Hallucinogens play a critical role in many neurotransmitter systems as well as various areas of the brain.(1) In particular, there are a wide range of recreational and pharmaceutical drugs that have been heavily studied and proven to create various types of hallucinations.(1,2) The understanding of hallucinogens and their overall effects on regions of the brain may help identify new treatment options and provide awareness on the abuse and overuse of such drugs. Gaining a better understanding of the chemistry and neurological basis of hallucinogens may provide pharmaceutical advancements into how drugs are administered and how current drugs may be altered to reduce any hallucinogenic effect. Thus far receptor binding interactions, neurotransmitter release within the brain and behavioural responses have been observed in both recreational and pharmaceutical drugs.(2) These drugs can create either short or long-term effects on the brain (sometimes both) and in some cases these effects can be reversed.(3) There are also treatment options that have been proposed such as antipsychotics which are meant to suppress different effects of hallucinogens.

Overview


Hallucinogens are substances (drugs) that alter the perceptions and/or consciousness of individuals in different ways be it visual, auditory or tactile.(4) Often the clinical symptoms of hallucinogens include somatic symptoms such as dizziness, weakness, tremors; perceptual symptoms such as altered shape and colours, difficulty focusing on objects and finally psychic symptoms which alters mood, depersonalization, visual hallucinations etc.(5) Even though hallucinogens play a critical role in various brain regions there has been significant cortical activity seen in drug-induced hallucinations.(6)

Hallucinogens: Receptors, Neurotransmitters and the Brain


Hallucinogens play a key role on the various receptors and neurotransmitters located in the brain. In particular, the main ones that are focused on are serotonergic and dopaminergic systems/pathways (receptor interactions) of the prefrontal cortex and other cortical areas.(2) Thus accordingly the neurotransmitters that play a significant role are dopamine and serotonin.(3) There is evidence present of other pathways (i.e glutamatergic) and neurotransmitters present as well.(5)



Recreational Drugs


LSD and HPPD


Lysergic acid diethylamide, also known as LSD, is a potent drug that can produce a variety of effects such as euphoria, hallucinations, depersonalization and psychoses.(7) LSD has a high affinity for the serotonin receptor family (5-HT2A) and studies have now shown that it has a direct effect on dopaminergic systems within the brain.(5,7) The effects of LSD have been studied in humans as well as animal models such as rats to understand the mechanisms behind receptor activation. In one particular study performed by Marona-Lewicka et al. (2009), rats that were administered LSD portrayed two time-dependent phasic responses as well as the involvement of dopamine D4 receptors (D2-like isoforms). The first phase was primarily facilitated by the stimulation of serotonin receptors (max. reached 15 – 30 mins) which lasted about 1 hour while the second phase was mediated by dopamine D2-like receptor activation (max. reached 60 – 90 mins).(7)

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Drawing of a visual experience by an HPPD patient watching an arrow turn counterclockwise

LSD has also been studied in humans, in particular pathologies that have arisen due to overuse or substance abuse. Hallucinogen persisting perception disorder (HPPD) occurs in individuals who have used LSD in the past and are currently visualizing images that are similar to other drug-induced hallucinations.(1) The effects of HPPD can appear as a result of having used LSD once or they may never appear regardless of how many times an individual might have used LSD. People who had taken LSD for therapeutic reasons had a lower occurrence of getting HPPD as opposed to those who take it for recreational purposes.(5) However, the frequency of people with HPPD is very low in comparison to the millions of people that have probably taken LSD.(5) Most often visual disturbances are characteristic for HPPD individuals and include geometric hallucinations (sparkles, lattices, complex patterns), colour intensities, trailing phenomena, halos around objects, afterimages and in some instances flashbacks which in most cases are subjective.(1,5). The figure to the right depicts the afterimages (dark arrows) of the blue and red arrow seen by HPPD patients.(1) Although there are many visual disturbances present, often one or a few are seen by individuals at various times. Individuals rarely believe that the visual disturbances that appear are real thus signifying a lower visual area such as the primary visual cortex (V1) – cortical area responsible for geometric processing of visual inputs - may be the underlying circuitry for this disorder.(1)


