How do hallucinogens work on the brain?
Robin Carhart-Harris, Mendel Kaelen and David Nutt consider a big question on several levels
The ‘classic’ hallucinogens – such as LSD (derived from ergotamine found in ergot fungi), dimethyltryptamine (DMT, the major hallucinogenic component of ayahuasca) and psilocybin (from magic mushrooms) – possess a unique and arguably unrivalled potential as scientific tools to study the mind and the brain.
For those of us who are currently fortunate enough to be researching them, there is a real sense that we are exploring something destined to become the ‘next big thing’ in psychopharmacology. But how much do we really know about how they act on the brain to produce their many unusual effects? Here, we summarise the relevant research, beginning at the level of single neurons and moving towards networks in the brain.
The level of single neurons
All classic hallucinogens stimulate a particular serotonin receptor subtype expressed on neurons in the brain, the serotonin 2A receptor. This receptor appears to be central to the action of hallucinogens because blocking it (with another drug called ketanserin) abolishes the occurrence of the hallucinatory state (Vollenweider et al., 1998). Also, the affinity (or ‘stickiness’) of different hallucinogens for the serotonin 2A receptor correlates positively with their potency, or ‘strength’; for example, LSD has an extremely high affinity for the serotonin 2A receptor and is remarkably potent (Glennon et al., 1984). That hallucinogens ‘stimulate’ serotonin 2A receptors means that they mimic the action of serotonin at the receptor by binding to it, altering its conformation or ‘shape’, and ultimately altering the internal conditions and therefore behaviour of the neuron it sits on.
For the serotonin 2A receptor, the key functional effect of its stimulation is an increase in the excitability of the hosting neuron. Serotonin 2A receptors are primarily expressed on an important type of neuron or brain cell in the brain, excitatory pyramidal neurons. More specifically, serotonin 2A receptors are especially highly expressed on excitatory pyramidal neurons in ‘layer 5’ of the cortex. The cortex is organised into layers of different cell types, like the different layers of a cake, and layer 5 is a deep layer, nearer the base than the icing (Weber & Andrade, 2010). Layer 5 pyramidal neurons are especially important functional units in the brain as they are the principal source of output from a cortical region. They project to hierarchically subordinate, or ‘lower’, cortical and subcortical regions (e.g. from a visual association region to the primary visual cortex).
Layer 5 pyramidal neurons project heavily onto inhibitory interneurons and so the net effect of their excitation seems to be inhibitory (Bastos et al., 2012). This is important because hallucinogen-induced excitation of layer 5 pyramidal cells has been interpreted by some as evidence of a more general excitatory effect of these drugs, but as will be discussed in the forthcoming sections, recent animal electrophysiological and human neuroimaging recordings have cast further doubt on the assumption that hallucinogens have a general excitatory effect on cortical activity (Carhart-Harris et al., 2012; Wood et al., 2012).
Captured by the idiom ‘failing to see the woods for the trees’, these results are a reminder that one should not be too hasty to extrapolate from the activity of certain single units in the brain, since the interconnected nature of cortical circuits means that local excitation can translate into net inhibition, or rather ‘disorder’, at a higher level of the system. If John Donne was a neuroscientist, he might have said: ‘no neuron is an island, entire of itself’.
Our videos describing different aspects of what we do.
Can Magic Mushrooms treat depression?- Robin Carhart-Harris at New Scientist Live 2017
Comeback of psychedelics in science and medicine: Robin Carhart Harris
Robin Carhart Harris 20th July 2016
Psychedelics: Lifting the veil | Robin Carhart-Harris | TEDxWarwick
Mendel Kaelen: Psychological & Neurophysiological Effects of Music in Combination with Psychedelics
- on The administration of psilocybin to healthy hallucinogen experienced volunteers I'm Karl a 40.yr Old Male who's Depressed & got Anxiety who also would like 2 try Philosybin Treatment as I don't believe in the treatment available @ the moment
- on The administration of psilocybin to healthy hallucinogen experienced volunteers Hello, I am 63 years old and am struggling with severe depression. I used many psycedelics during my teens and well into my 20s. Actually used LSD as a method of marriage communication. It was very helpful. Now 35-40 years later and nothing helps thi…
- on Help us treat depression! Hi. I would very much like to participate in a trial. I'm 49 and have suffered most of my life with anxiety and depression. I'm currently on dual reuptake inhibitors but they have limited effect for me. I've tried many, many things over the years to…
- on The administration of psilocybin to healthy hallucinogen experienced volunteers Hello everyone I'm on antidepressant from couple of years and I try many different types. Right now I have worst time ever. I try mushrooms which one found my self on last season 2016. I have found but that was very difficult for me. I go nearly ever…
- on Help us treat depression! I would be very interested to hear about your research on your use of psychedelics , I would be very interested if you are looking for new volunteers for further trials , I am 50 years old and I have suffered with depression for 25 years and have fou…
- on The administration of psilocybin to healthy hallucinogen experienced volunteers Hi, I have read your articles and I am currently on anti depressants. I have tried different kinds as I have mild PTSD from military service and suffer from depression constantly. I would very much like to assist and be a volunteer for future trials.
- on The administration of psilocybin to healthy hallucinogen experienced volunteers Hello, I’m am 43 year old male living in oxford and suffered from depression and anxiety for 20 some years and I am a chronic suffer. I am very interested in participating on this type of drug trial. In my 20’s I have picked my own mushrooms once or…
- on Are you having a psychedelic experience in the near future? Hi All, I suffer from depression and anxiety and have done so for many years. After being placed on anti-depressants (again), I had a very bad response and the side effects of increased suicidal thoughts became unbearable. It was an everyday battle o…