hallucinogens

April 16, 2020 PCI Centers

The psychedelics (or Hallucinogens) are a class of drugs that have a profound cultural mythos. They are often associated with social rebellion of the 1960’s and 70’s, and, conversely, with “spiritual” personalities and religious figures across dozens of cultures. Most people have either an automatically positive or negative view of these types of drugs. In this article, we want to briefly explain what they are and the state of research on psychedelics as potential treatments for mental health conditions.

Different Types

Psychedelic drugs are any drugs that induce hallucinations, delusions, or “mystical” experiences. There are many types of psychedelics, both natural (plants) and synthetic, with many more “lab” created drugs or “research chemicals.” In short there are, essentially, three classes of psychedelic drugs: Serotonergic, Glutamatergic, and cholinergic; however most use glutamate and Serotonin.

Serotonergic (5HT2a): LSD, Mescaline, Psilocybin (Mushrooms), MDMA (strong affinity for dopamine as well), and NBOME.

Glutamate drugs: PCP, Ketamine, MK801, Ibogaine

Cholinergic drugs: Scopolamine, Atropine

Brief History/Uses

Anthropologists have pretty detailed records about how many of the plant-based psychedelics were used across history. Some records show that mescaline and psilocybin (mushrooms) have been used in rituals for the past 5000 years, and the lab created drugs like LSD, MDMA, PCP, and Ketamine have only been around for approximately 70 years or so. Both LSD and MDMDA were created for other purposes (e.g., LSD for creating a new drug to make it easier to breath and increase blood flow) and then were misused later, typically on accident discovering their intoxicating capacity. A new (since 2003) category of lab created drugs called NBOME have, reportedly, worse negative side effects. Previously there was a drug Bromo-Fly, but now newer versions/altered versions are being created every year to keep up with consumer demand.

Research on Uses/Abuses

In animal studies, all of these drugs activate the dopamine system, or the “addictive” or “reward” pathway, which means they all possess addictive potential; HOWEVER, LSD and MDMA apparently have very low addictive potential in animal models compared to the glutamate built drugs. This means that people are able to get high with these drugs, but are at very low risk of “getting hooked.”

The good: LSD has been used by scientists to develop complex models of motor and mood problems, which helps with researching known disorders. Research consistently shows that drugs like psilocybin and LSD decrease functional connectivity in parts of the emotional and intellectual breaking system. This might be why they could help fight anxiety, PTSD, and other disorders. Another great finding from the literature is that low doses of LSD actually promote substantive changes in the personality trait of openness to experience, which is correlated with intelligence and creativity. The problem with drugs like ketamine for depression treatment and other psychedelics is we don’t have many long-term (i.e., over 6 month) studies and we’re not quite sure about dosing yet. It for sure works to relieve the affective, but less so the motivational/behavioral, component of depression at the neurological level, but does increase receptor connectivity, much like typical antidepressants.

The bad: It seems like LSD mixed with alcohol generally produces more negative effects mentally or during hallucinations. The other problem, and the research shows this consistently, using hallucinogens is that using them too often or intensely activates brain networks in essentially the same way as what we see in people with schizophrenia. As one study stated “regular use of psychedelic drugs could potentially lead to structural changes in brain areas supporting attentional processes, self-referential thought, and internal mentation.” A series of studies shows that, generally speaking, addictive potential is low, acute toxicity is in the moderate range, and chronic toxicity (i.e., damage to brain cells) is low to moderate. There’s also a “ceiling” to how “mystical” or transcendent you can feel/become when intoxicated on drugs like LSD, so there’s a misconception that people can just “trip” as much as they want.

At the end of the day, very mixed bag. We need much more research. Much of the stigma is unnecessary. The realistic consequences are minimal but still concerning.