The ingestion of LSD not only causes visual disturbances but has evoked the appearance of abnormal brain states as well as alterations in synaptic connectivity of the visual processing system often leading to HPPD.(1) Since LSD acts on the dopaminergic system, phenothiazines that are used to block dopamine end up causing worsened conditions of HPPD suggesting that HPPD may arise from increased excitation or inhibition of the visual networks.(1)

DOI


The hallucinogen DOI (2,5-dimethoxy-4-iodoamphetamine) is a derivative of amphetamine and a partial high affinity agonist of the serotonin receptor family 5HT2A/2C.(8,9) The mechanisms of DOI and its effects in the brain have not been fully elucidated as with many other hallucinogens. DOI has an indirect path of cortical activation which occurs through the activation of serotonin heteroceptors on thalamacortical neurons causing extracellular glutamate release and thus the activation of cortical neurons.(6) This is unlike the direct action of LSD on the dopaminergic system. In regards to the harmful effects caused by DOI in the brain, it can disrupt both cellular and network activities in the prefrontal cortex, alter pyramidal discharge in the medial prefrontal cortex and reduce low-frequency oscillations in the rat PFC.(9) The involvement of dopamine D4 receptors have also been mediated in the discriminative effects of this hallucinogen.(8) Drug-induced head twitches/movements have been noted as characteristic behaviour models when analyzing animals and the effects of hallucinogens.(2) The administration of DOI can cause a significant increase in firing rate of a subpopulation of PFC pyramidal neurons.(9)

Ecstasy


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MDMA ((±)-3-4 Methylenedioxymethamphetamine), commonly known as the ecstasy has been a widely used drug in many recreational settings (i.e clubs, raves).(3) The popularity of using this drug has grown due its transient effects. The high probability of producing a desirable effect and the low probability of producing adverse effects (such as nausea, hallucinations, headaches, dizziness etc) makes ecstasy one the most highly marketed party drugs.(10) It is most often taken orally in the form of tablets and many have different psychoactive components incorporated in them.(3,10) Similar to other recreational drugs, ecstasy has pronounced effects on various regions of the brain. MDMA is shown to stimulate regions of the hypothalamic-pituitary-adrenal axis in the brain as well as various neurotransmitters such as serotonin, dopamine and norepinephrine.(3,11) It is also possible that gender may play a role in the effects of ecstasy since women seem to portray more hallucinogenic symptoms.(10) As well, studies have shown that MDMA had increased levels of corticosterone in rats at all ages while glucose levels also increased except at the juvenile stage.(11) However, not much is known about age or gender differences in regards to the effects of ecstasy. MDMA can also produce long-lasting rewarding effects.(3) Long-term users of ecstasy have shown a decline in the positive subjective effects and a more delayed period of negative effects.(10) Overall, ecstasy users do display increases in impulsivity and long-term deficits in decision-making and verbal memory.(11) The figure above shows the various brain areas affected by ecstasy.*



Pharmaceutical Drugs


Methylphenidate and ADHD


Patients with ADHD (attention deficit/hyperactivity disorder) are often treated for with methylphenidate which has been reported to rescue core symptoms in 70% of children.(12) However, there have been reports of visual hallucinations occurring in children while taking methylphenidate as well some cases of auditory and somatic hallucinations.(12) Various mechanisms have been proposed as to the effects of methylphenidate on the brain. In particular, it is known to increase neurotransmitter (dopamine) signaling in the striatum using multiple mechanisms such as the disinhibition of D2 autonomic receptors on presynaptic dopaminergic neurons and activation of D1 receptors on postsynaptic neurons.(12) The failure to down-regulate dopamine transporters as well as the dopamine flooding that occurs at the prefrontostriatal circuitry may be responsible for the complex visual hallucinations seen by ADHD patients.(12) Further precautions should be taken when prescribing this drug to patients since in some instances it can cause adverse visual hallucinations in young children.

