Skeptical about drug laws – Part 2

Welcome to part 2 of my skeptical about drug laws series, based on a talk I gave at Birmingham Skeptics in the Pub open mic night on May 27th.  In part 1 I gave an overview of the problems encountered when medical researchers attempt to conduct research using schedule 1 drugs on any level, which in turn makes the research very expensive, surrounded in red tape and generally slows the progress of research into some serious medical issues to a halt.  I then looked at why the compounds in question were designated schedule 1 in the first instance – supposedly it related to their harm and abuse potential, however, this was shown to be completely out of line with the scientific data and research.

So now it is time to address these compounds individually, to explore the effects of these compounds, look at their harm potential in more detail and discuss what role they might play in medicine if drug laws are allowed to be based on actual science.  The first to be explored is MDMA.

MDMA

MDMA is more commonly referred to as “ecstasy” or “molly”.  Chemically, it is described as 3,4-methylenedioxy-methamphetamine.

MDMA was first synthesized by Merck chemicals way back in 1912 as an intermediate in the development of an anti-haemorrhagic drug.  It lay in obscurity until its rediscovery by the late great chemist Alexander Shulgin in the 1960s.  Alexander Shulgin was a pioneering chemist who synthesized in excess of 200+ novel compounds with psychoactive activity from a lab in his back garden in Lafeyette , California, and was renowned for self-administering the compounds that he synthesized!  He and his wife authored the books PIHKAL (Phenylethlamines I Have Known and Loved) and TIKHAL (Tryptamines I Have Known and Loved) as well as The Shulgin Index – a comprehensive textbook of chemical synthesis and data concerning psychedelic compounds.  Shulgins story is worthy of a long article in itself (see the link at the end for “Dirty Pictures”, a documentary about Shulgins life and legacy), but suffice to say he acted as a mentor to some of today’s leading neuropsychopharmacologists, and the compounds he developed may yet still hold many potential benefits.

But back to MDMA – after Shulgins rediscovery, recreational use started to be evidenced in the 1970s.  Typically the effects of MDMA include euphoria, increased well-being, sociability, self-confidence and extroversion.  It is also often described as an entactogen – increasing empathy or the feelings of closeness with others.  With this in mind it is not hard to see why it found a welcome home in the rave and dance scenes.  As well as recreational use, many psychiatrists and therapists were also finding utility in the drug, as they began to implement MDMA-based therapy into their sessions as they found it to have positive effects and outcomes with their patients, and was favoured due to its lack of hallucinatory effects, shorter duration of action and allowing the user to stay cognitive throughout the therapy sitting (LSD visuals were found to be rather distracting!). This was noticed to the point where Leo Zeff, a psychotherapist, came out of retirement to travel America introducing psychiatrists to the drug to promote its use in therapy.  MDMA was made a schedule I drug in 1985, despite the protest of many well respected psychiatrists on the basis that they had seen its medicinal benefits first hand.

MDMA Mechanism of action

Above you can see the chemical structure of MDMA, along with some of the main neurotransmitters present in the brain.  Note the similarity in shape and similar atoms present – in very general terms this is how MDMA mediates its actions within the brain, by resembling already existing structures such that it binds in a lock-and-key fashion, the slight differences in chemical composition affecting receptor activity and downstream processes.  A detailed explanation of MDMAs action in the brain isn’t really necessary here, but suffice to say it induces serotonin release and stimulates serotonin receptors which is largely responsible for producing its subjective effects. It also increases levels of oxytocin, prolactin and cortisol, effecting areas of the brain relating to mood and fear response.

MDMA Safety

So once again we approach the subject of MDMA safety.  One of the main arguments for the danger of MDMA is that it is neurotoxic (Parrott 2014).  The validity of such claims is hampered by bad study design.  Actually, that’s being overly kind.  The main study that got all of the press was a 2002 paper published in the well-respected Science journal (Ricaurte et al 2002), which stated that even a single dose of MDMA could lead to permanent neurological damage with a similar profile to that seen with Parkinsons patients.  The paper was later retracted, because it turned out that due to a mix up, instead of the experiments being run with MDMA, the scientists had in fact been using Methamphetamine (Crystal Meth for all you Breaking Bad fans).  I think at this stage it’s important to point out that despite MDMA having methamphetamine in its name, the two compounds are very different in their effects and mechanisms under which they work, and this is common in chemistry (Dimethyltryptamine, a powerful hallucinogen, differs from the neurotransmitter Serotonin (5-Hydroxytryptamine) by only two carbon atoms, one oxygen atom and four hydrogen atoms, for example).

So bad study design doesn’t quite cover the complete screw up evidenced here.  The retraction didn’t get nearly as much press, and in the meantime several laws were introduced in America on the basis of the original paper which meant club owners would be held accountable for any patrons using MDMA in their premises, ultimately putting MDMA users in more danger, and these remained in place after the retraction.