References

Abdallah, C. G., Adams, T. G., Kelmendi, B., Esterlis, I., Sanacora, G., & Krystal, J. H. (2016). Ketamine’s mechanism of action: A path to rapid-acting antidepressants. Depression and Anxiety, 33(8), 689–697. http://doi.org/10.1002/da.22501

Abdallah, C. G., Averill, L. A., Collins, K. A., Geha, P., Schwartz, J., Averill, C., … Murrough, J. W. (2017). Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology, 42(6), 1210–1219. http://doi.org/10.1038/npp.2016.186

Abdallah, C. G., Averill, L. A., & Krystal, J. H. (2015). Ketamine as a promising prototype for a new generation of rapid-acting antidepressants. Annals of the New York Academy of Sciences, 1344(1), 66–77. http://doi.org/10.1111/nyas.12718

Barrett, S. P., Archambault, J., Engelberg, M. J., & Pihl, R. O. (2000). Hallucinogenic drugs attenuate the subjective response to alcohol in humans. Human Psychopharmacology: Clinical and Experimental, 15(7), 559-565.

Bogenschutz, M. P., & Pommy, J. M. (2012). Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses. Drug Testing and Analysis, 4(7-8), 543-555.

Bouso, J. C., Palhano-Fontes, F., Rodríguez-Fornells, A., Ribeiro, S., Sanches, R., Crippa, J. A. S., … & Riba, J. (2015). Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans. European Neuropsychopharmacology, 25(4), 483-492.

Carhart-Harris, R. L., Kaelen, M., Bolstridge, M., Williams, T. M., Williams, L. T., Underwood, R., … & Nutt, D. J. (2016). The paradoxical psychological effects of lysergic acid diethylamide (LSD). Psychological Medicine, 46(7), 1379-1390

Carhart-Harris, R. L., Leech, R., Hellyer, P. J., Shanahan, M., Feilding, A., Tagliazucchi, E., … & Nutt, D. (2014). The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs. Frontiers in Human Neuroscience, 8, 20. https://doi.org/10.3389/fnhum.2014.00020

Carod-Artal, F. J. (2015). Hallucinogenic drugs in pre-Columbian Mesoamerican cultures. Neurología (English Edition), 30(1), 42-49.

Corazza, O., Schifano, F., Farre, M., Deluca, P., Davey, Z., Drummond, C., … & Mervo, B. (2011). Designer drugs on the internet: a phenomenon out-of-control? The emergence of hallucinogenic drug Bromo-Dragonfly. Current Clinical Pharmacology, 6(2), 125-129.

Creagh, S., Warden, D., Latif, M., & Paydar, A. (2018). The new classes of synthetic illicit drugs can significantly harm the brain: A neuro imaging perspective with full review of mri findings. Clinical Radiology & Imaging Journal, 2(1), 000116.

Cummings, J. L., Lyketsos, C., Peskind, E. R., Porsteinsson, A. P., Mintzer, J. E., Scharre, D. W., … & Tariot, P. N. (2015). Dextromethorphan/quinidine (AVP-923) for treatment of agitation in patients with Alzheimer’s disease: Analysis of week 10 results for patients treated only with AVP-923 versus patients receiving only placebo (NCT01584440). Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 11(7), P291-P292.

Driesen, N. R., McCarthy, G., Bhagwagar, Z., Bloch, M., Calhoun, V., D’Souza, D. C., … Krystal, J. H. (2013). Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans. Molecular Psychiatry, 18(11), 1199–1204. http://doi.org/10.1038/mp.2012.194

Dolder, P. C., Schmid, Y., Haschke, M., Rentsch, K. M., & Liechti, M. E. (2016). Pharmacokinetics and concentration-effect relationship of oral LSD in humans. International Journal of Neuropsychopharmacology, 19(1).

Doody, R., D’Amico, S., Cutler, A., Shin, P., Ledon, F., Yonan, C., & Siffert, J. (2015). PRISM II: An Open-Label Study to Assess the Safety, Tolerability, and Effectiveness of Dextromethorphan 20 mg/Quinidine 10 mg for Treatment of Pseudobulbar Affect Secondary to Dementia, Stroke, or Traumatic Brain Injury: Results from the Alzheimer’s Disease/Dementia Cohort (P7. 109). Neurology, 84(14 Supplement), P7-109.

