that whatever mu activity is present in thebain it is very low and whatever delta activity is found in thebain it must be quite high.  And we still do not know what causes the stimulation, the convulsions [said to be like strychnine], the  tremors, the twitching and the irritability.

GABA and  Glycine receptors

There is some evidence that opioids in general have some GABA and some Glycine receptor activity, possibly via the delta receptor. 

Thebaine has been shown to inhibit binding to the glycine receptor and the gamma amino-butyric acid receptor  GABA – both receptors seem to be involved in the convulsive properties of the opiates”. 

Both morphine and codeine produce convulsions at high doses.  So Thebaine could be a GABA and Glycine receptor antagonist.  [And maybe so are morphine and codeine but to a lesser extent].

  •  GABA antagonists - are drugs which inhibit the action of GABA. In general pharmaceutical drugs in this category produce stimulant and convulsant effects, clinically they are mainly used for counteracting overdose of sedative drugs. 
  • Glycine antagonists - The glycine receptor  - or GlyR, is the receptor for the amino acid neurotransmitter glycine. The receptor can be selectively blocked by the high-affinity competitive antagonist strychnine. Caffeine has recently been found to also be a competitive antagonist and what we may just have found is that thebaine at high enough doses also act as antagonists.  Functionally, antagonists at high doses can result in a state of central nervous system over-stimulation or "the jitters", with restlessness, fidgetiness, nervousness, excitement, euphoria, insomnia, flushing of the face, increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech, irritability, irregular or rapid heart beat, and psychomotor agitation.  In cases of much larger overdoses, mania, depression, lapses in judgment, disorientation, disinhibition, delusions, hallucinations, and psychosis may occur.

 So what we may have here is a substance that at low doses helps to counteract some of the more severe sedative properties of the other constituents in the opium poppy and thus in opium, but at high doses produces enough toxic effects that, for example, any animal or little bug experiencing them would not over-indulge again.  It is as if the plant is signalling that used in moderation it will help its attacker, but at high doses it will attack back.

In Summary

 Given that the effect at the mu receptors is so low we can summarise the main effects of thebaine as follows.  Thebaine in the opium poppy represents a very minor constituent and as such these effects are only likely to really manifest in cultivars with a high thebaine content, in adulterated opium or in thebaine itself.  They may also manifest in severe overdoses of opium. 

Positive

  • Pain relief
  • Euphoria

Negative

  • Heart arrythmias 
  • Stimulation – over stimulation, the jitters, restlessness, fidgetiness, nervousness, excitement
  • Convulsions and muscle twitching, psychomotor agitation
  • Dysphoria
  • Insomnia
  • Flushing of the face
  • Increased urination
  • Gastrointestinal disturbance
  • A rambling flow of thought and speech, lapses in judgment, disorientation
  • Irritability
  • Mania, delusions, hallucinations, and psychosis.