Hallucinogens, Serotonin and Obsessive-Compulsive Disorder

This theory-building paper makes the cases for using psychedelics to treat OCD as far back as 1998. It is hypothesized that psychedelics could exert therapeutic effects in the treatment of OCD given that they are serotonin receptor agonists (5-HT). The serotonin neurotransmitter system has been implicated in the pathophysiology of OCD.

Abstract

“The serotonin (5-HT) neurotransmitter system has been implicated in the pathophysiology of several neuropsychiatric disorders, especially obsessive-compulsive disorder (OCD). Blockade of 5-HT reuptake appears to be an important initial neurobiological event in the therapeutic mechanism of action of antiobsessional drugs. However, for reasons that continue to be poorly understood, clinical improvement following initiation of treatment with 5-HT reuptake inhibitors can take up to eight to 12 weeks, and most patients do not fully improve. Recent data suggest that activation of 5-HT2A and/or 5-HT2C receptors may be important for the improvement of OCD symptoms. Most psychedelic drugs are potent agonists at 5-HT2A and 5-HT2C receptors and their binding potency to these receptors is strongly correlated with their human potency as hallucinogens. This article will briefly review the relevant clinical and preclinical studies relating to the effects of hallucinogens on OCD. These data suggest that activation of 5-HT2 receptors by hallucinogens may lead to acute reduction of, as well as possible longer-lasting beneficial effects on, the symptoms of OCD. Evidence for and against involvement of 5-HT2A and/or 5-HT2C receptors in the therapeutic effects of drug therapies for OCD are rev iewed. Issues related to the pharmacological properties and safety of psychedelic drugs, when considered as potential treatments for patients with OCD, are summarized. The authors suggest that controlled trials of potent 5-HT2 agonists in people suffering from OCD are warranted.”

Authors: Pedro L. Delgado & Francisco Moreno

Summary

The term hallucinogen has been used to describe a wide variety of drugs with potent effects on sensory experience. These drugs include lysergamide, indolealkylamine, and phenethylamine.

Hallucinogenic drugs have been used for centu­ ries, but it was not until the discovery of their mind-altering properties by Western society that they were more widely used for treatment of mental disorders.

Numerous studies used LSD for the treatment of alcoholism, sociopathy, depression, schizophrenia, autism, or “obsessional neurosis”. However, few studies carefully assessed patients for adverse effects, and few prospectively quantified beneficial effec ts.

HALLUCINOGENS AND OCD

Hallucinogens have been reported to have beneficial effects in some individuals with “obsessional neurosis”, a term most often used to describe the condition currently known as obsessive-compulsive disorder.

A 30-year-old man with obsessive thoughts and fears about contamination and compulsive washing was treated with LSD and showed improvement over the next three months, and then continued to improve over the next year, until he became completely asymptomatic.

A 17-year-old man with OCD described the beneficial effects of hallucinogenic drugs on his symptoms. He used LSD for more than 100 prior experiences, and reported that his symptoms improved after each experience.

A 34-year-old male with obsessions and compulsions described abusing hallucinogens recreationally, but then realized that while intoxicated, he had no obsessions or compulsions.

PHARMACOLOGY OF HALLUCINOGENS

While early research focused on hallucinogens’ effects on dorsal raphe 5-HT neurons, it soon became clear that this property was not unique to hallucinogens. The search for a common mechanism of action for hallucinogens eventually led to the 5-HT2 receptor.

The 5-HT 2 receptors are activated by agonists in different brain areas, and this leads to different effects, such as the enhancement of sensory experience by hallucinogens and the perception of these amplified stimuli being distorted in the cerebral cortex.

How these effects could lead to rapid or sustained improvement in OCD is not clear, but it is possible that the benefit may have derived from the pharmacological effects of these drugs.

NEUROBIOLOGY AND TREAT MENT OF OBSESSIVE-COMPULSIVE DISORDER

OCD is a chronic and debilitating condition that can have its onset in childhood and adolescence. Most patients with OCD develop the disorder by age 25, and 67% of OCD patients have a lifetime prevalence of depression.

While classified as an anxiety disorder in DSM-IV, OCD involves a unique set of behaviors including obsessive thoughts and compulsive behaviors. Treatment data suggest that long-term enhancement of 5-HT neurotransmission may underlie the therapeutic efficacy of potent 5-HT reuptake inhibitors in patients with OCD.

Potent 5-HT reuptake inhibitors, such as fluvoxamine, fluoxetine, paroxetine, and sertraline, are effective for the treatment of OCD. These drugs block the 5-HT uptake pump, leading to an increase in stimulation of 5-HT 2 and 5-HT 1A receptors on post-synaptic neurons.