Erritzoe, D., Frokjaer, V. G., Holst, K. K., Christoffersen, M., Johansen, S. S., Svarer, C., … & Knudsen, G. M. (2011). In vivo imaging of cerebral serotonin transporter and serotonin2a receptor binding in 3, 4-methylenedioxymethamphetamine (mdma or “ecstasy”) and hallucinogen users. Archives of General Psychiatry, 68(6), 562-576.

Feder, A., Parides, M. K., Murrough, J. W., Perez, A. M., Morgan, J. E., Saxena, S., … & Iosifescu, D. (2014). Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry, 71(6), 681-688.

Gasser, P., Kirchner, K., & Passie, T. (2015). LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects. Journal of Psychopharmacology, 29(1), 57-68.

Grossman, L., Utterback, E., Stewart, A., Gaikwad, S., Chung, K. M., Suciu, C., … & Gilder, T. (2010). Characterization of behavioral and endocrine effects of LSD on zebrafish. Behavioural Brain Research, 214(2), 277-284.

Halberstadt, A. L. (2017). Hallucinogenic Drugs: A New Study Answers Old Questions about LSD. Current Biology, 27(4), R156-R158.

Halberstadt, A. L. (2015). Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behavioural Brain Research, 277, 99–120. http://doi.org/10.1016/j.bbr.2014.07.016

Halberstadt, A. L., & Geyer, M. A. (2014). Effects of the hallucinogen 2,5-dimethoxy-4-iodophenethylamine (2C-I) and superpotent N-benzyl derivatives on the head twitch response. Neuropharmacology, 0, 10.1016/j.neuropharm.2013.08.025. http://doi.org/10.1016/j.neuropharm.2013.08.025

Halberstadt, A. L., & Geyer, M. A. (2011). Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology, 61(3), 364–381. http://doi.org/10.1016/j.neuropharm.2011.01.017

Ionescu, D. F., Luckenbaugh, D. A., Niciu, M. J., Richards, E. M., Slonena, E. E., Vande, V. J., … & Zarate Jr, C. A. (2014). Effect of baseline anxious depression on initial and sustained antidepressant response to ketamine. The Journal of Clinical Psychiatry, 75(9), e932-8.

Kalueff, A. V., Kaluyeva, A., & Maillet, E. L. (2017). Anxiolytic-like effects of noribogaine in zebrafish. Behavioural Brain Research, 330, 63-67.

Kelly, T. F., & Lieberman, D. Z. (2014). The utility of the combination of dextromethorphan and quinidine in the treatment of bipolar II and bipolar NOS. Journal of Affective Disorders, 167, 333-335.

Kłodzinska, A., Bijak, M., Tokarski, K., & Pilc, A. (2002). Group II mGlu receptor agonists inhibit behavioural and electrophysiological effects of DOI in mice. Pharmacology Biochemistry and Behavior, 73(2), 327-332.

Krebs, T. S., & Johansen, P. Ø. (2012). Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. Journal of Psychopharmacology, 26(7), 994-1002.

Lapidus, K. A., Levitch, C. F., Perez, A. M., Brallier, J. W., Parides, M. K., Soleimani, L., … & Murrough, J. W. (2014). A randomized controlled trial of intranasal ketamine in major depressive disorder. Biological Psychiatry, 76(12), 970-976.

Lawn, W., Barratt, M., Williams, M., Horne, A., & Winstock, A. (2014). The NBOMe hallucinogenic drug series: patterns of use, characteristics of users and self-reported effects in a large international sample. Journal of Psychopharmacology, 28(8), 780-788.

Leary, T. (1983).  Flashbacks:  An Autobiography.  Los Angeles, CA: J.P. Tarcher, Inc.

Leary, T. & Alpert, R. (1962).  Letter to the Editor.  The Harvard Crimson, December 13, 1962.

Lebedev, A. V., Kaelen, M., Lövdén, M., Nilsson, J., Feilding, A., Nutt, D. J., & Carhart‐Harris, R. L. (2016). LSD‐induced entropic brain activity predicts subsequent personality change. Human Brain Mapping, 37(9), 3203-3213.

Lee, H. M., & Roth, B. L. (2012). Hallucinogen actions on human brain revealed. Proceedings of the National Academy of Sciences, 109(6), 1820-1821.

