John H. Halpern

The Pharmacology of Lysergic Acid Diethylamide: A Review

Lysergic acid diethylamide (LSD) was synthesized in 1938 and its psychoactive effects discovered in 1943. It was used during the 1950s and 1960s as an experimental drug in psychiatric research for producing so‐called “experimental psychosis” by altering neurotransmitter system and in psychotherapeutic procedures (“psycholytic” and “psychedelic” therapy). From the mid 1960s, it became an illegal drug of abuse with widespread use that continues today. With the entry of new methods of research and better study oversight, scientific interest in LSD has resumed for brain research and experimental treatments. Due to the lack of any comprehensive review since the 1950s and the widely dispersed experimental literature, the present review focuses on all aspects of the pharmacology and psychopharmacology of LSD. A thorough search of the experimental literature regarding the pharmacology of LSD was performed and the extracted results are given in this review. (Psycho‐) pharmacological research on LSD was extensive and produced nearly 10,000 scientific papers. The pharmacology of LSD is complex and its mechanisms of action are still not completely understood. LSD is physiologically well tolerated and psychological reactions can be controlled in a medically supervised setting, but complications may easily result from uncontrolled use by layman. Actually there is new interest in LSD as an experimental tool for elucidating neural mechanisms of (states of) consciousness and there are recently discovered treatment options with LSD in cluster headache and with the terminally ill.

Psychological and Cognitive Effects of Long-Term Peyote Use Among Native Americans

BACKGROUND Hallucinogens are widely used, both by drug abusers and by peoples of traditional cultures who ingest these substances for religious or healing purposes. However, the long-term residual psychological and cognitive effects of hallucinogens remain poorly understood. METHODS We recruited three groups of Navajo Native Americans, age 18-45: 1) 61 Native American Church members who regularly ingested peyote, a hallucinogen-containing cactus; 2) 36 individuals with past alcohol dependence, but currently sober at least 2 months; and 3) 79 individuals reporting minimal use of peyote, alcohol, or other substances. We administered a screening interview, the Rand Mental Health Inventory (RMHI), and ten standard neuropsychological tests of memory and attentional/executive functions. RESULTS Compared to Navajos with minimal substance use, the peyote group showed no significant deficits on the RMHI or any neuropsychological measures, whereas the former alcoholic group showed significant deficits (p < .05) on every scale of the RMHI and on two neuropsychological measures. Within the peyote group, total lifetime peyote use was not significantly associated with neuropsychological performance. CONCLUSIONS We found no evidence of psychological or cognitive deficits among Native Americans using peyote regularly in a religious setting. It should be recognized, however, that these findings may not generalize to illicit hallucinogen users.

Mitigation of post-traumatic stress symptoms by Cannabis resin: a review of the clinical and neurobiological evidence.

It is known from clinical studies that some patients attempt to cope with the symptoms of post-traumatic stress disorder (PTSD) by using recreational drugs. This review presents a case report of a 19-year-old male patient with a spectrum of severe PTSD symptoms, such as intense flashbacks, panic attacks, and self-mutilation, who discovered that some of his major symptoms were dramatically reduced by smoking cannabis resin. The major part of this review is concerned with the clinical and preclinical neurobiological evidence in order to offer a potential explanation of these effects on symptom reduction in PTSD. This review shows that recent studies provided supporting evidence that PTSD patients may be able to cope with their symptoms by using cannabis products. Cannabis may dampen the strength or emotional impact of traumatic memories through synergistic mechanisms that might make it easier for people with PTSD to rest or sleep and to feel less anxious and less involved with flashback memories. The presence of endocannabinoid signalling systems within stress-sensitive nuclei of the hypothalamus, as well as upstream limbic structures (amygdala), point to the significance of this system for the regulation of neuroendocrine and behavioural responses to stress. Evidence is increasingly accumulating that cannabinoids might play a role in fear extinction and antidepressive effects. It is concluded that further studies are warranted in order to evaluate the therapeutic potential of cannabinoids in PTSD.

Genuine and drug-induced synesthesia: A comparison

Despite some principal similarities, there is no systematic comparison between the different types of synesthesia (genuine, acquired and drug-induced). This comprehensive review compares the three principal types of synesthesia and focuses on their phenomenological features and their relation to different etiological models. Implications of this comparison for the validity of the different etiological models are discussed. Comparison of the three forms of synesthesia show many more differences than similarities. This is in contrast to their representation in the literature, where they are discussed in many respects as being virtually similar. Noteworthy is the much broader spectrum and intensity with the typical drug-induced synesthesias compared to genuine and acquired synesthesias. A major implication of the phenomenological comparison in regard to the etiological models is that genuine and acquired synesthesias point to morphological substrates, while drug-induced synesthesia appears to be based on functional changes of brain activity.

