“DEBUNKING THE MYTH” SERIES

TOPIC 1 – SMOKE AND MIRRORS OF DRUG ADDICTION

 Author: FRANCESCA KEEFE | 14 APR 2021

THE ILLICIT DRUG USER IS MORE THAN A LOW LIFE: DEBUNKING THE MYTH

Is the public perception of illicit drug users wrong? The media often promotes the stereotype of illicit drug users as violent thugs, always on the hunt for their next “high”.  In reality 3.2 million adults, across England and Wales (that is nearly 10% of adults), reported illicit drug use in 2019 alone (Office of National Statistics, 2020). Crucially, these individuals were largely law-abiding, successful and respectable citizens (Harrison, 1994). So why does the social stigmatisation continue? Here, I challenge an assortment of neuromyths in drug addiction, which have, arguably, tainted public perception and have had severe repercussions on clinical research and innovation (Nutt et al. 2013; Ross, 2020). 

NOT ALL PSYCHEDELIC DRUGS ARE ADDICTIVE: DEBUNKING THE MYTH

Drugs that act artificially to alter mood, perception and behaviour are classed as psychedelic drugs (Nutt et al. 2013). Depending on the psychedelic, the effect can be energising, calming and/or hallucinogenic. This is due to the different substances having different modes of action – targeting different brain pathways and different neurotransmitter signals (Nutt et al. 2015; De Gregorio et al. 2021). Of significance is the ability of some (but not all) psychedelic drugs to activate the reward pathway, an innate learning mechanism that positively reinforces specific behaviours (in this case, drug use). Unfortunately, this mode of action has the potential to drive drug misuse and drug dependency (aka drug addiction) in vulnerable individuals. 

DRUG ADDICTION – DEFINED

Drug addiction is a state where an individual craves the drug to the extent of sacrificing other rewards, along with making irrational (often detrimental) tradeoffs to obtain the substance (Wakefield, 2020; Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, 2013). Consequently, leading to the neglect of work, hobbies and relationships. When an addict attempts to become drug-free (abstinence) they inevitably suffer withdrawal symptoms. These can be physical (i.e. headaches, vomiting, shakes), or psychological (intrusive thoughts).  The common outcome being to relapse back into drug taking. People struggling with drug addiction are prone to repeated relapses, even after long periods of abstinence (Pang et al. 2019). 

DRUG ADDICTION – INSIDE THE BRAIN  

The neural mechanisms underpinning this clinical profile have been described in a number of theories, the reward pathway being central to them all (Wakefield 2020). Addictive drugs manipulate neurotransmitter signals, be it GABA, serotonin, glutamate, or dopamine, to the same end: activation of the reward pathway (Nutt et al. 2015; De Gregorio et al. 2021). Significantly, addictive drugs overload the system in a uniquely detrimental way, not observed for non-addictive rewards. According to the “hijacking theory” of drug addiction, this unnaturally high activation of the reward pathway triggers maladaptive learning, which ultimately marks the point of drug dependency: when an individual’s ability to control drug consumption deteriorates.

DRUG ADDICTION IS CURABLE: DEBUNKING THE MYTH

By breaking free of the
narrow view that all
illicit drugs are bad, our
research community has demonstrated their
potential for good.

The hijacking theory of drug addiction provides a more favourable output for a drug addict’s recovery. Instead of being an incurable chronic disease, the hijacking theory suggests that addictive behaviour has the potential to be unlearnt. This outlook has led to rehabilitation strategies focused on retraining the reward pathway to associate rewards with being drug-free. The practice of these so-called contingency management schemes has transformed the treatment of addiction (Petry 2011, Ross 2020). Their efficacy far surpassing that achieved with a pharmacological intervention (i.e. substance substitute) (Petry 2011, Ross 2020). 

The hijacking theory of drug addiction provides a more favourable output for a drug addict’s recovery. Instead of being an incurable chronic disease, the hijacking theory suggests that addictive behaviour has the potential to be unlearnt. This outlook has led to rehabilitation strategies focused on retraining the reward pathway to associate rewards with being drug-free. The practice of these so-called contingency management schemes has transformed the treatment of addiction (Petry 2011, Ross 2020). Their efficacy far surpassing that achieved with a pharmacological intervention (i.e. substance substitute) (Petry 2011, Ross 2020). 

ILLICIT DOES NOT MEAN ADDICTIVE: DEBUNKING THE MYTH

The illegal branding of specific psychedelics has been justified by the reported harm associated with the use of each drug. At the centre of this is the claim that illicit drugs are more addictive than their legal counterparts (such as tobacco and alcohol). However, this remains a matter of debate (Nutt et al. 2007; Hart, 2020). The ranking of a drug’s addictive potential is a combination of if/how strongly a drug activates the reward pathway, along with practical considerations of how easy the substance is to obtain/what does the substance cost. Unsurprisingly, at the top of the ranking are the illicit drugs: opioids (heroin, morphine, opium) and cocaine (Nutt et al. 2007). However, closely following are tobacco and alcohol (Nutt et al. 2007). Although both substances have high addictive potentials, tobacco and alcohol retain their legal status. Whereas, LSD and psilocybin (aka magic mushrooms) have no physical addictive properties, but are illegal.   