Liester, M. B., & Prickett, J. I. (2012). Hypotheses regarding the mechanisms of ayahuasca in the treatment of addictions. Journal of Psychoactive Drugs, 44(3), 200-208.

Lyvers, M., & Meester, M. (2012). Illicit use of LSD or psilocybin, but not MDMA or nonpsychedelic drugs, is associated with mystical experiences in a dose-dependent manner. Journal of Psychoactive Drugs, 44(5), 410-417.

Majić, T., Schmidt, T. T., & Gallinat, J. (2015). Peak experiences and the afterglow phenomenon: when and how do therapeutic effects of hallucinogens depend on psychedelic experiences?. Journal of Psychopharmacology, 29(3), 241-253.

Marona-Lewicka, D., Nichols, C. D., & Nichols, D. E. (2011). An animal model of schizophrenia based on chronic LSD administration: old idea, new results. Neuropharmacology, 61(3), 503-512.

Marona-Lewicka, D., & Nichols, D. E. (2007). Further evidence that the delayed temporal dopaminergic effects of LSD are mediated by a mechanism different than the first temporal phase of action. Pharmacology Biochemistry and Behavior, 87(4), 453-461

McGirr, A., Berlim, M. T., Bond, D. J., Fleck, M. P., Yatham, L. N., & Lam, R. W. (2015). A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychological Medicine, 45(4), 693-704.

Moreno, J. L., Holloway, T., Albizu, L., Sealfon, S. C., & González-Maeso, J. (2011). Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neuroscience Letters, 493(3), 76–79. http://doi.org/10.1016/j.neulet.2011.01.046

Moreno, J. L., Holloway, T., Rayannavar, V., Sealfon, S. C., & González-Maeso, J. (2013). Chronic treatment with LY341495 decreases 5-HT2A receptor binding and hallucinogenic effects of LSD in mice. Neuroscience Letters, 536, 69-73.

Mori, T., Yoshizawa, K., Shibasaki, M., & Suzuki, T. (2012). Discriminative stimulus effects of hallucinogenic drugs: a possible relation to reinforcing and aversive effects. Journal of Pharmacological Sciences, 120(2), 70-76.

Morgan, C. J., Noronha, L. A., Muetzelfeldt, M., Feilding, A., & Curran, H. V. (2013). Harms and benefits associated with psychoactive drugs: findings of an international survey of active drug users. Journal of Psychopharmacology, 27(6), 497-506.

Müller, C. P., & Schumann, G. (2011). Drugs as instruments: A new framework for non-addictive psychoactive drug use. Behavioral and Brain Sciences, 34(6), 293-310.

Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K., Green, C. E., Perez, A. M., … & Charney, D. S. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. American Journal of Psychiatry, 170(10), 1134-1142.

Murrough, J. W., Perez, A. M., Pillemer, S., Stern, J., Parides, M. K., aan het Rot, M., … & Iosifescu, D. V. (2013). Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biological Psychiatry, 74(4), 250-256.

Neelkantan, N., Mikhaylova, A., Stewart, A. M., Arnold, R., Gjeloshi, V., Kondaveeti, D., … Kalueff, A. V. (2013). Perspectives on zebrafish models of hallucinogenic drugs and related psychotropic compounds. ACS Chemical Neuroscience, 4(8), 1137–1150. http://doi.org/10.1021/cn400090q

Nguyen, L., Robson, M. J., Healy, J. R., Scandinaro, A. L., & Matsumoto, R. R. (2014). Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan. PloS one, 9(2), e89985.

Nguyen, L., Thomas, K. L., Lucke-Wold, B. P., Cavendish, J. Z., Crowe, M. S., & Matsumoto, R. R. (2016). Dextromethorphan: An update on its utility for neurological and neuropsychiatric disorders. Pharmacology & Therapeutics, 159, 1-22.

Nichols, C. D., & Sanders-Bush, E. (2002). A single dose of lysergic acid diethylamide influences gene expression patterns within the mammalian brain. Neuropsychopharmacology, 26(5), 634-642.

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), 577-581.

