Pharmacopsychiatry 2001; 34(Suppl1): 61-69
DOI: 10.1055/s-2001-15451
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Hypericum Extract and Hyperforin:
Memory-Enhancing Properties in Rodents

V. Klusa1 , S. Germane2 , M. Nöldner3 , S. S. Chatterjee3
  • 1Department of Pharmacology, Faculty of Medicine, University of Latvia, Riga, Latvia
  • 2Laboratory of Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia
  • 3Department of Pharmacology, Dr. Willmar Schwabe GmbH & Co., Karlsruhe, Germany
Further Information

Publication History

Publication Date:
31 December 2001 (online)

Effects of a Hypericum extract in therapeutic use and hyperforin sodium salt were evaluated in rat and mouse avoidance tests. In a conditioned avoidance response (CAR) test on the rat, oral daily administration of hyperforin (1.25 mg/kg/day) or of the extract (50 mg/kg/day) before the training sessions considerably improved learning ability from the second day onwards until the day 7. In addition, the memory of the learned responses acquired during 7 consecutive days of administration and training was largely retained even after 9 days without further treatment or training. The observations made using different doses indicate that these learning-facilitating and/or memory-consolidating effects by the agents follow inverse U-shaped dose-response curves in dose ranges lower than (for hyperforin) or equal to (for Hypericum extract) their effective dose in the behavioral despair test for antidepressants. In a passive avoidance response test on the mouse, a single oral dose (1.25 mg/kg) of hyperforin not only improved memory acquisition and consolidation, but also almost completely reversed scopolamine-induced amnesia. The single Hypericum extract dose tested (25 mg/kg) did not reveal any significant effects in the passive avoidance response (PAR) test on the mouse. These observations suggest that the Hypericum extract could be a novel type of antidepressant with memory enhancing properties, and indicate that hyperforin is involved in its cognitive effects. Pure hyperforin seems to be a more potent antidementia agent than an antidepressant.