The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: An open, non-randomized case series

Cluster headache (CH) is a stereotyped primary headache characterized by strictly unilateral severe orbital or periorbital pain and categorized as either episodic or chronic (1,2). Its prevalence is 0.1% (3). Oxygen and sumatriptan are the treatments of choice for individual attacks, whereas verapamil, lithium, corticosteroids and other neuromodulators can suppress attacks during cluster periods (1). All standard medication treatments may be ineffective. Surgical treatment may be an option for medication non-responders, including deep brain (4) or occipital nerve stimulation (5). However, serious complications from brain surgery, including death, can occur (6). An Internet survey of 53 CH patients reported on claims that psilocybin is better at aborting acute attacks than either oxygen or sumatriptan and that LSD and psilocybin are both better at triggering and extending remission than standard drugs (7). However, due to hallucinogenicity and the absence of established medical indication, these drugs are criminalized and placed within the most restrictive Schedule I of the Controlled Substances Act, which sanctions only limited research use. Although the hallucinogenic properties of LSD and psilocybin are undesirable from both regulatory and patient safety perspectives, it was unclear to us at the outset whether a non-hallucinogenic analog could also provide meaningful relief to CH patients. To address the question of whether the CH relief associated with these two structurally diverse compounds is related to the mechanisms triggering intoxication, we decided to investigate the efficacy of a nonhallucinogenic analog of LSD. LSD’s hallucinogenic effects are completely lost when the double bond in the D ring is saturated and with substitution at R2 (e.g. by bromination in 2-bromo-LSD) (BOL-148) (8). BOL-148 has been studied in volunteers (up to 20mg per os) (9) and in patients suffering from vascular headaches but not, apparently, in patients with CH (9,10). These past studies concluded that BOL-148 is non-toxic and non-hallucinogenic. Only very mild side effects, if any, have been observed, when given in the dose range used in our project (30mg/kg/body weight) (9). No long-term behavioral or psychological effects from BOL-148 have been reported from past studies with more than 300 healthy, normal subjects (11), and 30mg BOL-148 administered daily over four to five weeks failed to alter active psychosis in chronically ill schizophrenic women (12).

Response to Tfelt-Hansen P: Is BOL-148 hallucinogenic?

This is an interesting note about the observation of an altered state of perception and body awareness after ingestion of a single dose of 0.5 mg BOL-148 (1). However, several considerations should be made about the questionable causal relationship of the observed symptoms and the ingestion of BOL-148. It was reported that the young man was ‘‘a moderately anxious . . .worker . . .who usually controlled and repressed his affective expressions.’’ Subsequently, we learn that—15 (!) minutes after BOL-148 ingestion—‘‘he complained of lightheadedness and expressed the fear that he might lose consciousness’’ and ‘‘his elevated mood gave way to one of intense anxiety merging into panic.’’ Everything is told in this: small changes in body awareness had turned into a strong panic attack against the background of an anxious personality increasingly seeking attention for myriad complaints after BOL-148 ingestion, which seems to have been surreptitious (‘‘about 15 minutes later [from ingestion] . . . he sought aid for his state’’). Altered and intensified body experiences, such as described in this report, are typical for panic reactions and may be promoted by fixed attention to those bodily reactions to anxiety. Reactions as early as 15 minutes after drug intake also points to anxiety rather than a direct effect of BOL-148: in all published clinical experiments with BOL-148, effects appeared only after a minimum of 30 minutes. Although antipsychotics do not intensify hallucinogenic effects (2,3), this lab worker also complained of a rekindling of peak effects from co-administration of 10 mg of the lowpotency neuroleptic chlorpromazine approximately four hours post BOL-148 ingestion. Moreover, it is reasonable to presume that a worker in the laboratory of H.G. Wolff in 1957 knew what an altered state looks like after ingestion of an hallucinogenic substance (4), and therefore may have been well-prepared to express certain expectations about the reactions following ingestion of LSD or LSD derivatives. It is not quite clear what, if any, informed consent was offered prior to drug administration, and it also appears that this lab worker may have self-administered BOL-148 without permission, as noted above. No information is mentioned about the source of the BOL-148, its purity and chemical composition, and so on. Finally, no evidence of the major typical effects of LSD—such as pseudo-hallucinations, intensification of visual imagery with eyes closed, synesthesias, or distortions of time and space—was given in this case report (5). The altered state described cannot be characterized as a ‘‘toxic delirium’’ because it was reported that the subject was always completely oriented to time, space, situation and person, and had no consistent clouding of consciousness and no hallucinations. In contrast, there are numerous reports describing no typical LSD-like alterations from BOL-148 at doses comparable to that in this single case report, such as our study (6), and at much larger doses (2,7–11). The overall consistency of research reports on the mild subjective effects of BOL-148 is why this drug is currently referred to as the ‘‘non-hallucinogen BOL’’ (5). We therefore conclude that the single case report mentioned was not worthy of discussion in our original report, but we are grateful to have this opportunity to provide reassuring clarification for what remains a quite promising new approach for the treatment of cluster headache.