Price, R. B., Iosifescu, D. V., Murrough, J. W., Chang, L. C., Al Jurdi, R. K., Iqbal, S. Z., … & Mathew, S. J. (2014). Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment‐resistant depression. Depression and Anxiety, 31(4), 335-343.

Reissig, C. J., Eckler, J. R., Rabin, R. A., & Winter, J. C. (2005). The 5-HT1A receptor and the stimulus effects of LSD in the rat. Psychopharmacology, 182(2), 197.

Riga, M. S., Soria, G., Tudela, R., Artigas, F., & Celada, P. (2014). The natural hallucinogen 5-MeO-DMT, component of Ayahuasca, disrupts cortical function in rats: reversal by antipsychotic drugs. International Journal of Neuropsychopharmacology, 17(8), 1269-1282.

Sessa, B. (2005). Can psychedelics have a role in psychiatry once again?. The British Journal of Psychiatry, 186(6), 457-458.

Sewell, R. A., Halpern, J. H., & Pope, H. G. (2006). Response of cluster headache to psilocybin and LSD. Neurology, 66(12), 1920-1922.

Stewart, A., Riehl, R., Wong, K., Green, J., Cosgrove, J., Vollmer, K., … Kalueff, A. V. (2011). Behavioral effects of MDMA (“Ecstasy”) on adult zebrafish. Behavioural Pharmacology, 22(3), 275–280. http://doi.org/10.1097/FBP.0b013e328345f758

Storck, M., Black, L., & Liddell, M. (2016). Inhalant Abuse and Dextromethorphan. Child and Adolescent Psychiatric Clinics, 25(3), 497-508.

Tagliazucchi, E., Carhart‐Harris, R., Leech, R., Nutt, D., & Chialvo, D. R. (2014). Enhanced repertoire of brain dynamical states during the psychedelic experience. Human Brain Mapping, 35(11), 5442-5456.

Tagliazucchi, E., Roseman, L., Kaelen, M., Orban, C., Muthukumaraswamy, S. D., Murphy, K., … & Bullmore, E. (2016). Increased global functional connectivity correlates with LSD-induced ego dissolution. Current Biology, 26(8), 1043-1050.

Taylor, C. P., Traynelis, S. F., Siffert, J., Pope, L. E., & Matsumoto, R. R. (2016). Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacology & therapeutics, 164, 170-182.

The Conversation(2018, August 19). The Real Promise of LSD, Mushrooms and MDMA for Medical Science. NeuroscienceNews. Retrieved August 19, 2018 from http://neurosciencenews.com/mdma-lsd-medicine-9715/

van Amsterdam, J., Opperhuizen, A., & van den Brink, W. (2011). Harm potential of magic mushroom use: a review. Regulatory Toxicology and Pharmacology, 59(3), 423-429.

Vollenweider, F. X., & Kometer, M. (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nature Reviews Neuroscience, 11(9), 642-651.

Winkelman, M. (2014). Psychedelics as medicines for substance abuse rehabilitation: evaluating treatments with LSD, peyote, ibogaine and ayahuasca. Current Drug Abuse Reviews, 7(2), 101-116.

Wood, J., Kim, Y., & Moghaddam, B. (2012). Disruption of prefrontal cortex large scale neuronal activity by different classes of psychotomimetic drugs. Journal of Neuroscience, 32(9), 3022-3031.

Wu, L. T., Schlenger, W. E., & Galvin, D. M. (2006). Concurrent use of methamphetamine, MDMA, LSD, ketamine, GHB, and flunitrazepam among American youths. Drug and Alcohol Dependence, 84(1), 102-113.

Zarate, C., Gould, T., Zanos, P., & Machado-Vieira, R. (2017). 80-Theories on the Mechanism of Action of Ketamine: From NMDA Receptor Inhibition to the (2R, 6R)-HNK Metabolite. Biological Psychiatry, 81(10), S33-S34.

Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G. I., … & Dossou, K. S. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature, 533(7604), 481-486.

Zawilska, J. B., & Wojcieszak, J. (2013). Salvia divinorum: from Mazatec medicinal and hallucinogenic plant to emerging recreational drug. Human Psychopharmacology: Clinical and Experimental, 28(5), 403-412.