DRUG USE IS UNLIKELY TO END IN DRUG ADDICTION: DEBUNKING THE MYTH

How addictive is a “highly addictive” drug? Despite the propaganda, the path of illicit drug use to addiction is not a simple one. 70-90% of illicit drug users never develop drug dependency (Grifell & Hart, 2018). Expectedly, the type of drug and the frequency of use significantly impacts an individual’s risk. The higher proportion of users that transition to addicts typically being those using higher ranked addictive drugs (i.e heroin and cocaine). Nonetheless, this fact awakens us to the truth: illicit drug use is not sufficient to cause addiction (Ross, 2020). Logically, it follows that additional factors mark an individual’s risk of drug addiction (Ersche et al. 2020).  Seemly unrelated factors have been robustly implicated in marking an individual as vulnerable, including: genetics, gender, social (i.e. life adversities) and economic status (Redonnet et al. 2012; Ersche et al. 2020; Oliverio et al. 2020; Munn‐Chernoff et al. 2021). 

REPERCUSSIONS OF THE MYTHS

Despite the above, the ban on illicit drugs remains.  The repercussions of which impacts the society, economy and health sectors (Nutt et al. 2013).  In regards to society, illicit drug users and addicts are often treated as outcasts. The negative impact of which can fuel continued drug use, and hinder the rehabilitation and acceptance of recovering addicts back into society. Moreover, our economy is drained by law enforcement costs against the illicit drug trade that amounts to an estimated £780 million annually (Fell et al. 2019). Despite this staggering figure, law enforcement impact is marginal at best. In terms of health, the transition of banned psychedelics into the clinic has been an uphill battle, despite evidence of their efficacy and safety (Krediet et al. 2020). Fortunately, the last decade has seen a boom in the clinical application of illicit drugs (including LSD, ecstasy and ketamine) in the treatment of neuropsychiatric disorders (Nutt et al. 2013; De Gregorio et al. 2021). By breaking free of the narrow view that all illicit drugs are bad, our research community has demonstrated their potential for good.

Edited by: Steliana Yanakieva and Peter Richardson

REFERENCES

  • De Gregorio, D., Aguilar-Valles, A., Preller, K. H., Heifets, B. D., Hibicke, M., Mitchell, J., & Gobbi, G. (2021). Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine. The Journal of Neuroscience, 41(5), 891–900. https://doi.org/10.1523/JNEUROSCI.1659-20.2020
  • Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, 2013
  • Ersche, K. D., Meng, C., Ziauddeen, H., Stochl, J., Williams, G. B., Bullmore, E. T., & Robbins, T. W. (2020). Brain networks underlying vulnerability and resilience to drug addiction. Proceedings of the National Academy of Sciences, 117(26), 15253–15261. https://doi.org/10.1073/pnas.2002509117 
  • Fell, E., James, O,. Dienes, H., Shah, N., & Grimshaw, J. (2019). Home Office Research Report 103. Understanding organised crime 2015/16: Estimating the scale and the social and economic costs. Second edition. 
  • Grifell, M., & Hart, C. (2018). Is Drug Addiction a Brain Disease? American Scientist, 106(3), 160. https://doi.org/10.1511/2018.106.3.160 
  • Krediet, E., Bostoen, T., Breeksema, J., van Schagen, A., Passie, T., & Vermetten, E. (2020). Reviewing the Potential of Psychedelics for the Treatment of PTSD. International Journal of Neuropsychopharmacology, 23(6), 385–400. https://doi.org/10.1093/ijnp/pyaa018 
  • Munn‐Chernoff, M. A., Johnson, E. C., Chou, Y., Coleman, J. R. I., Thornton, L. M., Walters, R. K., … Agrawal, A. (2021). Shared genetic risk between eating disorder‐ and substance‐use‐related phenotypes: Evidence from genome‐wide association studies. Addiction Biology, 26(1). https://doi.org/10.1111/adb.12880 
  • Nutt, D., King, L. A., Saulsbury, W., & Blakemore, C. (2007). Development of a rational scale to assess the harm of drugs of potential misuse. The Lancet, 369(9566), 1047–1053. https://doi.org/10.1016/S0140-6736(07)60464-4 
  • Nutt, D. J., King, L. A., & Nichols, D. E. (2013). Effects of Schedule I drug laws on neuroscience research and treatment innovation. Nature Reviews Neuroscience, 14(8), 577–585. https://doi.org/10.1038/nrn3530 
  • Nutt, D. J., Lingford-Hughes, A., Erritzoe, D., & Stokes, P. R. A. (2015). The dopamine theory of addiction: 40 years of highs and lows. Nature Reviews Neuroscience, 16(5), 305–312. https://doi.org/10.1038/nrn3939
  • Office of National Statistics 2020
  • Oliverio, R., Karelina, K., & Weil, Z. M. (2020). Sex, Drugs, and TBI: The Role of Sex in Substance Abuse Related to Traumatic Brain Injuries. Frontiers in Neurology, 11. https://doi.org/10.3389/fneur.2020.546775
  • Pang, T. Y., Hannan, A. J., & Lawrence, A. J. (2019). Novel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment. Neuropharmacology, 145, 25–36. https://doi.org/10.1016/j.neuropharm.2018.02.021 
  • Redonnet, B., Chollet, A., Fombonne, E., Bowes, L., & Melchior, M. (2012). Tobacco, alcohol, cannabis and other illegal drug use among young adults: The socioeconomic context. Drug and Alcohol Dependence, 121(3), 231–239. https://doi.org/10.1016/j.drugalcdep.2011.09.002

How being sick could make you sicker: The role of peripheral inflammation in depressive disorders.