There are other issues with MDMA neurotoxicity studies in that animal models don’t match up well with human models in terms of the receptors present and the concentrations of drug required to observe the detrimental effects.  Moreover, my own issue with these studies is that they are based on recreational drug users – these will be people who have used the drug many times, on consecutive weeks for durations lasting weeks, months and even years.  This I believe means it is in no way reflective of the type of long term effects that may be observed in a therapeutic MDMA user, since the dosage and frequency of administration does not come anywhere close to that of the recreational user.  In addition, we cannot possibly hope to account for the quality and consistency of street sourced MDMA with regards to its purity – frequently powders and pills sold as MDMA are found to contain 5% or less and are often substituted with other stimulants such as BZP, mephedrone or methamphetamine, so to use “MDMA” users as a data set when an untold number of drugs may be at play in regards to detrimental effects witnessed is not reflective in any way of the actual safety profile of MDMA itself.  As we saw in Part 1 – clinical trials require pure compounds in order to perform research, so to disregard this rule when looking at safety data is, quite frankly, ludicrous and detrimental to medical research.

So if MDMA is so safe, why has it been attributed to so many deaths in newspapers?  The main problems encountered with recreational drug use are threefold:

• Hyperthermia – Due to vigorous dancing in poorly ventilated areas with inadequate water intake.
• 
  
• Hyponatremia – Due to overconsumption of water.  A classic example of ecstasy being attributed to death in the UK would be the 1996 case of 18 year old Leah Betts, whose picture was on the front page of many newspapers showing her attached to life support equipment after taking ecstasy which prompted a strong campaign against ecstasy use.  What was less published was the fact that after taking ecstasy, she consumed 7 litres of water in a 90-minute period.  This leads to the dilution of electrolytes within the blood, and as such water enters into the cell due to a higher sodium concentration gradient, and those cells swell as a result.  When those cells happen to be brain cells, the result is cerebral oedema, leading to coma and death.  MDMA also has an antidiuretic effect due to promoting secretion of anti-diuretic hormone (ADH) which in essence stops the kidneys from releasing water in the urine, furthering the dilution effect of sodium in the blood, which exacerbated the situation.  This I believe is more a testament to poor education in drug safety than lack of safety of the drug itself.  People have died from water intoxication when no MDMA has been involved 

• (https://en.wikipedia.org/wiki/Water_intoxication#Notable_cases).

• In addition we have again the problem whereby there is no way to verify what is being sold as MDMA actually is MDMA.  In recent media a lot of deaths attributed to “bad ecstasy” have been because what was consumed was actually a compound called PMA (para-methoxyamphetamine) which has a very narrow window between the dosage that would be used for recreational purposes and that which is toxic.  To call this “bad ecstasy” is akin to me filling a beer glass with bleach and giving it to someone to drink, and calling the fallout the result of a “dodgy pint”.

In either case, the therapeutic setting is not a rave, and dancing is not encouraged as far as I’m aware, and excessive water consumption is completely unnecessary in this scenario so these issues do not come into play, and therefore are not valid arguments against the safety of MDMAs use in therapy in my opinion

Medical use of MDMA

So what are the potential medical benefits of MDMA?

Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder characterised by re-experiencing of trauma, hyperarousal and avoidance symptoms, and is a major worldwide public health problem.  It is seen frequently in war veterans and army personnel, rape victims, victims of child molestation and violent crime, as well as first-responders such as paramedics, fire fighters and police.  It can occur due to any traumatic event.  To give a scale of the seriousness of this condition, one study indicated that there is an average of one suicide per 65 minutes in US veterans with additional studies attributing this to a higher degree of PTSD suffered by those that had experienced combat or dealing with post-combat guilt (Sher et al 2012).  The death rate of soldiers is four times higher as a result of suicide than of those killed in the line of duty.  Clearly, there is a problem here that is not being resolved with conventional treatment.  I’m not sure if we need studies to confirm any suspicions that being a victim of rape or child molestation would leave lingering issues, so I think it’s safe to assume they suffer the same kind of mental anguish on a daily basis.

The current treatments available for PTSD include serotonin-selective reuptake inhibitors (SSRIs) – the same drugs primarily used to treat depression - cognitive behavioural therapy and other psychotherapies, though these all have limited efficacy.  MDMA is thought to be useful in treating PTSD since it allows the patient to stay emotionally engaged while revisiting previous traumatic incidents without being overwhelmed by anxiety, allowing psychotherapy to occur within the “window of tolerance”.