  • 1 Bassuk S S, Berkman L F, Wypij D. Depressive symptomatology and incident cognitive decline in an elderly community sample.  Arch Gen Psychiat. 1998;  55 1073-1081
  • 2 Bhattacharya S K, Chakrabarti A, Chatterjee S S. Activity profiles of two hyperforin-containing hypericum extracts in behavioral models.  Pharmacopsychiatry. 1998;  31 (Suppl 1) 22-29
  • 3 Biber A, Fischer H, Römer A, Chatterjee S S. Oral bioavailability of hyperforin from hypericum extracts in rat and human volunteers.  Pharmacopsychiatry. 1998;  31 (Suppl 1) 36-43
  • 4 Boone K B, Lesser I, Miller B, Wohl M, Berman N, Lee A, Palmer B. Cognitive functioning in a mildly to moderately depressed geriatric sample: Relationship to chronological age. J. Neuropsychiat.  Clin Neurosci. 1994;  6 267-272
  • 5 Butterweck V, Wall A, Liefländer-Wulf U, Winterhoff H, Nahrstedt A. Effects of the total extract and fractions of hypericum perforatum in animal assays for antidepressant activity.  Pharmacopsychiatry. 1997;  30 (Suppl 2) 117-124
  • 6 Butterweck V, Petereit F, Winterhoff H, Nahrstedt A. Solubilized hypericin and pseudohypericin from hypericum perforatum exert antidepressant activity in the forced swimming test.  Planta Med. 1998;  64 291-294
  • 7 Butterweck V, Jürgenliemk G, Nahrstedt A, Winterhoff H. Flavonoids from Hypericum perforatum show antidepressant activity in the forced swimming test.  Planta Med. 2000;  66 3-6
  • 8 Chatterjee S S, Koch E, Nöldner M, Biber A, Erdelmeier C. Hyperforin and hypericum extract: Interactions with some neurotransmitter systems.  Phytomedicine. 1999;  3 ( Suppl 1) 106
  • 9 Chatterjee S S, Nöldner M, Koch E, Erdelmeier C. Antidepressant activity of Hypericum perforatum and Hyperforin: the neglected possibility.  Pharmacopsychiat. 1998;  31 ( Suppl 1) 7-15
  • 10 Chatterjee S S, Bhattacharya S K, Wonnemann M, Singer A, Müller W E. Hyperforin as a possible antidepressant component of hypericum extracts.  Life Sci. 1998a;  63 499-510
  • 11 Chatterjee S S, Erdelmeier C, Klessing K, Marmé D, Schächtele C. Stable hyperforin salts, method for producing same and their use in the treatment of Alzheimer's disease. PCT WO 99/41220 1999
  • 12 Czygan F C. Kulturgeschichte und Mystik des Johanniskrautes.  Zeitschrift für Phytotherapie. 1993;  14 276-282
  • 13 Daniel K. Johanniskraut (Hypericum perforatum) bei psychischen Störungen.  Hippokrates. 1935;  10 929-932
  • 14 DeWied D, Bohus B. Long term and short term effects on retention of conditioned avoidance response in rats by treatment with long acting pitressin and α-MSH.  Nature. 1966;  212 98-100
  • 15 Evenhuis H M. The natural history of dementia in ageing people with intellectual disability.  J Intellect Disability Res. 1997;  41 92-96
  • 16 Gaster B, Holroyd J. St. John's Wort for depression - A systematic review. Arch.  Intern Med. 2000;  160 152-156
  • 17 Johnson D, Siebenhüner G, Hofer E, Sauerwein-Giese E, Frauendorf A. Einfluß von Johanniskraut auf die ZNS-Aktivität.  TW Neurol Psychiatr. 1992;  6 436-444
  • 18 Johnson D, Ksciuk H, Woelk H, Sauerwein-Giese E, Frauendorf A. Effects of hypericum extract LI 160 compared with maprotiline on resting EEG and evoked potentials in 24 volunteers.  J Ger Psychiat Neurol. 1994;  7 (Suppl 1) S 44-S 46
  • 19 Kokmen E, Beard C M, Chandra C, Offord K B, Schoenberg B S, Ballard D J. Clinical risk factors for Alzheimer's disease: a population-based case-control study.  Neurology. 1991;  41 1393-1397
  • 20 Laakmann G, Schüle C, Baghai T, Kieser M. St. John's Wort in mild to moderate depression: The relevance of Hyperforin for clinical efficacy.  Pharmacopsychiatry. 1998;  31 (Suppl 1) 54-59
  • 21 Lehrl S, Willemsen A, Papp R, Woelk H. Ergebnisse von Messungen der kognitiven Leistungsfähigkeit bei Patienten unter der Therapie mit Johanniskraut-Extrakt.  Nervenheilkunde. 1993;  12 281-284
  • 22 Linde K, Ramirez G, Mulrow C D, Pauls A, Weidenhammer W, Melchart D. St. John's Wort for depression - an overview and meta-analysis of randomized clinical trials.  Brit Med J. 1996;  313 253-258
  • 23 Maisenbacher P, Kovar K A. Analysis and stability of hyperici-oleum.  Planta Med. 1992;  58 351-354
  • 24 McGaugh J L, Liang D C, Bennet C, Sternberg D B. Adrenergic influences on memory storage interaction of peripheral and central systems.  In: Lynch G. (Ed.) Neurobiology of learning and memory. Guilford Press, New York 1984
  • 25 Mitchell A J. The contribution of hypercortisolaemia to the cognitive decline of geriatric depression.  Int J Ger Psychiat. 1995;  10 401-409
  • 26 Mitchell A J, Dening T R. Depression-related cognitive impairment: Possibilities for its pharmacological treatment.  J Affect Disord. 1996;  36 79-87
  • 27 Müller W E, Rolli A, Schäfer C, Hafner U. Effects of hypericum extract (LI 160) in biochemical models of antidepressant activity.  Pharmacopsychiatry. 1997;  30 (Suppl 2) 102-107
  • 28 Müller W E, Kasper S. Editors of: “Hypericum extract (LI 160) as a herbal antidepressant”.  Pharmacopsychiatry. 1997;  30 (Suppl 2) 71-134
  • 29 Müller W E, Singer A, Wonnemann M, Hafner U, Rolli M, Schäfer C. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract.  Pharmacopsychiatry. 1998;  30 (Suppl 1) 16-21
  • 30 Müller W E, Chatterjee S S. Editors of: “Hyperforin and the antidepressant activity of St. John's Wort.”  Pharmacopsychiatry. 1998;  31 (Suppl 1) 1-60
  • 31 Nöldner M, Chatterjee S S, Erdelmeier C. Pharmacological studies leading to the identification of hyperforin as a CNS-Active component of Hypericum perforatum.  Naunyn-Schm Arch Pharmacol. 1998;  358 R 495
  • 32 Okpanyi S N, Weischer M L. Tierexperimentelle Untersuchungen zur psychotropen Wirksamkeit eines Hypericum-Extraktes.  Arzneim-Forsch. 1987;  37 (I) 10-13
  • 33 Palsson S, Aevarsson O, Skoog I. Depression, cerebral atrophy, cognitive performance and incidence of dementia - population study of 85-year-olds.  Br J Psychiat. 1999 ;  174 249-253
  • 34 Popoli M, Brunello N, Perez J, Racagni G. Second messenger-regulated protein kinases in the brain: Their functional role and the action of antidepressant drugs.  J Neurochem. 2000;  74 21-33
  • 35 Reh C, Laux P, Schenk N. Hypericum-Extrakt bei Depressionen - eine wirksame Alternative.  Therapiewoche. 1992;  42 1576-1581
  • 36 Sandler M. Forty years in conceptual wilderness.  Science. 1998;  280 1709-1710
  • 37 Schulz V. Johanniskraut als pflanzliches Antidepressivum. Phytopharmaka in Forschung und klinischer Anwendung. In: Eds. Loew D. and Rietbrock N. Steinkopff Darmstadt 1995: 159-175
  • 38 Singer A, Wonnemann M, Müller W E. Hyperforin, a major antidepressant constituent of St. John's Wort, inhibits serotonin uptake by elevating free intracellular Na + 1 .  J Pharmacol Exptl Therap. 1999;  290 1363-1368
  • 39 Steffens D C, Plassmann B L, Helms M J, Welsh-Bohmer K A, Saunders A M, Breitner J CS. A twin study of late-onset depression and apolipoprotein E ε 4 as risk factors for Alzheimer's disease.  Biol Psychiat. 1997;  41 851-856
  • 40 Suzuki O, Katsumata Y, Oya M, Bladt S, Wagner H. Inhibition of monoamine oxidase by hypericin.  Planta Med. 1984;  3 273-276
  • 41 Volz H P. Controlled clinical trials of hypericum extracts in depressed patients: An overview.  Pharmacopsychiatry. 1997;  30 ((Suppl. 2)) 72-76
  • 42 Vorbach E U, Arnoldt K H, Wolpert E. St. John's Wort: A potential therapy for elderly depressive patients?.  Drugs and Aging. 2000;  16 189-197
  • 43 Wonnemann M, Singer A, Müller W E. Inhibition of synaptosomal uptake of 3H-L-glutamate and 3H-GABA by hyperforin, a major constituent of St. John's Wort: The role of amiloride sensitive sodium conductive pathways.  Neuropsychopharmacol. 2000;  23 188-197

Dr. V. Klusa

University of Latvia
Faculty of Medicine

Sarlotes st. 1A

LV-1001 Riga