Valentina Bart | 01 April 2021

“Mens sana in corpore sano” – a healthy mind in a healthy body

Mental health is a topic that is becoming increasingly important in everyday life. Presently, 1 in 6 children between the ages of 5 and 16 struggle with mental health issues, with the NHS reporting mental health problems to be the biggest cause of disability in the UK. It is often said that physical exercise is important for mental well-being. Taking this idea further and looking at current research, it becomes clear that a sick body could severely harm your mental health. 

But how does physical sickness link to our mental wellbeing? 

Inflammation is the natural reaction of the organism to an insult, such as exposure pathogens, severe trauma, stress, obesity, and normal aging. In an initial response, fast-responding immune cells, which are your body’s first line of protective soldiers, recognise pathogens by their specific proteins. Your “soldier cells” respond to these proteins by producing inflammatory mediators, which is the equivalent of sending out an emergency response team to do some damage control. This reaction causes the typical symptoms of inflammation: redness, swelling, pain, heat, and possibly loss of function. In an otherwise healthy organism this immune response is balanced so that after the damage caused by inflammation anti-inflammatory processes are induced to tidy up the mess. Eventually, that would restore homeostasis and  bring you back to your normal healthy self.

While these processes occur in most areas of the body, the brain was long considered an immune privileged site, meaning it was thought not to be affected by any of these immune processes occurring in the blood. However, over the last decades the idea that the central nervous system (CNS) is protected from inflammation has been challenged from two directions. On the one hand, there are CNS diseases such as Alzheimer’s disease and multiple sclerosis which are characterised and directly driven by immune responses and inflammation in the brain. On the other hand, it has been noted that peripheral immune responses, happening elsewhere in the body, also influence brain health. One example is “sickness behaviour”, a state of depressed mood, fatigue, and disrupted appetite associated with diseases. It drives sick individuals to rest and thus allows energy to be redirected to the immune system to combat pathogens. This is why you may feel lethargic and yucky when you get the flu. Interestingly, there is an overlap between the symptoms of “sickness behaviour” and major depressive disorder (MDD) which has led researchers to investigate the role of the immune system in neuropsychiatric disorders. 

MDD is a severe form of depression with symptoms that include loss of appetite, sleep disruption, fatigue and feelings of worthlessness. With a great increase in suicide (Chesney, Goodwin & Fazel, 2014) and around 30% of patients not responding to the standard treatments (Rush et al., 2006). It is troubling how little we know about this disease. Although there is a genetic component, this seems to interact with environmental factors, such as stress and trauma, to develop full blown MDD (Caspi et al., 2006). 

Additionally, several studies have described a direct link between inflammation and MDD. For example, the incidence of MDD is increased in patients suffering from inflammatory diseases such as rheumatoid arthritis (Dickens et al., 2002) or cancer (Linden et al., 2012) and vice versa. Also, approximately one-third of people struggling with MDD show increased inflammatory biomarkers in the absence of medical disease (Liu, Ho and Mak, 2012). Lastly, variants in some genes associated with inflammation are also associated with increased risk of MDD (Gałecki et al., 2012). With this increasing body of evidence, it is becoming very clear that peripheral inflammation is very important when it comes to understanding the biological mechanisms driving depression.

To appreciate how peripheral inflammation can affect the brain, we will follow two such pro-inflammatory mediators on their journey; IL-1 and TNF.

Naturally, we start at the beginning – the moment when our soldier immune cells are activated by the intrusion of pathogens. As a first line of defence, they produce and release a variety of pro-inflammatory substances, the job of which is to attract more specialised immune cells and direct the immune response. This is crucial, since different types of these specialised  cells are trained to respond to different types of pathogens more efficiently than the brute force offered by the soldier cells. You wouldn’t want an air force unit to deal with a marine attack. This is where IL-1 and TNF come in. 

During a regulated immune response, these cytokines alert your specialised forces, before being removed by anti-inflammatory signals to resolve inflammation and restore homeostasis. Although these inflammatory processes are great at dealing with pathogens, they also inflict a lot of self-damage which can easily be repaired after the inflammation has died down… assuming it does die down. If it doesn’t, this is known as chronic inflammation and can cause a lot of issues since the body is unable to repair itself. Indeed, studies consistently report high levels of pro-inflammatory mediators in patients struggling with depression (Dahl et al., 2014) and inflammation can even predict symptoms of depression later in life (Khandaker et al., 2014).

So, as now we know their role in an immune response, how could IL-1 and TNF affect mental health?

Crucially, they need to affect brain-resident cells. If they are present in the body in very high quantities, they can directly cross into the CNS. Considering the brain is the master regulator of the whole body and mediators are typically kept in a delicate balance, this can be dangerous. This is illustrated by the fact that while low doses of IL-1 are needed for memory formation, high levels as observed during inflammation actually impair the same process (Kelly et al., 2003), which is reflected in memory disturbances experienced by individuals with MDD (Lam et al., 2014).

Within the brain, IL-1 also activates the hypothalamic-pituitary-adrenal (HPA) axis, a complex system of glands in the brain and in the abdomen that influence each other and regulate how the body responds to stress. This axis is thought to be overactivated in MDD, causing an overproduction of stress-related hormones. Stress hormones once again have been linked to impaired memory formation in animal models (Alfarez, Joëls and Krugers, 2003).

