Could Mind-Expanding Drugs Lead to Medical Breakthroughs?
A Q&A with David Nutt and Robin Carhart-Harris


September 7, 2012

Researchers have long thought that psychedelic drugs might effectively treat a range of psychiatric and neurological ailments. But, Professor David Nutt and Dr Robin Carhart-Harris of Imperial College London argue, government bans in the late 1960s have prevented researchers from studying these compounds for decades. While recent research has lent credence to early hypotheses about their potential, more research needs to occur before any resulting treatments could come into widespread use, and governments must amend restrictions on the substances, they say.

Q: What are psychedelics?

A: Psychedelic most literally means “mind manifesting." In practice, that covers a range of drugs, but the name is meant to convey a particular property, that these drugs make latent psychological material accessible to consciousness. Psychedelics occur in nature in "magic" mushrooms (psilocybin), peyote cactus (mescaline), plant roots (ibogaine), plant bark (ayahuasca), and in cereal fungal growths (ergot derivatives).

Work on fungi  led to the discovery of the most famous psychedelic, LSD, by Albert Hofmann in 1938. LSD produces profound changes in the conscious state, with marked alterations in time perception, visual perception, and sensory integration. It can also alter one’s sense of self in a way that few other experiences can. For these reasons LSD was considered an important new tool for understanding the brain. Unfortunately, it was banned in the United Kingdom and United States, and research halted.

Some of the results from early LSD trials were striking. A recent meta-analysis of the six published studies in alcoholism found it to be at least as effective as any current treatment.(1) Another area of treatment where LSD was extensively used was as an adjunct to psychotherapy.(2) Between the 1950s and mid-1960s there were more than 1,000 clinical papers discussing 40,000 patients, several dozen books, and six international conferences on LSD-assisted psychotherapy.(3) A particularly remarkable benefit was helping patients with terminal illness come to terms with dying. They said LSD gave them a sense of being at one with themselves, allowing them to die feeling fulfilled rather than frightened.

In addition, some medicinal stimulant derivatives have interesting mood-altering properties; the best known of these is MDMA. Developed in the 1950s and originally known as “empathy,” MDMA was widely used in the United States to help couples get over their anger and hostility so they could engage more fruitfully in psychotherapy. It entered youth culture as “ecstasy” and became associated with the dance/rave scene; after a social backlash against this culture in the 1980s, the substance was banned.

Since the banning of these drugs there have been amazing advances in the techniques to study the brain, particularly magnetic resonance imaging (MRI). This has revolutionized our understanding of the location of brain functions and the interactions between brain regions. Temporary "mind-altering" substances like psychedelics and MDMA should be central to neuroscience research and our understanding of many brain functions. They also offer exciting new approaches to treatments of brain disorders. It is hugely disappointing that the opportunities offered by these drugs have been so impeded by their legal status.(4)

Q: Aside from LSD, what other psychedelics did researchers test?

A: The most popular was psilocybin mushrooms, although psilocybin itself was also banned around the same time as LSD. Psilocybin mushrooms grow widely around the world and can easily be obtained at least at certain times of year. Psilocybin is shorter-acting than LSD, so if unwanted effects emerge they are easier to ride out. Although largely used recreationally, there are case reports of people using this drug to self-treat disorders ranging from obsessive compulsive disorder (OCD) to cluster headaches.

Cluster headache is one of the worst pain syndromes known (mothers who suffer say the pain is worse than childbirth), with limited treatments and high suicide rates. Although psilocybin is used by many sufferers, its status as a controlled substance means it has not been formally studied. When we approached a cluster headache charity in the UK to ask for support for a trial of psilocybin in the clinic, they replied they could not consider working with “illegal” drugs! This sentiment is not uncommon and explains why researchers have conducted so little research on psychedelics. Funding bodies are apprehensive about being seen to “encourage” illegal drug use, researchers find the regulations required for use of these drugs expensive and oppressive, and patients who might benefit are scared they might fall foul of the law.

Still, there have been a few scientific studies of psilocybin that have highlighted its potential value. Roland Griffiths at Johns Hopkins University found that when used in a psychotherapy context, psilocybin can have profound effects on a sense of meaning. Many of the subjects who took the drug said that this was one of the top five most significant experiences in their lives, comparable to such things as the birth of their first child or the death of a parent (the control group was given the stimulant methylphenidate and did not report such effects).(5) Moreover, these effects were long lasting—a follow-up two years later showed that subjects still viewed their experience as profoundly meaningful.(6)

In the clinic, Charles Grob and colleagues at UCLA conducted a trial of psilocybin-assisted psychotherapy for patients with cancer.(7) In a similar fashion to the value of LSD in terminal illness, psilocybin helped people cope better with their illness and make sense of their lives.

Q: How does MDMA fit in?

A: Since its ban in the 1980s, the Multidisciplinary Association for Psychedelic Studies and others have campaigned to defend MDMA's potential as a therapy. They argue for its utility as an adjunct to psychotherapy, run scientific symposia on this topic, and make the drug available for some small scientific and clinical proof-of-concept studies.