Anti-psychotics


Antipsychotic drugs often used to treat hallucinations fall into two main categories – atypical and typical – atypical drugs are the ones that show greater efficiency and less side effects than typical drugs.(13,14) Differences between the categories are determined by their receptor affinities.(13) Two highly used drugs in particular are clozapine and olanzapine in the treatment of various diseases as well as drug-induced hallucinations.(3) Both of these drugs are used to treat the various symptoms in schizophrenia including the positive symptoms such as hallucinations.(13) As well, clozapine and olanzapine both have serotonin and dopamine receptor antagonist activity which can create a significant inhibitory effect against drugs such as LSD and DOI.(8) Some side effects people have focused on in regards to antipsychotics is weight gain and diabetes.(13)

Treatments



There a wide range of treatments for drug-induced hallucinations. One of the main ones mentioned earlier are antipsychotic drugs (typical and atypical) which can alleviate many hallucinogenic symptoms.(13,14) Other treatments can include receptor antagonists and even endogenous cannabinoids which can block drug-elicited head movements.(2,15) In particular, the endogenous cannabinoid anandamine has been proven to inhibit the DOI-induced head twitches in mice.(15) Pharmacological treatments are available for HPPD patients in that they can take benzodiazepines to reduce the intensity and frequency of visual disturbances, take antipsychotic drugs such as haloperidol or even take SSRIs – selective serotonin reuptake inhibitors.(1) Many treatment options are available for drug-induced hallucinations and some are subjective depending on overuse or addiction. Some hallucinogens can also be used to treat or help patients cope with diseases. For example, the use of LSD for cancer patients resulted in improved mood, reduced anxiety and fear of death.(5) As well, there is also promising exploration made in using LSD to treat alcoholism and even substance abuse.(5)




References

1. Kilpatrick, Z.P. and Ermentrout, G.B. (2012) Hallucinogen persisting perception disorder in neuronal networks with adaptation. Journal of Computational Neuroscience. 32(1): 25 – 53

2. Schindler, E.A.D., Dave, K.D., Smolock, E.M., Aloyo, V.J. and Harvey, J.A. (2012) Serotonergic and dopaminergic distinctions in the behavioral pharmacology of (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Pharmacology, Biochemistry and Behaviour. 101:69-76

3. Mohamed, W.M.Y., Hamida, S.B., Cassel, J., Pereira de Vasconcelos, A. and Jones, B.C. (2011) MDMA: Interactions with other psychoactive drugs. Pharmacology, Biochemistry and Behaviour. 99:759-774

4. Halberstadt, A.L. and Geyer, M.A. (2011) Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology. 61:364-381

5. Nichols, D.E. (2004) Hallucinogens. Pharmacology & Therapeutics. 101:131-181

6. Scruggs, J.L., Schmidt D. and Deutch, A.Y. (2003) The hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) increases cortical extracellular glutamate levels in rats. Neuroscience Letters. 346:137-140

7. Kyzar E.J. et al. (2012) Effects of hallucinogenic agents mescaline and phencyclidine on zebrafish behavior.and physiology. Progress in neuro-psychopharmacology & biological psychiatry. 37:194-202

8. Maruno-Lewicka, D., Chemel, B.R., and Nichols, D.E. (2009) Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI. Psychopharmacology. 203:265-277

9. Celeda, P. Puig, M.V., Diaz-Mataix, L. and Artigas, F. (2008) The Hallucinogen DOI Reduces Low-Frequency Oscillations in Rat Prefrontal Cortex: Reversal by Antipsychotic Drugs. Biological Psychiatry. 64:392-400

10. Brunt, T.M., Koeter, M.W., Niesink, R.J.M., and Brink, W. (2012). Linking the pharmacological content of ecstasy tablets to the subjective experiences of drug users. Psychopharmacology. 220:751-762

11. Graham, D.L., Herring, N.R., Schaefer, T.L., Vorhees, C.V., and Williams, M.T. (2010). Glucose and corticosterone changes in developing and adult rats following exposureto (±)-3,4-methylendioxymethamphetamine or 5-methoxydiisopropyltryptamine. Neurotoxicology and Teratology. 32:152-157

12. Porfirio, M.C., Giana, G., Giovinazzo, S., and Curatolo, P. (2011) Methylphenidate-induced Visual Hallucinations. Neuropediatrics. 42:30-31

13. Diamantouros, A. (2002). Atypical Antipsychotics. Pharmacy Practice. 18:49

14. Howard, P., Twycross R., Shuster, J., Mihaylo, M., and Wilcock D.M. (2011) Antipsychotics. Journal of Pain and Symptom Management. 41:956-965

15. Nobuaki, E. et al. (2004) Anandamide inhibits the DOI-induced head-twitch response in mice. Psychopharmacology. 171:382-389

* Figure: Brain Areas Affected by Ecstasy - m.drugabuse.gov