Stress hormones also affect the release of neurotransmitters (brain hormones) and how they act on their receptors. One example is the serotonin 1A receptor, the expression of which in the brain is decreased by stress hormones (Meijer et al., 2001). This receptor normally binds to serotonin, the “happy chemical” that is known to play a role in depression.

When two neurons interact with each other in what is called a synapse, the one sending out a signal is called presynaptic, and the receiving neuron is called postsynaptic. Both of these neurons can express the Serotonin 1A receptor, but it will play different roles. When the receptor is expressed on the firing (presynaptic) neuron, it takes up serotonin released by the very same neuron and thereby prevents it reaching the receiving neuron. This is bad, as serotonin is important in regulating your mood via serotonin actually reaching the postsynaptic neuron. This presynaptic receptor is acted on by selective serotonin reuptake inhibitors (SSRIs, drugs prescribed for MDD) which cause its desensitisation, making serotonin available to the receiving neuron and alleviate symptoms of depression.

In contrast, the same receptor on the receiving neuron does not seem to be affected by SSRIs, which is good, as this receptor needs to bind serotonin to transmit the “happy signal”. This receptor however is affected by stress hormones, and a decrease of the postsynaptic receptor numbers has been linked to suicide by depression (Cheetham et al., 1990). 

IL-1 and TNF can also affect the brain without even gaining access. That is because they can interact with cells lining the barrier to the brain and cause them to produce other mediators that then act on brain-resident cells. In experiments with mice, researchers found that the injection of TNF triggers these brain-bordering cells to produce a lipid that has also been detected in the fluid surrounding the brain of depressed patients (Linnoila et al., 1983). Within the CNS this lipid stimulates the production of other pro-inflammatory cytokines that will further disturb the balance and has also been implicated in the activation of the HPA axis that we discussed before (García-Bueno, Serrats and Sawchenko, 2009).

In one last trick, IL-1 and TNF do not even have to be in close proximity to the brain to affect mental health: they can stimulate the vagus nerve which runs between the brain and the abdomen and relays information from the periphery into the brain. This is the major component of the parasympathetic nervous system involved in the control of heart rate, digestion, mood, and immune responses. In rats, researchers showed that peripheral IL-1 activates the afferent vagus nerve (Hansen et al., 2001), thereby informing the brain of inflammation detected in the body. By disrupting signalling through this nerve, the researchers demonstrated that they could prevent sickness behaviour in rats without affecting the amount of circulating IL-1 (Bluthé et al., 1994).

So, since IL-1 and TNF are thought to be key players involved in the symptoms of MDD, could they be a potential therapeutic target for MDD? Indeed, various anti-inflammatory agents have demonstrated anti-depressive effects: data from clinical trials in which people received medications that block inflammatory cytokines to treat medical diseases showed significant improvement of depressive symptoms (Kappelmann et al., 2018). Similar results were reported from another study where 5 out of 6 anti-inflammatory drugs could improve depression symptoms compared to placebos (Köhler‐Forsberg et al., 2019). While these are important findings, studies have failed to show consistent associations between inflammatory cytokines and disease severity, suggesting that only certain subtypes of depression are based on or exacerbated by inflammatory processes. Indeed, only a fraction of patients struggling with mental diseases present with markers of peripheral inflammation such as IL-1 and TNF. 

A study comparing cancer patients receiving pro-inflammatory cytokine therapy with MDD patients with no physical illness showed an overlap in depressive symptoms. However, this study also showed that psychomotor retardation and weight loss were stronger in depressed cancer patients while increased feelings of guilt were stronger in (otherwise healthy) MDD patients (Capuron et al., 2009). While this study investigated a very small number of people, the results fit with the idea of a high heterogeneity of mood disorders that would respond to different types of treatments. It is unclear at the moment whether the group of patients that benefits from anti-inflammatory drugs overlaps with the group of people that does not respond to traditional MDD medication.

To date, most studies of the interaction between immune activation and psychiatric diseases provide correlational evidence rather than causal relationships. While animal studies can show the direct production of depressive symptoms following cytokine exposure, such results cannot directly be translated into the complex reality of human mood disorders. Nevertheless, the link between peripheral inflammation and mental health can help explain mental side effects of immune activating therapeutics for the treatment of cancer. The mental health of patients receiving such medication should carefully be monitored.

In the future, continuous research into how exactly inflammatory mediators could trigger or exacerbate mental conditions will not only help us understand mental disease heterogeneity, but potentially also result in the development of immune-based strategies that might help improve the lives of mental health patients that do not respond to current therapeutics.

Editors: Steliana Yanakieva and Katie Sedgewick

References:

  • Alfarez, D. N., Joëls, M. and Krugers, H. J. (2003) ‘Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro’, European Journal of Neuroscience. John Wiley & Sons, Ltd, 17(9), pp. 1928–1934. doi: 10.1046/j.1460-9568.2003.02622.x.
  • Bluthé, R. M. et al. (1994) ‘Lipopolysaccharide induces sickness behaviour in rats by a vagal mediated mechanism – PubMed’, Comptes Rendus de l’Academie des Sciences – Series III, 317(6), pp. 499–503. Available at: https://pubmed.ncbi.nlm.nih.gov/7987701/ (Accessed: 5 January 2021).
  • Capuron, L. et al. (2009) ‘Does cytokine-induced depression differ from idiopathic major depression in medically healthy individuals?’, Journal of Affective Disorders. NIH Public Access, 119(1–3), pp. 181–185. doi: 10.1016/j.jad.2009.02.017.
  • Cheetham, S. C. et al. (1990) ‘Brain 5-HT1 binding sites in depressed suicides’, Psychopharmacology. Springer-Verlag, 102(4), pp. 544–548. doi: 10.1007/BF02247138.
  • Dahl, J. et al. (2014) ‘The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery’, Psychoneuroendocrinology. Elsevier Ltd, 45, pp. 77–86. doi: 10.1016/j.psyneuen.2014.03.019.
  • Dickens, C. et al. (2002) ‘Depression in rheumatoid arthritis: A systematic review of the literature with meta-analysis’, Psychosomatic Medicine. Lippincott Williams and Wilkins, pp. 52–60. doi: 10.1097/00006842-200201000-00008.
  • Gałecki, P. et al. (2012) ‘The expression of genes encoding for COX-2, MPO, iNOS, and sPLA2-IIA in patients with recurrent depressive disorder’, Journal of Affective Disorders. Elsevier, 138(3), pp. 360–366. doi: 10.1016/j.jad.2012.01.016.
  • García-Bueno, B., Serrats, J. and Sawchenko, P. E. (2009) ‘Cerebrovascular cyclooxygenase-1 expression, regulation, and role in hypothalamic-pituitary-adrenal axis activation by inflammatory stimuli’, Journal of Neuroscience. Society for Neuroscience, 29(41), pp. 12970–12981. doi: 10.1523/JNEUROSCI.2373-09.2009.
  • Hansen, M. K. et al. (2001) ‘The contribution of the vagus nerve in interleukin-1β-induced fever is dependent on dose’, American Journal of Physiology – Regulatory Integrative and Comparative Physiology. American Physiological Society, 280(4 49-4). doi: 10.1152/ajpregu.2001.280.4.r929.
  • Kappelmann, N. et al. (2018) ‘Antidepressant activity of anti-cytokine treatment: A systematic review and meta-analysis of clinical trials of chronic inflammatory conditions’, Molecular Psychiatry. Nature Publishing Group, 23(2), pp. 335–343. doi: 10.1038/mp.2016.167.
  • Kelly, Á. et al. (2003) ‘Activation of p38 plays a pivotal role in the inhibitory effect of lipopolysaccharide and interleukin-1β on long term potentiation in rat dentate gyrus’, Journal of Biological Chemistry. American Society for Biochemistry and Molecular Biology, 278(21), pp. 19453–19462. doi: 10.1074/jbc.M301938200.
  • Khandaker, G. M. et al. (2014) ‘Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life a population-based longitudinal study’, JAMA Psychiatry. American Medical Association, 71(10), pp. 1121–1128. doi: 10.1001/jamapsychiatry.2014.1332.
  • Köhler‐Forsberg, O. et al. (2019) ‘Efficacy of anti‐inflammatory treatment on major depressive disorder or depressive symptoms: meta‐analysis of clinical trials’, Acta Psychiatrica Scandinavica. Blackwell Publishing Ltd, 139(5), pp. 404–419. doi: 10.1111/acps.13016.
  • Lam, R. W. et al. (2014) ‘Cognitive dysfunction in major depressive disorder: Effects on psychosocial functioning and implications for treatment’, Canadian Journal of Psychiatry. Canadian Psychiatric Association, pp. 649–654. doi: 10.1177/070674371405901206.
  • Linden, W. et al. (2012) ‘Anxiety and depression after cancer diagnosis: Prevalence rates by cancer type, gender, and age’, in Journal of Affective Disorders. Elsevier, pp. 343–351. doi: 10.1016/j.jad.2012.03.025.
  • Linnoila, M. et al. (1983) ‘CSF Prostaglandin Levels in Depressed and Schizophrenic Patients’, Archives of General Psychiatry. American Medical Association, 40(4), pp. 405–406. doi: 10.1001/archpsyc.1983.01790040059008.
  • Liu, Y., Ho, R. C. M. and Mak, A. (2012) ‘Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: A meta-analysis and meta-regression’, Journal of Affective Disorders. Elsevier, pp. 230–239. doi: 10.1016/j.jad.2011.08.003.
  • Meijer et al. (2001) ‘Transcriptional Repression of the 5-HT1A Receptor Promoter by Corticosterone Via Mineralocorticoid Receptors Depends on the Cellular Context’, Journal of Neuroendocrinology, 12(3), pp. 245–254. doi: 10.1046/j.1365-2826.2000.00445.x.

The Mad King of England: Neuroscience behind the Royal Malady

Ian Fox | 17 MAR 2021

George III was King of Great Britain and Ireland from 1760 to 1820. He ascended the throne of Britain when he was only 23 years old and he reigned for just over 40 years – making him one of Britain’s longest ruling monarchs. His reign was marked by great national unrest, including the loss of the American War of Independence and then – only a few years later – the constant threat of invasion by Napoleonic France. Under his leadership, Britain navigated through the storm of war, eventually triumphing over France in 1815, and this brought about a 100-year long peace in Europe – known as ‘Pax Britannia’.

Now, I know what you are thinking – what does this have to do with neuroscience and the brain? Well, despite George III’s great political achievements, he is most commonly remembered in history as the ‘Mad King of England’ (Rohl, Warren, & Hunt, 1998). Although he was one of Britain’s longest reigning monarchs, George III was recorded to be relatively weak, both physically and mentally, especially during the latter half of his life. He suffered from a series of ailments, including ‘flying gout’, colic, insomnia, delirium, and acute mania (Rohl et al., 1998). Interestingly, he was also afflicted with hallucinations and delusions, often believing that two of his children – who had died in childhood – were still alive. It was also reported that he would talk rapidly and incoherently, apparently chattering endlessly for over 70 hours before he died, but this is disputed (Brooke, 1972). Altogether, he suffered from four, possibly five, manic attacks, the last of which occurred between 1810-1820 and eventually claimed his life.