The first clinical study was recently completed in the United States in patients with treatment-resistant post-traumatic stress disorder (PTSD).(8) Current therapeutic strategies for PTSD aim towards decreasing anxiety associated with traumatic memories, but this requires the patient to relive his or her trauma and then overcome it. For many people, the traumatic memories are so powerful and distressing that they cannot cope with the emotions and so cannot proceed with the therapy. MDMA enables patients to open-up emotionally and talk about their trauma—when previously this would have been impossible. Psychiatrist and clinical researcher Michael Mithoefer and colleagues have continued to follow up their group of treated patients for more than a year and the effects seem to be enduring.(8) Other researchers now need to replicate the findings.

There are other potential clinical uses for MDMA. Most obviously it could be used more broadly in psychotherapy, particularly in couples counseling as it was originally. There are examples of its being useful in helping people come to terms with their loved one’s terminal illness. Some have suggested the apparent empathy-enhancing actions of MDMA might help people with autism, and MAPS has made a grant available to test this hypothesis. One person has written about how it keeps his depression at bay [Anonymous (2001) Confessions of a middle-aged ecstasy eater. Granta 74.].

Other less obvious possibilities include the treatment of disabling motor dyskinesias associated with Parkinson’s disease; case reports suggest some patients might respond well to MDMA. Animal studies suggest MDMA might also facilitate healing from brain trauma, something that needs testing in humans.(9) It may also be useful for disorders outside the brain. We received a remarkable e-mail from a man who said it had eased the symptoms of his severe asthma for several years after all known treatments had previously failed. This sounds implausible, but the lung is full of serotonin, a chemical messenger now known to play a role in the effects of MDMA, so it certainly warrants further scientific exploration.

Q: How do these drugs work, exactly?

A: Psychedelics mimic serotonin at the 5HT2A receptor, one of the 14 or so serotonin receptors in the brain.(10) This particular receptor plays a critical role in integrating diverse brain functions. The potency of psychedelics is directly related to their affinity at the 5HT2A receptor. Not all drugs that act on this receptor are psychedelics but we think that subtle differences in the way psychedelics interact with the receptor leads to different intracellular messenger actions specific to these drugs. We don't yet know why; if we could find out, it might help explain disorders such as schizophrenia, where psychedelic-like changes in perception can occur in its initial stages.

MDMA also works indirectly on serotonin: It prevents its reuptake back into the nerve terminals, and may also produce serotonin release, increasing the levels of the chemical messenger. MDMA also increases the release of noradrenaline and dopamine, chemical messengers involved in stress and pleasure responses, respectively.

Q: What have you found in your recent research with these compounds?

A: We have now conducted three imaging studies with psilocybin and one with MDMA as part of collaborations with Cardiff University and the Beckley Foundation. Our first study looked at the effects of psilocybin on brain blood flow using the MRI technique arterial spin labeling (ASL). We predicted an increase in blood flow, particularly in visual regions since psilocybin produces a lot of visual disturbances. To our amazement we found the opposite: Psilocybin reduced blood flow and the greater the reduction, the bigger the drug’s effects [see figure 1]. (11)

Fig_1_Nutt_Carhart-Harris_c 

Figure 1. The upper chart shows the relationship between anterior cingulate blood flow after psilocybin and the drug’s subjective effects. It shows that people who experienced more intense effects had bigger decreases in blood flow in the anterior cingulate. The bottom image shows the average regional decreases in brain blood flow after psilocybin. See (11) for methods. Circled in yellow is the ventromedial PFC; there is over-activity here in depression. (Courtesy of David Nutt & Robin Carhart-Harris) [Click image to enlarge]

When we repeated this experiment using BOLD fMRI, we found essentially the same result (11). Both studies showed that the main targets of psilocybin were the front and back connector hubs of the brain—the anterior and posterior cingulate cortex—plus the thalamus, a subcortical hub structure in the centre of the brain. We now believe that switching off these key connector hubs is responsible for the psychedelic effects, decreasing the brain’s internal order so that it can operate more freely. Aldous Huxley predicted these findings 50 years ago in his famous book The Doors of Perception. He postulated that normal consciousness is forced on the brain by a “reducing valve” that limits or constrains what we think and perceive.(12)

We believe that the reductions of brain activity produced by psilocybin are due to the density of the 5HT2A receptors in connector hub regions of the brain [see figure 2]. Serotonin 2A receptors are found on both inhibitory and excitatory neurons in the brain and both may contribute to the net decreases we have seen with fMRI (13).

 Fig_1_Nutt_Carhart-Harris_c 

Figure 2. Regional 5-HT2A receptor binding potentials: 5-HT2A binding potential was assessed with 18F-altanserin PET in 136 healthy adult human subjects. Note that the cingulate cortex hub structures have some of the highest densities of 5-HT2A receptors. For methods, see (14). (Courtesy of David Nutt & Robin Carhart-Harris) [Click image to enlarge]

Subsequently, we have used magnetoencephalography (MEG) to explore in more detail the actions of psilocybin in the cortex. Again we confirmed the original findings: Psilocybin reduces activity across the whole range of frequency bands in the brain. Again the predominant effect was in the two connector regions, the anterior and posterior cingulate cortex. (The relevant paper is currently in preparation.)