In spite of the established efficacy of potent 5-HT reuptake inhibitors in the treatment of OCD, the length of time required for improvement is quite long, and most patients that do improve only have a 30% to 50% decrease in symptoms.

WHY IS ENHANCEMENT OF 5-HT NEUROTRANSMISSION THERAPEUTIC FOR PATIENTS WITH OCD?

Blier and deMontigny (1994) suggested that the delay in improvement with 5-HT reuptake inhibitors may be due to feedback on the 5-HT 1A autoreceptor. Over a period of weeks, the inhibitory 5-HT 1A autoreceptors become less sensitive, leading to a more substantial enhancement of 5-HT neurotransmission.

Studies in patients with OCD who have improved after chronic treatment with potent 5-HT reuptake inhibitors have shown that the improvement may be due to adaptive changes in areas innervated by 5-HT neurons rather than simply due to higher synaptic levels of 5-HT.

Studies using combination of a 5-HT2A antagonist and a 5-HT reuptake inhibitor in patients with OCD have not shown an exacerbation of symptoms. However, some patients with OCD who have not sufficiently improved after chronic treatment with a potent 5-HT reuptake inhibitor seem to improve with the addition of a mixed dopamine/ 5-HT antagonist.

Some contradictory data has been published, including that the nonselective 5-HT 2 antagonist ritanserin may exacerbate OCD symptoms in some patients.

Administration of the 5-HT 2c agonist m-chloro­ phenylpiperazine may exacerbate symptoms in some OCD patients, although this finding remains controversial.

Hallucinogens and chronic treatment with potent 5-HT reuptake inhibitors may be causing a desensitization of some aspects of 5-HT 2 receptor­ mediated responses, which may be why three cases of OCD were improved following hallucinogen use.

Potent 5-HT reuptake inhibitors reduce 5-HT2 receptor numbers, but more consistently lead to a down-regulation of 5-HT2 receptor-mediated behavioral responses. Therefore, chronic treatment with potent 5-HT reuptake inhibitors may lead to a kind of “cross-tolerance” with hallucinogens.

Many unanswered questions remain about the effects of hallucinogens on OCD, but it is possible that activation of 5-HT 2 receptors and possibly the desensitization of these receptors may be therapeutic for some people with OCD.

ADVERSE EFFECTS OF HALLUCINOGENS

Hallucinogens are powerful drugs that alter perception and thinking. They can cause intense mood swings, dizziness, increased pulse and blood pressure, dilated pupils, slightly elevated temperature, piloerection, and increased reflexes, but there are no known cases of death or serious medical consequences directly due to their use.

One of the most notorious and possibly most common adverse events from hallucinogens is the “bad trip”. Risperidone and olanzapine are potent 5-HT2A/2C antagonists that can be used to stop a “bad trip”.

At times, psychedelic sensations or memories of these sensations may be reexperienced in the future. These are called flashbacks, and it is not entirely clear whether these events are normal reexperiencing phenomena or if there is some long-term biological change that leads to these events.

Psychosis has been associated with the use of hallucinogens, but a follow-up study of 247 LSD users found little evidence of long-term effects on personality, belief systems, values, attitudes, or behavior.

The syndrome of post-hallucinogen perceptual dysfunction has been described. It includes chronic alteration in visual perception, often associated with psychological distress, and can occur after a single exposure.

Rarely, cases of suicide and homicide have been reported in association with hallucinogen use, but the literature is highly controversial due to uncon­ trolled settings, concomitant use of other drugs, or unusual circumstances involved.

CONCLUSIONS

Hallucinogen use may lead to acute therapeutic effects in some patients with OCD. The biological mechanism of these effects most likely involves agonist activation of 5-HT2 receptors.

Hallucinogens can have severe adverse effects, and the risk may be greater in individuals with preexisting psychiatric illnesses. However, it is not clear whether people with OCD are at higher risk for adverse effects than “healthy” subjects.

OCD is a serious, chronic, and debilitating disorder, and hallucinogens pose real risks. However, carefully controlled studies are essential to confirm the effects of hallucinogens in patients with OCD.

Authors

Authors associated with this publication with profiles on Blossom

Francisco Moreno
Francisco A. Moreno, M.D. is Professor of Psychiatry and Associate Vice President at the University of Arizona

Institutes

Institutes associated with this publication

University of Arizona
Dr Franscio Moreno at the University of Arizona has been exploring the potential of psychedelic's to treat OCD.