It is clear then that the King was gripped by a terrible illness that overwhelmed his mind. But what exactly caused George III to go ‘mad’? This question has interested many historians and scientists for centuries, but to this day no one has solved the case of George III and ‘the Royal Malady’. For many years, the official diagnosis of the King was ‘madness’, a term widely used by 18th century medical professionals to describe any patient suffering from any form of mental disturbance causing a drastic change in character and personality (Rohl et al., 1998). Psychiatrists in the 19th century would eventually change this diagnosis to ‘mania’ which, as you can imagine, is still not very helpful, since mania can be implied of any mental disorder which causes rapid mood changes (Ray, 1855).

Whenever God of his infinite goodness shall call me out of this world, the tongue of malice may not paint my intentions in those colours she admires, nor the sycophant extol me beyond what I deserve.

King George III

It is clear then that the King was gripped by a terrible illness that overwhelmed his mind. But what exactly caused George III to go ‘mad’? This question has interested many historians and scientists for centuries, but to this day no one has solved the case of George III and ‘the Royal Malady’. For many years, the official diagnosis of the King was ‘madness’, a term widely used by 18th century medical professionals to describe any patient suffering from any form of mental disturbance causing a drastic change in character and personality (Rohl et al., 1998). Psychiatrists in the 19th century would eventually change this diagnosis to ‘mania’ which, as you can imagine, is still not very helpful, since mania can be implied of any mental disorder which causes rapid mood changes (Ray, 1855).

It would not be until 1966 that the case of George III and the Royal Malady would suddenly be reopened when two British psychiatrists, Ida Macalpine and Richard Hunter, proposed an intriguing and controversial hypothesis. They suggested that George III suffered from an acute and rare genetic disorder, known as ‘porphyria’ (Macalpine & Hunter, 1966). Porphyria itself is not considered a disorder of the brain in the classical sense such as Alzheimer’s disease and Parkinson’s disease. Instead, porphyria is actually a blood disorder that, in some instances, can cause detrimental effects on the brain. Macalpine and Hunter insisted their theory was correct via a retrospective diagnosis based on the fact that the King suffered from sporadic attacks with unusual symptoms that can also be found in modern day porphyria patients. For instance, the King would experience periods of severe and rapid mood changes, such as going from a state of depression to intense manic episodes. These derangements would also coincide with other health problems, such as gall stones, ‘bilious attacks’, chest infections, and mostly importantly – the dark discolouration of his urine, which is a hallmark feature of porphyria (Macalpine & Hunter, 1966). Like porphyria patients, the King would often recover from these attacks; his mental health would improve, and the colour of his urine would return to normal. Since his first major attack in 1788, he would not relapse until 1795 – almost 7 years later. However, from then on, the relapse periods would become shorter and the symptoms would worsen; the King’s psychotic episodes would become more intense and he even gradually lost his sight (Macalpine & Hunter, 1966).

As previously stated, porphyria is a genetic disorder and therefore it is often inherited. With this in mind and to further support their claim that George III suffered from porphyria, Macalpine and Hunter traced signs of the disease in some of the King’s ascendants, notably Mary Queen of Scots. Additionally, they also traced porphyria in some of George III’s descendants, including possibly Queen Victoria and two members of the current royal family, however their identities remain anonymous (Rohl, Warren, & Hunt, 1998). Ida Macalpine and Richard Hunter were simultaneously praised and despised upon their publication of this new theory. Many claimed it was a meaningful breakthrough, whilst others contested their diagnosis, suggesting that their interpretation was misleading and in some cases, fraudulent (Peters, 2011). Nevertheless, there is no doubt that the publication of Macalpine and Hunter’s theory sparked a huge public interest into porphyria, as demonstrated by the publication of the best-selling books ‘George III and The Mad Business’ and ‘The Purple Secret’. However, not much is actually known about porphyria, especially at the neuroscientific level. How, for example, does porphyria affect the brain and how does it cause ‘madness’?

As stated before, porphyria is a blood disorder, but more specifically it is a disease that affects how blood is made. Porphyria itself is not a single disorder but refers to a group of eight disorders, each of which is characterised by the unique effect it has on how blood is produced (Meyer, Schuurmans, & Lindberg, 1998). Blood, obviously, is very important and without it our tissues and cells would not be able to receive oxygen. Oxygen is transported in the blood through a molecule called heme which also gives blood its characteristic red pigment. Heme is made through the heme biosynthetic pathway – a multistep process – in which several intermediate molecules (heme precursors) are treated by specific enzymes and are eventually converted into heme. The proper function of these enzymes is imperative to the production of heme – if one enzyme is faulty, then the heme precursors cannot be properly processed. Porphyria is caused when one of these enzymes becomes faulty either through genetic changes (i.e. mutations), or sometimes through the use of specific drugs (Elder, Gray, & Nicholson, 1972). The heme precursors then begin to accumulate in the body and eventually become toxic, causing problems such as motor neuropathy (difficulty moving), gastrointestinal distress, skin lesions, and of course – neuropsychiatric problems (Meyer et al., 1998). It is important to note that not all of the porphyrias cause neuropsychiatric problems, but the ones that do are called the ‘neuroporphyrias’ (Lin et al., 2008).