In our fMRI studies we also found that some subjects had enduring benefits on mental wellbeing two weeks after the drug administration. These may have been because psilocybin reduces brain activity in parts of the medial prefrontal cortex over-active in depression.(15) Based on these findings we have now obtained grant support from the UK Medical Research Council to conduct the first trial of psilocybin in treatment-resistant depression.

Subjectively, MDMA can be thought of as half stimulant, half psychedelic, and our recent fMRI work has supported this. Similar to psilocybin, we have found decreases in brain blood flow with MDMA and decreases in functional connectivity between the brain’s frontal and parietal hubs. We have also looked at how MDMA interacts with remembering very positive and negative personal memories and found enhanced activations to positive memories under MDMA and reduced activations to negative memories. (The relevant paper is currently in preparation.) Other researchers have found reduced amygdala activations (the brain’s main fear reflex center) when people are exposed to fearful faces.(16, 17) Altogether, these results are exciting and are what we would expect for a drug capable of reducing anxiety and facilitating the revisiting of painful memories in psychotherapy for PTSD.

 Q: How do you think substance-laws should be changed?

A: One urgent need is to revise the law so that patients can access these new treatment options should their efficacy become established. A simple way forward in the short term would be to abolish in the international conventions the concept of schedule 1 drugs (those without medical use). This could be done at the national level; a good example is the countries where medicinal cannabis is available, like The Netherlands.

A more radical alternative would be to look for variants of these drugs that have therapeutic effects without being psychedelic or of high recreational value. Non-psychedelic variants of LSD, such as 2Bromo-LSD, have been shown to be useful in cluster headaches but have not yet been made available publicly. Some chemistry groups have worked on variants of MDMA-like drugs that might be more effective therapies(18); sadly some of these have already been banned because they have entered, or even because they might enter, the recreational arena. We need the authorities to take a more mature approach to new compounds even if they might also be of interest to young people seeking thrills.

References

1.  Krebs TS, Johansen PO. Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. J Psychopharm. 2012;26(7):994–1002. Epub 2012/03/13.

2. Pahnke WN, Kurland AA, Unger S, Savage C, Grof S. The experimental use of psychedelic (LSD) psychotherapy. Int Z Klin Pharmakol Ther Toxikol. 1971;4(4):446–54. Epub 1971/06/01.

3.  Grinspoon L, Bakalar JB. Psychedelic drugs reconsidered. New York: Basic Books; 1979. xiv, 343 p. p.

4.  Nutt DJ, King LA. How the drug laws impede advances in health and science. International Journal of Drug Science, Policy and Law. 2012:in press.

5.  Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berl). 2006;187(3):268–83; discussion 84–92. Epub 2006/07/11.

6.  Griffiths R, Richards W, Johnson M, McCann U, Jesse R. Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. J Psychopharm. 2008;22(6):621–32. Epub 2008/07/03.

7.  Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 2011;68(1):71–8. Epub 2010/09/08.

8.  Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R. The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: The first randomized controlled pilot study. J Psychopharm. 2011;25(4):439–52. Epub 2010/07/21.

9.  Edut S, Rubovitch V, Schreiber S, Pick CG. The intriguing effects of ecstasy (MDMA) on cognitive function in mice subjected to a minimal traumatic brain injury (mTBI). Psychopharmacology (Berl). 2011;214(4):877–89. Epub 2010/12/02.

10. Nichols DE. Structure–activity relationships of serotonin 5-HT2A agonists. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 2012.

11.  Carhart-Harris RL, Erritzoe D, Williams T, Stone JM, Reed LJ, Colasanti A, et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(6):2138-43. Epub 2012/02/07.

12.  Huxley A. The doors of perception. 1st ed. New York: Harper; 1954. 79 p. p.

13.  Weber ET, Andrade R. Htr2a Gene and 5-HT(2A) Receptor Expression in the Cerebral Cortex Studied Using Genetically Modified Mice. Frontiers in neuroscience. 2010;4. Epub 2010/08/31.

14.  Erritzoe D, Frokjaer VG, Haugbol S, Marner L, Svarer C, Holst K, et al. Brain serotonin 2A receptor binding: relations to body mass index, tobacco and alcohol use. NeuroImage. 2009;46(1):23-30. Epub 2009/05/22.

15.  Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45(5):651–60. Epub 2005/03/08.

16.  Bedi G, Phan KL, Angstadt M, de Wit H. Effects of MDMA on sociability and neural response to social threat and social reward. Psychopharmacology (Berl). 2009;207(1):73–83. Epub 2009/08/15.

17.  Bedi G, Hyman D, de Wit H. Is ecstasy an "empathogen"? Effects of +/-3,4-methylenedioxymethamphetamine on prosocial feelings and identification of emotional states in others. Biol Psychiatry. 2010;68(12):1134–40. Epub 2010/10/16.

18.  Meltzer PC, Butler D, Deschamps JR, Madras BK. 1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors. J Med Chem. 2006;49(4):1420–32. Epub 2006/02/17.