The MAPS (Multidisciplinary Association for Psychedelic Studies) organisation is currently carrying out a number of studies with the end goal to get MDMA listed as a FDA approved medicine by 2021.  These include an already completed pilot study which involved 20 patients with chronic PTSD refractory from both psychotherapy and psychopharmacology, with an 83% positive response rate in the non-placebo group (Mithoefer et al 2010) with zero adverse effects.  An additional 5 studies are currently in progress.  All are conducted under double-blind placebo conditions and adhere to proper experimental design.  An additional point that I think is worthwhile taking into consideration is that the CAPS score (the gold standard measurement of PTSD severity) was reduced by an average of 53.2 points across participants taking MDMA compared to 20.5 for the placebo control group (those who unknowingly did not take the drug).  This is important because Zoloft, an SSRI, is an FDA approved treatment for PTSD and was shown to reduce CAPS score by just 10.2 overall across 187 participants (Brady et al 2000).  It is also very important to note that MDMA use in therapy consists of 2-3 sessions spaced out over a number of weeks with non-drug therapy before, in-between and after.  It is not intended as a regular prescription and the patient will not be dependent on its use.    I encourage you to look into the common side effects of taking a regular prescription of Zoloft when contemplating the harm potential of MDMA in a therapeutic setting and have a think about which has the greater risk.  You might find yourself rather disturbed or surprised.  Or both.  This is not to say that SSRIs like Zoloft and others are not without their uses and benefits even when potential adverse effects are taken into consideration, but if nothing else it seems nonsensical to approve the use of a low efficacy drug whilst denying the medical utility of one which has been shown to be 5 times more effective based on what I believe is non-justified safety concerns.

Social Anxiety in Autistic Adults

Social anxiety is characterized by a fear of scrutiny and avoidance of social interactions and is frequently observed in those with autism.  Higher functioning autistic adults have a greater risk for developing psychiatric problems including social anxiety, due to the lack of obvious autistic traits and an expectation to conform to societal norms.  Increased oxytocin leads to an increased ability to infer emotions from facial cues and thus react more appropriately to a give interaction – in autism, interpretation of non-verbal communication is at a much lower level than those who do not have autism.  It isn’t hard to see how this can lead to awkward and misinterpreted social interactions, particularly when coupled with an inability to understand abstract concepts and metaphors and idioms (phrases such as “its raining cats and dogs” or “I have got butterflies in my stomach” are likely to be taken literally, and thus make no sense – a good comparison is Dave Batistas character Drax in the Guardians of the Galaxy film).  MDMA increases oxytocin levels and therefore assists effective interpretation of feelings and intents.

Early work from the 1960s/1970s indicates that the positive effects of MDMA could help relieve symptoms and feelings of social anxiety and its related issues to due increased openness, talkativeness and increased social interaction that is observed under the influence of MDMA.  It is hoped that better study design and improved ethics, safety, monitoring and follow up will show MDMA as a viable treatment in alleviating the symptoms of social anxiety in autistic adults (Danforth et al 2015).

Summary

What I hoped to have demonstrated in the above paragraphs is that MDMA has a very real medicinal potential for treating conditions which affect a huge number of the population, for which the current treatments aren’t satisfactorily effective.  Thus they remain suffering from their conditions – and I think it is important to take into consideration that it is not only themselves that are effected by their illness – as with so many mental health problems, those close to them also feel the brunt, whether it be in relation to job performance or ability to function as a husband/wife/father/mother.  The science doesn’t seem to justify to restrictions placed on research using MDMA, and I think that the research is vital and needs to be done urgently to clarify exactly to what extent we can use the compounds we have available to us now in a safe manner.  Once again I will state my belief that current drug laws, based on politics and not science, have caused far more harm than they have ever prevented.



References

BRADY K., PEARLSTEIN T., ASNIS G.M., BAKER D., ROTHBAUM B., SIKES C.R. and FARFEL G.M (2000)  Efficacy and safety of sertraline treatment of posstraumatic stress disorder.  A randomized controlled trial.  The Journal of the American Medical Association.  Vol.283, No.14, pp1837-pp1844.

DANFORTH A.L., STRUBLE C.M., YAZAR-KLOSINSKI B., and GROB C.S. (2015) MDMA-assisted therapy:  A new treatment model for social anxiety in autistic adults.  Progress in Neuro-Psychopharmacology and Biological Psychiatry.

MITHOEFER M.C., WAGNER M.T., MITHOEFER A.T, JEROME L. and DOBLIN R. (2011)  The safety and efficacy of 3,4-methylenedioxymethamphetamine assisted psychotherapy in subjects with chronic, treatment-resistant post-traumatic stress disorder: the first randomized controlled pilot study. Journal of psychopharmacology, Volume 25, No.4, pp439-pp452.

PARROTT A.C (2014) The potential dangers of using MDMA for psychotherapy.  Journal of Psychoactive Drugs, Volume 46, Iss.1, pp37-pp43.

RICAURTE G.A., YUAN J., HATZIDIMITRIOU G., CORD B.J. and MCCANN U.D (2002) Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA (“Ecstasy”).  Science, Vol.297, No.5590, pp2260-pp2263.

SHER L., BRAQUEHAIS M.D. and CASAS M (2012)  Posttraumatic stress disorder, depression, and suicide in veterans.  Cleveland Clinic Journal of Medicine, Vol.79, No.2, pp92-pp97.

Useful links

Dirty Pictures – Alexander Shulgin Documentary

Podcasts featuring Rick Doblin from MAPS:

Tangentially Speaking No. 98 -

 London Real “Rick Doblin – Fighting the good fight”  June 2013 

London Real “Rick Doblin – MDMA therapy” May 2014

Duncan Trussell Family Hour No. 149

Joe Rogan Experience No. 371