So, what exactly are the neuropsychiatric symptoms of the neuroporphyrias, and what are the causes behind them? As mentioned previously, porphyria is not traditionally seen as a neurological disorder. This, in addition to the large variation in neuropsychiatric symptoms between patients, means that the brain-based symptoms of the disorder have not been well characterised. For instance, Kuo et al (2011) was one of the first to clearly define several neurological manifestations in patients with acute intermittent porphyria (AIP). Out of 12 patients, 8 had ‘conscious disturbances’, 4 had seizures, and 7 had motor paresis (inability to move arms or legs) (Kuo et al., 2011). Other researchers have also reported aggression, psychosis, and hallucinations, as well as a high comorbidity with other disorders such as depression and schizophrenia (Suh et al., 2019). Nerve atrophy (i.e. the degeneration of brain tissue overtime) has also been reported in AIP patients, especially in brain areas that control vision and where visual information is processed, known as the parieto-occipital lobes (Suh et al., 2019).

Some AIP patients also display a condition called posterior reversible encephalopathy syndrome (PRES) (Zhao, Wei, Wang, Chen, & Shang, 2014). PRES also affects the parieto-occipital lobes by degenerating the white matter in the region. The white matter is important for nerves in the brain to relay signals at a much faster speed; in other words, it acts as an insulator for nerve signalling. MRI scans from AIP patients with PRES show a white ‘bleeding’ in the parieto-occipital lobes, signifying the loss of white matter, which causes patients to have headaches, seizures, and visual abnormalities (Suh et al., 2019; Zhao et al., 2014). Blindness is not unusual with cases of porphyria, and so it was with the case of George III – could PRES explain why the King lost his sight, and does this further support the ‘porphyria hypothesis’? White matter atrophy has also been observed in the nerves that control the movement of the arms and legs, which may also explain why many porphyria patients experience motor paresis.

It is quite clear then that porphyria is more than just a blood disorder and it can have a detrimental impact on the functioning of the brain. But how exactly do the heme precursors exert their toxic effect on the brain? What are the underlying mechanisms behind the neuroporphyrias? The answer to these questions has remained elusive to neuroscientists for many decades, and to this day the exact mechanisms are poorly understood. One of the leading theories is that one of the heme precursors behind porphyria, called aminolevulinic acid (or ‘ALA’) looks and acts very similarly to a type of neurotransmitter called γ-aminobutyric acid (or ‘GABA’). GABA is vital for regulating nerve signalling activity and it has been theorised that ALA might interfere with normal GABA function (Windebank & Bonkovsky, 2005). This means that ALA may impair how nerves send their signals around the brain which could result in headaches, seizures, and possibly psychiatric problems like hallucinations and delusions.

Experiments have also been done on cells that have been grown in petri dishes. From these experiments, researchers have found that elevated ALA levels cause other harmful chemicals to build-up and damage the cells (Kazamel, Desnick, & Quigley, 2020). They also reported that ALA damages the DNA of the cells, and also that the cells showed decreased energy production – very harmful indeed! Researchers have also tried to model porphyria in mice, with some success. They have shown that when they genetically engineer the ALA enzyme and reduce its functionality, the mice show similar motor symptoms as porphyria patients, as well as damage to the brain (Kazamel et al., 2020). Although we still do not understand much about the mechanisms of porphyria, perhaps with this animal model researchers can begin to describe the exact neuroscientific underpinnings of the disorder.

There are still many questions that neuroscientists are asking about porphyria. For example, why is the white matter targeted? Why does porphyria seem to affect the posterior regions of the brain that control visual processing? And above all, why are some patients more affected than others? Although the porphyria theory about George III is still, well – a theory, and many researchers believe that George III instead suffered from bipolar disorder (Peters, 2011), there is no doubt that ever since the publication of Macalpine and Hunter’s paper, interest in porphyria has only gone up. From the perspective of a neuroscientist, porphyria becomes more and more interesting the more we unveil about it, and perhaps soon we will acquire a full picture of the disorder that may (or may not!) have driven one of Britain’s greatest Kings to madness.

Editors: Matt Higgs and Uroosa Chughtai

References:

Rachael Stickland | 13 FEB 2017

Whatever you end up doing this Valentine’s day, we hope you enjoy this cathartic moan about your very closest companion, your brain. This poem is inspired by one from this film, but I didn’t have to tell you that, did I?  Please follow the links (underlined text) in the poem to learn more about the brain facts that grab your attention. 


♥ 11 things I hate about you, Brain ♥

I hate the way you’re soaked in blood
Taking more than your fair share
I hate that you ignore my touch
But get tricked by what’s not there

I hate your big dumb blood brain barrier
That closes off your mind
I hate that cars still make you sick
And that you make me rhyme

I hate your stupid fixations
with really annoying songs
I hate the way you speak in Latin
I hate it when you’re wrong

I hate the way you don’t remember
How things actually went
But mostly, I hate that your dreams aren’t real
Yes brain, get bent.

 Tune in next year for another masterpiece, ‘12 things I hate about you, oesophagus’.

(Very helpfully) edited by Jonathan Fagg

Things that look like your brain but actually aren’t

Rachael Stickland | 24 DEC 2016

When you’re drunk and merry celebrating Christmas today, remember to watch out for the brain imposters! The Brain Domain team have put together a list of some of the most convincing brain imposters – things that look like your brain but actually aren’t!

                             A WALNUT                                                   A CAULIFLOWER

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BRAIN CORAL IN GREAT BARRIER REEF

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A PRIMATE’S BRAIN

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A folded cerebral cortex allows a much greater surface area of brain to be packed in to the skull. This makes them similar to a human brain in appearance. Watch out for your peanuts this Christmas!

SOMEONE ELSE’S BRAIN

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Though it may be difficult, never confuse someone else’s brain with your own! This can cause all kinds of awkward conversations, particularly at Christmas.

…. Do come back in January to read some neuroscience content that’s a lot more informative!

Walnut, Coral, and Cauliflower images sourced from Dreamstime
Coral: © Surpasspro | Dreamstime.com – Brain Coral In Barrier Reef Photo
Cauliflower: © Jultud | Dreamstime.com – Cauliflower Photo)

 Animal Brain image adapted from the Mammalian Brain Collection

Mini-Update of Neuroscience News

Our regular postings have been interrupted by the holiday period and several conferences, so until we have things back to normal we have a small update of neuroscience news!

Firstly, The Brain Domain will be presenting at the Neuropalooza conference later this month. Good luck to all the other presenters! Remember to check out our Join Us page if you’re interested in writing for The Brain Domain!

In other news, a new board game has appeared on kickstarter. It’s called ‘DNA Ahead Game & More‘, and is designed to help educate players about the history and current thinking of DNA in science. The overall aim of the project is to increase awareness of genetics, by making it accessible and interactive at home! It looks to be an interesting project, definitely worth checking out, maybe even worth backing?


Can we cure drug addiction with more drugs? – Oly Bartley

Work published by researchers at the Medical University of South Carolina has demonstrated that by activating the neurons of the ventromedial prefrontal cortex (vmPFC) relapse of cocaine use in rats can be reduced. It works because cocaine hijacks a normally very useful and normal brain behaviour: when the brain is exposed to high levels of neurotransmitters (e.g. dopamine), it forms powerful cue memories associating that neurotransmitter influx with environmental cues. In this instance, upon encountering that familiar environment this associated memory creates an intense desire for that influx, and pushes cocaine users to relapse. The vmPFC plays a pivotal role in extinction of associated memories, so by activating it that intense desire, and thus the relapse behaviour, could be repressed.

The researchers used a viral injection to add designer receptors to the vmPFCs neurons, then they delivered a drug that activates those designer receptors specifically to increase vmPFC activity. This suppressed the pathological component of the cued memory response and relapse due to cued memory reduced significantly. So yes, the lab group are hoping that they will be able to help drug addicts with a different drug!

Source: J.Neuroscience


Social Neuroscience: MEG talks to MEG – Rachael Stickland

Magnetoencephalography (MEG) is a functional neuroimaging technique that records magnetic fields produced by electrical brain activity. MEG is used by many researchers to investigate social cognition. However, studies into how the brain processes information during social interactions typically have one common limitation…. there is only one person’s brain being monitored at one time! Researchers in Finland have introduced a novel MEG dual scanning approach, where they connect two MEG scanners at different centres (5km apart) via the internet, and the two respective subjects talk over landlines. MEG has very good temporal resolution, so it is a good candidate for studying something as dynamic and unpredictable as social interactions.  They managed to create a stable and short-latency audio connection (the subjects could not perceive the lag) which had accurate synchronisation of the two MEG scanners. They recorded auditory evoked cortical responses, and showed them to be similar in the two subjects.

Their study is a proof of concept, that can hopefully be extended to connecting MEG labs all over the world. Once some improvements and technical barriers have been overcome (e.g. including a stable visual link) many interesting questions within social neuroscience can start to be unravelled.

Source: Frontiers in Human Neuroscience

Dogs and Coffee Shops on the Brain

Dogs understand human, but do you understand Dog?

If you’ve ever heard the claim that dogs don’t understand what you’re saying to them, only how you say it, then it’s time to check your facts! An MRI study in Hungary has established dogs not only process intonation, but also words. Dogs need both words and intonation to be positive to activate their reward centre. So saying “Aren’t you a stupid dog?” in a praising manner won’t fly any more…

Watch this video for a quick overview
Read a bit more about it here

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Got writing work to do? Going to Coffee shops is no longer just for the pretentious! It’s just common sense.

All hipster-jokes aside, have you ever noticed that sometimes you get more done working in a Coffee Shop? Is it the background noise? The caffeinated air? A change of scenery? Perhaps, but it may actually be because concentration is contagious. A new study has found when you sit near people working hard, then your efforts also improve, regardless of whether you can see what they’re working on or not. It’s far from conclusive (we have a couple of questions ourselves), but this could go some way to establishing why some of us prefer to work in “free wifi establishments” instead of in the office.

Read some more about it here
Read the original paper here

Image sourced from imgur

Content coming soon..

The brain is a wonderful organ. It starts working the moment you get up in the morning and does not stop until you get into the office. Robert Frost

The team at The Brain Domain are working hard to make this site a useful resource for people interested in neuroscience, at all different levels. We are currently collecting lots of useful resources to make a good go-to list of where you can find the information you need, as well as writing some interesting articles of our own.

Find out more about us here.

So follow us, bear with us, and please come back soon to find out what we have for you!

In the mean time, if you have any suggestions or questions, please let us know: